NPRCs at the Society for Neuroscience Conference 2017

Visit the National Primate Research Centers at Exhibit Hall Booth 3326!

We’ll have researchers from the seven NPRCs on site to talk with you about helping you conduct your research at one of our centers!

You can also learn more about NPRC research by participating in the two nanosymposia NPRC researchers are giving as well as attending one of our more than 30 poster presentations. Details are below. Please stop by to learn more!



Don’t miss this year’s Animals in Research Panel!

How to Effectively Communicate Your Animal Research: Elevator Speech, Social Media and Best Practices

Monday, November 13, Noon - 2 p.m., Room 103A

In today’s environment, animal researchers need to engage with different audiences to promote the understanding of and need for animal models. However, scientists often face specific challenges when discussing this matter with the public, policymakers, and the press. This interactive panel will provide a basic understanding of, and show attendees strategies to engage with, various audiences on the importance and benefits of animal research.



National Primate Research Center Presentations at Neuroscience 2017

Monday, November 13, Noon - 2 p.m.

Special Workshop:

Animals in Research Panel

How to Effectively Communicate Your Animal Research: Elevator Speech, Social Media and Best Practices

Room 103A

Organizer: Mar Sanchez, PhD

Support contributed by: National Primate Research Centers

In today’s environment, animal researchers need to engage with different audiences to promote the understanding of and need for animal models. However, scientists often face specific challenges when discussing this matter with the public, policymakers, and the press. This interactive panel will provide a basic understanding of, and show attendees strategies to engage with, various audiences on the importance and benefits of animal research.


Also of interest:

Tuesday, Nov. 14, 2:30 pm – 4 pm

Public Advocacy Forum

Advocating for Basic Science in a Disease-Focused World

Room: 201

Organizer: William Martin, PhD

Basic research is the foundation for all biomedical advances. For policymakers accustomed to the immediate impact of federal investments, the lag between scientific discoveries and medical breakthroughs clouds the long-term value of basic research. This panel will discuss the essential role of basic scientific research to the research continuum. Attendees will learn how this research continuum influences advocacy and gain tips for advocating to policymakers to secure financial and political support.



Posters for Saturday Afternoon, November 11

1 pm, Halls A-C, QQ21

082. Learning and Memory: Aging, Circuits, and Molecules
Theme H: Cognition

82.13 The effects of aging on spine type and density on layer III pyramidal cells in area 7a of the intraparietal sulcus of behaviorally characterized primates.


Icahn Sch. of Med. at Mount Sinai, Icahn Sch. of Med. at Mount Sinai, Icahn Sch. of Med. At Mount Sinai, California Natl. Primate Res. Ctr., Natl. Inst. On Aging, Univ. of California Davis.

Abstract: Aging is associated with decreased working memory performance, and the integrity of this cognitive domain has been assessed using the delayed response (DR) task. Critically, this task has a delay period during which the presented stimulus is absent and the animal must retain task-relevant information in memory until the delay ends. The firing of a subset of pyramidal cells in area 46 of the prefrontal cortex (PFC), termed "delay cells" because of their firing during the delay period, has been shown to correlate with DR behavioral performance. It is proposed that this persistent firing maintains information across the delay, and disruption to delay cell firing impairs behavioral performance. Another correlate to DR performance is density of thin spines on layer III pyramidal cells in area 46. In aging, loss of thin spines correlates with decreased DR performance. It is proposed that thin spines in the PFC contribute to working memory because their instability would allow for rapid, experience-dependent remodeling of a circuit. Very little is known about age-related effects on working memory outside of the PFC. Area 7a of the intraparietal sulcus (IPS) projects to area 46 and, like area 46, has cells whose firing during the delay period correlates with DR performance. It is unknown if thin spines in area 7a are critical for DR behavioral performance, or if there are age-related changes to spines in this region. To better understand the role of the IPS in working memory and how age-related changes to this region affect behavioral performance, we have investigated differences in spine type and density in layer III pyramidal cells of area 7a in the IPS of young and aged, male and female, rhesus monkeys (Macaca mulatta) that were behaviorally characterized using the DR task. These data will be compared against our evolving model of a healthy synaptic profile to further define the effects of cognitive aging and the morphological changes across the brain that are associated with cognitive decline.

3 pm, Halls A-C, C52

036. Brain Evolution
Theme A: Development

36.03 Oxytocin and arginine-vasopressin innervation of cerebral cortex in human and chimpanzee brains.


Emory Univ., Yerkes Natl. Primate Res. Ctr., Georgia State Univ., Georgia State Univ., Yerkes Natl. Primate Res. Ctr., Brown Univ., Brown Univ., Emory Univ., Emory Univ., Emory Univ. Sch. of Med.

Abstract: Oxytocin (OT) and arginine-vasopressin (AVP) are involved in the regulation of complex social behaviors across a wide range of taxa. OT is associated with social recognition, pair-bonding, and maternal bonding in rodents. In humans, OT is implicated in the promotion of trust, cooperation, and in-group altruism. AVP is associated with aggressive and territorial behaviors, but also pair-bonding, paternal behavior, and mate-guarding in males. OT and AVP exert these effects via release in the central nervous system, and their effects are mediated by the distribution of receptors across brain regions. OT and AVP v1a receptors are found in regions far from the nuclei of the hypothalamus where they are produced. This raises the question of how these peptides reach their remote receptors. Optogenetic evidence from rats suggests that projections from hypothalamic OT and AVP neurons can release peptide from axon terminals into synapses. Moreover, neuroimaging evidence shows that intranasal administration of OT and/or AVP in humans can modulate neural activity in the cortex. To determine whether OT and AVP projections actually innervate the cortex in primates, we performed immunohistochemistry for fibers containing OT and AVP in humans (n=3), chimpanzees (n=3), and rhesus macaques (n=5). We found AVP fibers in various subregions of the insular cortex in humans, including frontoinsular cortex and agranular insula. Chimpanzees exhibited lower AVP innervation of the insula, limited to the agranular insula and piriform cortex. OT fibers were found in the straight gyrus of human brains and the anterior cingulate cortex in chimpanzee brains. Our results contrast with previous reports of OT and AVP immunohistochemistry in human brains, which did not report the presence of fibers in the cortex. Interestingly, nonapeptide innervation was present in regions known to contain von Economo neurons (AVP in frontoinsular cortex in humans and OT in cingulate cortex in chimpanzees), suggesting that they may play a role in modulating the activity of this class of neurons. Overall, our results help to address the issue of how OT and AVP exert effects on brain regions far from the hypothalamus, particularly in primates, and provide evidence of species differences in OT and AVP neuroanatomy.



Posters for Sunday Morning, November 12

8 am to noon, Halls A-C, C51

119. Neurodevelopmental Disorders: Behavioral Studies
Topic: A.07. Developmental Disorders

119.10 A non-invasive eye tracking study using rhesus macaques


California Natl. Primate Res. Ctr., Univ. of California-Davis, Davis, CA; Dept. of Psychiatry and Behavioral Sci., The MIND Inst., Univ. of California-Davis, Sacramento, CA; Biomarker Group, Drug Develop. Res. Labs., Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan

Abstract: Visual information is one of the most important cues in social cognition for both humans and non-human primates (NHPs). Individuals diagnosed with neurodevelopmental or neuropsychiatric disorders, such as autism or schizophrenia, display aberrant gaze patterns toward social stimuli. Investigating the nature of gaze patterns of NHPs and comparing them with those in humans could help us understand etiology of and drug effects on the disorders. In this study, social and nature videos (30 seconds long) were presented to two age-category rhesus monkeys and their gaze patterns were investigated using a non-invasive eye-tracking protocol. Six infant (one male and five females) and four juvenile (two males and two females) rhesus macaques were presented five social and five nature videos in each session. Each monkey performed six eye tracking sessions within 60 days with a minimum 3-day interval between sessions. The social videos included rhesus macaque social behaviors such as aggression, grooming, play, mounting, foraging or sitting in groups without overt social behavior (nonspecific social behavior videos). The nature videos depicted birds, insects/invertebrates, land mammals, marine mammals/fish and landscapes/flowers. Six different stimulus sets were prepared, and every animal saw the same stimulus set at each testing time point. Calibration and data acquisition succeeded in all sessions. It is noteworthy that none of the animals were trained or habituated prior to testing. In both age groups, monkeys looked at the social videos significantly longer than the nature ones. Interestingly, juveniles looked at each video longer than infants. These results suggest that rhesus monkeys recognize conspecifics and are attentive to their behaviors from an early age. In addition, attention to visual information appears to increase during the juvenile stage. In future studies, this non-invasive eye tracking method can be applied to monkeys with low-sociability, either spontaneous or drug-induced, and it can contribute to a better understanding of monkeys’ visual processing of social cognition and development of novel treatments for neurodevelopmental and neuropsychiatric disorders. This study is funded by R21HD080498 and OD011107.

8 am – noon, Halls A-C, II8

150. Eye Movements
E.01. Eye Movements

150.12 Investigating the potential neural basis of pattern strabismus in the horizontal and vertical oculomotor neural integrators

A. PALLUS1, M. M. WALTON2, M. J. MUSTARI3 1Ophthalmology, 2WanPRC, Univ. of Washington, Seattle, WA; 3Univ. Washington, Seattle, WA

Abstract:Infantile strabismus is a common disorder that is characterized by multiple visual and oculomotor abnormalities, including chronic horizontal and vertical misalignment of the eyes. Often, this includes a pattern strabismus, in which the misalignment of the eyes varies orthogonally with eye position. Several researchers have proposed that this is due to abnormal cross coupling between normally horizontal and vertical oculomotor subsystems. The development of non-human primate models of infantile strabismus has allowed researchers to investigate the neural mechanisms underlying the symptoms of the disorder. Previous studies from our laboratory have shown abnormal directional tuning in saccadic burst generators. Because cross coupling persists across multiple movement types, we hypothesized that the oculomotor neural integrators may encode abnormal signals strabismus. In this study, we test the hypothesis by recording the activity of individual neurons in the nucleus prepositus hypoglossi (NPH) and the interstitial nucleus of Cajal (INC) in three monkeys (Macaca mulatta), one normal and two with pattern strabismus, during a saccade task. These two structures are considered to be the locations of the horizontal and vertical neural integrators, respectively. In general, we found increased variability in the tonic firing rate compared with normal controls in both structures. The preferred directions of the two populations of cells were still in the appropriate direction, on average, but the distribution of directional preferences was more widely distributed in strabismus. Stimulation of the normal INC has been shown to produce conjugate vertical eye movements, but stimulation of the INC in the same region of our neurophysiological recordings produced disconjugate eye movements, often with the ipsilateral eye moving horizontally. Importantly, the eyes remained in the new positions after stimulation ended suggesting that this effect was due to activity within the integrator rather than an activation of the nearby oculomotor nucleus. These results are consistent with the hypothesis that the oculomotor neural integrators are involved in the inappropriate cross-coupling that may be responsible for producing pattern strabismus, but further study is required to determine whether this is sufficient to produce the behavior or if the cross-coupling is distributed among multiple structures within the oculomotor system.



Posters for Sunday Afternoon, November 12

1 pm – 5 pm Halls A-C, W28

218. Spinal Cord Injury: Models and Mechanisms
C.09. Brain Injury and Trauma

218.23 Chondroitinase improves anatomical and functional outcomes after primate spinal cord injury


Neurosciences, Univ. of California San Diego Dept. of Neurosciences, La Jolla, CA; California Natl. Primate Res. Ctr., Univ. of California, Davis, Davis, CA; VAMC, La Jolla, CA; Acorda Therapeutics, Inc., Ardsley, NY; Cambridge Univ., Cambridge, United Kingdom; Dept. of Neurolog. Surgery, Brain and Spinal Injury Ctr. (BASIC), UCSF, San Francisco, CA; Dept. of Neurol., UCLA, Los Angeles, CA; Col. of Vet. Med. and Biomed. Sci., Colorado State Univ., Fort Collins, CO

Abstract: Inhibitory chondroitin sulfate proteoglycans (CSPGs) in the extracellular matrix hinder axonal regeneration after spinal cord injury (SCI). In particular, CSPGs form ‘peri-neuronal nets’ that may limit axonal regrowth and synaptic plasticity. Moreover, CSPGs are newly synthesized at sites of central nervous system injury and directly block axon growth. Administration of the enzyme chondroitinase (Chase) degrades inhibitory portions of CSPGs and improves axonal sprouting and functional recovery after SCI in rodents. Here we show for the first time that Chase treatment is also effective in a non-human primate model of SCI. Adult rhesus monkeys received C7 spinal cord lateral hemisection lesions. Four weeks later, subjects received intraparenchymal spinal cord injections of 20 U/ml Chase (or saline) caudal to the lesion. Five μl of Chase / saline were injected at each of 10 sites (spaced 1.5 mm apart in the rostrocaudal axis) on the right side of the spinal cord from C7-T1. This effectively targets spinal cord circuits below the lesion that control hand function. Hand function and locomotion were assessed weekly in a large enriched environment and in a cage-based Brinkman task (retrieval of small food items from wells in a board). Corticospinal axons were labeled with dextran-conjugated tracer injections into right and left motor cortices 6 weeks before sacrifice. Chase-treated monkeys recovered hand function (but not locomotion) better than control monkeys (Condition x Time, P<0.001, Linear Mixed Model [LMM]). The fact that the beneficial effect is specific to hand function is consistent with the hypothesis that Chase increases axonal sprouting in the treated region (segments C7-T1). Indeed, Chase increased corticospinal axon growth (P=0.036, LMM) and the number of corticospinal synapses (P=0.001, LMM) in gray matter caudal to the lesion. Thus, intraparenchymal Chase is an effective treatment in a primate model of SCI that recapitulates some aspects of traumatic human SCI. Chase treatment for SCI therefore warrants further research and translational development.

1 pm – 5 pm, Halls A-C, QQ18

248. Cortical Circuits and Behavior
A.02. Postnatal Neurogenesis

248.13 Development of functional connectivity of macaque cerebral cortical networks: Comparison of infants fed breast milk or formulas with low or high carotenoid content and synthetic or natural α-tocopherol


Behavioral Neurosci., Med. Informatics and Clin. Epidemiology, Oregon Natl. Primate Res. Ctr., Oregon Hlth. and Sci. Univ., Portland, OR; Div. of Nutritional Sci., Univ. of Illinois at Urbana-Champaign, Urbana, IL; Abbott Nutr., Columbus, OH; Behavioral Neurosci., Oregon Hlth. Sci. Univ., Portland, OR

Abstract: BACKGROUND/OBJECTIVE: While it has been shown that lutein, the predominant carotenoid in primate brain, and α-tocopherol are correlated with measures of cognition and visual perception, little is known about roles of these nutrients in brain development. This study used resting-state functional connectivity MRI (rs-fcMRI) to characterize cortical organization in monkey infants as a function of carotenoid intake and α-tocopherol source. DESIGN: From birth, rhesus macaques were breastfed (BF, n=8), or fed either a commercial formula supplemented with lutein, zeaxanthin, β-carotene and lycopene plus natural α-tocopherol (SF, N=8), or an identical control formula, but with low levels of these carotenoids and with synthetic α-tocopherol (CF, N=7). Functional connectivity was characterized at 2, 4 and 6 mo of age. Cortex was parcellated into 82 regions of interest (ROIs) as defined for rhesus macaque by Bezgin et al. (2012), and each ROI was assigned to a unique functional network (Grayson et al. (2016)). A repeated measures ANOVA was used to identify longitudinal changes in functional connectivity within and between functional networks, where the functional connectivity from each ROI (82x82 connectivity matrix) was grouped according to diet, functional network, and time. RESULTS: We found significant differences among networks, diet groups, ages, and for all interactions (p<0.05, corrected for multiple comparisons and lack of sphericity). Connectivity between and within each functional network followed distinct maturational patterns. For some network pairs, the formula groups showed a divergent pattern of maturation compared with BF. The group fed the low carotenoid control formula diverged the most, as clearly seen in the interconnections between the default and sensory-motor, default and dorsal attention, and visual and somatosensory networks. In some cases, despite strong initial differences between formula-fed and BF infants, their patterns of brain connectivity converged, as shown within the default mode network. CONCLUSION: This study provides the first examination of developmental changes in rs-fcMRI in macaque cerebral cortex. Patterns of functional connectivity in infants receiving formula with supplemental carotenoids and natural α-tocopherol more closely resembled breastfed infants than did those in infants fed a formula without supplemental carotenoids and with synthetic α-tocopherol.



Nanosymposia for Monday Morning, November 13

8 am, Room 144A

279. Chemogenetics in Rodents and Primates
Theme H: Cognition

279.01 Developmental model of nonhuman primate DREADDs: hM4Di transfection in the amygdala of infant rhesus monkeys.


Yerkes Natl. Primate Res. Ctr., Marcus Autism Ctr., Emory Univ.

Abstract: Chemogenetics are powerful new tools for nonhuman primate behavioral studies, with several advantages over previous lesion and reversible inactivation techniques. Unlike permanent lesions, there is no opportunity for reorganization or compensation from other brain areas. Also, unlike previous reversible inactivation techniques, it does not require chambers and headpost, which are not feasible in infant animals with a rapidly developing body and brain. Therefore, chemogenetic tools, such as designer receptors exclusively activated by designer drugs (DREADDs) are ideally suited for developmental research questions. The current study used one male and one female infant rhesus monkeys to examine how transient inactivation of the amygdala impacted socioemotional behavior and cortisol stress reactivity. At 7 months of age infant monkeys underwent MRI-guided neurosurgery to inject AAV5-hSyn-HA-hM4D(Gi)-IRES-mCitrine bilaterally into the amygdala. We utilized the Human Intruder (HI) paradigm to assess emotional behavior and cortisol stress reactivity in the monkeys. The HI paradigm was chosen because 1) it is robust task at assessing monkeys behavioral and stress response toward the presence and specific gaze direction of a novel human and 2) it has been previously shown to be sensitive to perturbation in amygdala activity. Prior to expression of the hM4Di receptors, animals were tested for sensitivity to clozapine-N-oxide (CNO) by administering 10mg/kg CNO prior to the HI task. Neither infant exhibited any sensitivity or side effect of CNO, and both expressed species-typical responses on the HI task. Four weeks after surgery, animals were tested again on the HI task either with 10mg/kg CNO or saline administered before the task to activate the hM4Di receptors and inhibit amygdala activity or not. Blood samples were collected immediately before and after each HI task for assay of cortisol, CNO, and metabolites (clozapine and n-desmethylclozapine) levels in plasma. CNO and metabolites were detectable in plasma samples collected during the HI task. These data will demonstrate whether activation of hM4Di receptors bilaterally in the amygdala can inhibit amygdala activity during an acute stressor leading to decreased cortisol stress response similar to previous data from adult monkeys with DREADDs or after permanent lesions of the amygdala. This study demonstrates proof-of-principle, that chemogenetics can be effectively used in infant monkeys and paves the way for future development studies using chemogenetic manipulation of neuronal activity.

9:45 am, Room 144A

279.08 Characterization of DREADD manipulation in rhesus monkeys trained to discriminate ethanol.


Oregon Hlth. and Sci. Univ., Oregon Natl. Primate Res. Center/OHSU, Icahn Sch. Of Med. at Mount Sinai.

Abstract: The nucleus accumbens (NAc) core is a primarily GABAergic brain nucleus that has been demonstrated to mediate the discriminative stimulus effects of ethanol in rodents. Additionally, self-report measures of intoxication directly correlate with BOLD signal within the NAc in human subjects, providing translational evidence of this brain nucleus in ethanol’s interoceptive (subjective) effects. The goal of the current study is to characterize the role of the NAc in ethanol discrimination in rhesus monkeys utilizing a chemogenetic viral strategy (DREADDs). Five young adult male rhesus monkeys were trained on a two-choice food-reinforced ethanol (1.0 g/kg, 20% w/v in water, i.g.) vs. water discrimination with a 60-minute pretreatment interval (BEC: 70±5 mg%, n=5). All monkeys successful acquired the discrimination (≥90% accurate responding for 5 consecutive sessions) in 72 ± 19 sessions (M±SD), with an ED50 for ethanol substitution of 0.7 ± 0.1 g/kg. Substitution testing was conducted with ethanol, midazolam and pentobarbital. Upon completion of initial tests, monkeys were bilaterally injected into the NAc core with hM4D Gi-coupled DREADD receptors (plasmid: AAV1-hSyn-hM4Di-mCherry, 50 ul/injection, 1e12 vg/ml), with individually determined coordinates from the surface of the brain using an MRI-compatible stereotaxic frame. For DREADD testing, a water-soluble form of CNO was used (CNO-HCl) and administered 30 min prior to ethanol/water administration (i.m., 5.6 mg/kg, 30 mg/ml in saline). A separate pharmacokinetics study indicated that CNO concentrations at the time of ethanol administration (t=30 min post-injection) were 1052 ± 260, and rose to 1840 ± 877 ng/ml at the start of the behavioral test (t=90 min). Reverse metabolism to clozapine from CNO was between 1-1.5%, with plasma concentrations of 12 ± 4 (t=30 min) and 27 ± 8 (t=90 min). Administration of 5.6 mg/kg CNO with water resulted in partial ethanol-like discriminative stimulus effects in two subjects (24% and 50%, respectively). Pretreatment of 0.56 mg/kg CNO prior to 0.5 g/kg ethanol resulting in full substitution in one monkey. These preliminary data demonstrate that the rhesus monkeys has a ratio of clozapine:CNO of <2% following i.m. CNO administration, suggesting the effect of CNO activation is unlikely due to clozapine. Further, activation of the inhibitory hM4D receptor within the NAc enhances the potency of the ethanol discrimination in a subset of rhesus monkeys. Additional work is necessary to investigate extent of DREADD expression in the NAc across monkeys, as well as the extent of extra-NAc mediation of the ethanol cue in those monkeys that did not demonstrate changes with NAc inhibition.



Posters for Monday Morning, November 13

8 am – noon, Halls A-C, T6

299. LRRK2 Mechanisms, Targets, and Pathways
Topic: C.03. Parkinson’s Disease

299.14 CRISPR/Cas9 genomic editing of leucine-rich repeat kinase 2 (LRRK2) in marmoset stem cells


Neurosci. Training Program, Wisconsin Natl. Primate Res. Ctr., Obstetrics and Gynecology, Comparative Biosci., Med. Physics, Univ. of Wisconsin-Madison, Madison, WI

Abstract: LRRK2 G2019S is the most common mutation associated with familial Parkinson’s disease (PD). Located in the kinase domain of LRRK2, G2019S facilitates substrate access to the kinase thus increasing the catalytic rate of the enzyme. Patient-derived induced pluripotent stem cells present increased activated caspase-3, simplification of neurites and cell body accumulation of α-synuclein after dopaminergic differentiation of the A9 subtype. Although some transgenic rodent species overexpressing human LRRK2 G2019S exist, there have not yet been similar modeling strategies applied to nonhuman primates. Moreover, utilization of clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 for precision editing, models that more closely mimic natural disease progression are now more achievable. In an effort to validate the common marmoset as a candidate species for a genomic model of PD, we first chose to investigate in vitro cell modeling strategies. The p.G2019S mutation derives from a g.G6055A mutation within exon 41. Here we report utilization of CRISPR/Cas9 that recognizes the G6055 region of the marmoset LRRK2 genome. We have successfully isolated a marmoset embryonic stem cell clone that contains bi-allelic nucleotide deletions that lead to a truncated form of LRRK2 (tLRRK2). After the clone was expanded, we administered a dual-SMAD inhibition protocol that our group previously validated for differentiating marmoset stem cells to neurons. The wild type (WT) parental cell line was differentiated in parallel as a control for phenotypic comparison. On day 28 of differentiation, the cells were incubated in a maturation medium for two weeks. The cells were then lifted, quantified, and replated to cover slips at an equal density for morphological analysis and fixed one week later. After immunostaining for βIII-tubulin, 30 different fields for parental and edited cell lines were imaged. The ImageJ plugin NeuriteQuant was used for objective quantification of neurite complexity. Preliminary results suggest that tLRRK2 in neurons leads to a significant increase in average neurite length, number of branches per cell and overall neurite length per cell when compared to WT controls. There was no significant difference in the number of cells evaluated, number of neurites per cell, branches per neurite length and branches per neurite. Our results demonstrate that LRRK2 may play a critical role in the level of neurite complexity in marmoset neurons, and that disrupting functional LRRK2 expression may have a reverse effect of the gain-of-function G2019S mutation phenotype observed in human neurons. We are currently evaluating LRRK2 G2019S marmoset cells.

8 am to noon, Halls A-C, NN12

326. Metabolism Control and Obesity
Topic F.10: Food Intake and Energy Balance

326.09 The glucose sensitivity of mesencephalic cells: Effect on tyrosine hydroxylase regulation


Lab. of Neurochemistry, Rio De Janeiro, Brazil; 2Federal Univ. of Rio de Janeiro, Rio de Janeiro, Brazil; 3California Natl. Primate Res. Ctr., UC Davis, Davis, CA; UFRJ, Rio de Janeiro, Brazil; The J. B. Pierce Lab. and Yale Univ. Sch. of Med., New Haven, CT

Abstract: Different lines show that the expression of preferences for highly palatable foods depends on the gastrointestinal and/or metabolic effects produced by caloric foods. It remains to be determined how the central nervous system converts the sensing of metabolic signals into behavioral preferences. Previous studies show that the midbrain dopaminergic system is a central mediator of food preference formation, given its critical role in the expression of normal feeding behaviors. It is thus of great interest the identification of the physiological pathways allowing the midbrain dopaminergic system to sense metabolic post-ingestive effects. Our results show that cultured dopaminergic neurons are highly sensitive to glucose levels. Exposing cultured murine mesencephalic neurons to hypoglycemic media, or to the glucose anti-metabolite 2-DG, suppressed dopamine levels. Moreover, we show in adult mice that intraperitoneal injections of glucose, but not of 2-DG, 30 minutes after were sufficient to increase the phosphorylation of tyrosine hydroxylase residues Ser40 (2.4-fold) and Ser31 (1.5-fold), molecular events critical for dopamine synthesis. Finally, increases in Ser40 phosphorylation levels were closely associated with increases in blood glucose levels induced by the intraperitoneal injections. Our results suggest that midbrain dopaminergic regions may be activated by metabolic stimuli such as increased glycemic levels.

8 am to noon, Halls A-C, VV85

344. Large-Scale, Deep, and High-Speed Functional Light Microscopy
Topic: I.04. Physiological Methods

344.17 Optical coherence tomography reveals depth-resolved responses during functional cerebral activation by infrared neural stimulation

P. LI1, P. LI3, W. XI5, E. AKSHAY4, A. W. ROE2 1Dept. of Optical Engin., 2ONPRC-NEUROSCIENCE, Zhejiang Univ., Zhejiang, China; 4ZIINT, 3zhejiang university, Hangzhou, China; 5Zhejiang Univ., ZIINT, Hangzhou, China

Abstract: Infrared neural stimulation (INS) has been reported as a promising modality for evoking neural response during cerebral activation. Optical imaging is an effective tool for measuring the activated dynamics and responses. In contrast to conventional optical intrinsic signal imaging (OISI) modality that provides two-dimensional, depth-integrated maps of stimulus-evoked dynamic activation, we used optical coherence tomography (OCT) to provide depth-resolved, cross-sectional images of functional cerebral activation by INS. In this study, 0.5s-lasting pulsed infrared light (central wavelength 1.875 μm, pulse width 250 μs and fiber diameter 200 μm) was utilized to stimulate the cortex of anesthetized rats with different radiant exposure (0~1 J/cm2) and different repetition rates (50~200 Hz), respectively. Temporal fractional OCT signal change was calculated to evaluate INS efficacy. It revealed statistically significant depth-resolved signals, comprised of both positive and negative responses. These responses were detectable at cortical depths of >1 mm during functional activation. This suggests that OCT is a promising in vivo imaging method for mapping functional cortical responses along the depth axis, and may provide a method for further investigating functional neural coupling in neuroscience research.



Posters for Monday Afternoon, November 13

1 pm, Halls A-C, C53

372. Insights Into Developmental Vulnerabilities
Theme A: Development

372.05 Social stress and the dietary environment affect infant brain volumes in macaques: Modulation by maternal factors.


Emory Univ., Yerkes Natl. Primate Res. Ctr., Univ. of North Carolina, Inst. of Child Develop., Ctr. for Behavioral Neurosci.

Abstract: Social stress has adverse effects on brain structure and function linked to psychopathology, including changes to amygdala and prefrontal volumes. It is not well understood how these alterations emerge during development and interact with other risk factors, including obesogenic diets. Here we examined the potential for a synergistic impact of social stress and diet on infant brain development longitudinally, using a translational macaque model of social subordination stress. We also probed whether maternal care and breast milk mediate the effects of stress and diet on neural development. Forty-four socially-housed rhesus monkey infant-dam pairs (n=21 dominant (DOM), n=23 subordinate (SUB)) were randomly assigned to either a chow-only, low-calorie diet (LCD) condition, or had access to both LCD and high-calorie diet (HCD) from birth (choice). Behavioral observations of the infant-dam pairs were collected from birth through 6 months, and maternal care quality was also rated. Plasma cortisol and structural MRI scans were collected at 2 weeks and 6 months. Preliminary results of the 6-month imaging data reveal significantly larger overall brain volumes in infants on the choice diet, with regional increases in the caudate, and insular, cingulate, and parietal cortices. SUB infants had larger amygdala and hippocampal volumes. The SUB and the choice conditions were associated with larger white matter (WM) volume in the frontal lobe, and a diet by social rank interaction was detected for WM in temporal visual and auditory cortices, with DOM LCD infants showing the smallest volumes. Baseline cortisol at 6 months was higher in the choice than LCD condition, which predicted larger right amygdala volumes. Among several rank (and diet) effects on maternal care, those on maternal permissiveness/attachment at 2 weeks were interesting, as stronger attachment predicted smaller left amygdala volume at 6 months. Greater milk yield at 6 weeks also predicted larger brain development, particularly of amygdala, and cingulate and frontal cortices WM. These preliminary findings suggest that exposure to social subordination and obesogenic diet early in life impacts infant brain development and stress hormones. Maternal care was also influenced by rank and diet, with more competent maternal care seeming to protect against some of the negative impacts of stress and diet on brain development, specifically in the amygdala.

1 pm to 5 pm, Halls A-C, II13

402. Visual Cortex: Functional Architecture and Circuits
Topic: D.07. Vision

402.20 Mapping visual cortical processing networks with infrared neural stimulation


Neuroscience, Oregon Natl. Primate Resource Ctr., Oregon Hlth. and Sci. Univ., Beaverton, OR; Div. of Neurosci., Oregon Hlth. & Sci. Univ. - ONPRC, Beaverton, OR; Zhejiang Univ., Zhejiang, China; Neurosci., Oregon Hlth. and Sci. University- ONPRC, Beaverton, OR

Abstract: Microelectrodes for brain mapping have been the gold standard for over a century. However, the technique suffers from several drawbacks, such as poor spatial precision and technical issues that arise when this type of stimulation is combined with state of the art recording methods, such as electrophysiology or MRI. Over the past two decades, significant progress has been made into optical alternatives to electrophysiological techniques. One such method is infrared neural stimulation (INS), which uses short (on the order of 10-4 s) pulses of 1875 nm light to create focal thermal transients that lead to generation of action potentials in both the CNS and peripheral nerves (Wells et al. 2005, Opt. Lett., Cayce et al. 2014, Neuroimage, Chernov and Roe 2014, Neurophotonics). Because light at this wavelength is quickly absorbed by water in tissue, the stimulation is essentially confined to the radius of the illuminating spot produced by light from an optical fiber and spreads a few hundred microns into tissue. The high spatial precision of the method, its minimally invasive nature (stimulation can be contact-free) and its compatibility with a variety of imaging modalities including intrinsic optical imaging (IOS) and MRI, as well as electrophysiological recordings make it an excellent tool for the study of functional connections in cortex.
We are interested in using INS as a probe to reveal the organization of functional connections in primate sensory cortices when used in combination with IOS and other imaging methods. Previously, we have found that ocular dominance (OD) eye columns in visual cortex can show enhanced activation following INS (Cayce et al. 2011, Neuroimage). In this study, we use focal (~200-micron diameter illumination spot) INS to reveal short-range projections between functional domains in primary visual cortex, including OD columns, orientation domains and blobs when applied combination with relevant visual stimuli. We report that focal INS leads to patches of activation that line up with the location of functional domains. Moreover, we show that the strength of these connections is modulated by visual input. We conclude that INS is a useful tool for in vivo functional dissection of cortical circuits.

1 pm, Halls A-C, QQ4

416. Neuropeptide Regulators
Theme F: Integrative Physiology and Behavior

416.01 Estradiol protects proopiomelanocortin neurons against insulin resistance.


Oregon Hlth. and Sci. Univ., Oregon Natl. Primate Res. Ctr.

Abstract: The incidence of metabolic syndrome sharply increases in women after menopause. Neurons, similar to fat and muscle cells, can develop hyperinsulinemia-induced IR, which results in severe injury to the nervous system as seen in diabetic neuropathies and stroke. At the center of the regulation of energy homeostasis, and hence the central feedback of insulin, are the anorexigenic proopiomelanocortin (POMC) and orexigenic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons in the hypothalamic arcuate nucleus. Since 17β-estradiol (E2) augments the excitability of the anorexigenic POMC neurons, we investigated the electrophysiological effects of insulin in diet-induced obese (DIO) male and female mice, and the neuroprotective effects of E2 in females. We found that the ability of insulin to activate canonical transient receptor potential 5 (TRPC5) channels and depolarize POMC neurons was significantly reduced in DIO male (by 70%) but not in DIO female mice. However, the insulin response in POMC neurons was attenuated in ovariectomized, DIO females but restored with E2 replacement. E2 increased T-type calcium channel Cav3.1 mRNA expression and currents but downregulated stromal-interaction molecule1 (Stim1) mRNA, which rendered POMC neurons more excitable and responsive to insulin-mediated TRPC5 channel activation. Also, in females E2 prevented the increase in Socs3 mRNA expression with DIO that was seen in males. Therefore, E2 protects female POMC neurons from insulin resistance with DIO by enhancing POMC neuronal excitability and the coupling of insulin receptor to TRPC5 channel activation.

1 pm – 5 pm, Halls A-C, UU10

425. Learning and Memory: Hippocampal-Parahippocampal-Limbic Interactions
Topic: H.01. Animal Cognition and Behavior

425.23 Conjunctive coding in the primate entorhinal cortex


Physiol. and Biophysics, Natl. Primate Res. Ctr., Univ. of Washington, Seattle, WA

Abstract: Primate entorhinal cortex neurons respond to the appearance of visual stimuli in the context of visual recognition memory or association tasks in which the neural responses are typically analyzed during time periods lasting about 0.5 seconds. Given the heterogeneity of entorhinal response types identified in vitro, including responses that continue many seconds after stimulation, it is possible that distinct cell classes could also be observed in vivo across longer time periods. Here, we recorded the responses of individual neurons (n = 349) while monkeys freely viewed large, natural scene stimuli. Monkeys were allowed to view the scenes for up to 5 seconds, and up to 120 distinct scenes were presented within each session. Results revealed that entorhinal neurons exhibit vastly distinct responses locked to the onset of visual stimuli, both enhanced and reduced firing rates, with some neurons returning to baseline firing rate quickly, and others showing an exceptionally long decay, continuing well over 1 second after stimulus onset. Responses spanning this dynamic range were reliably encountered across experimental sessions and animals, suggesting distinct cell types.
To determine whether these separate cell types reflected anatomical specificity or differed in other aspects of their response profile, we compared the properties of cells with “Brief” vs. “Sustained” responses (responses that respectively returned to baseline firing rate within 0.5 sec or no sooner than 1.5 sec following image onset). Compared to Brief cells, Sustained cells included a significantly greater proportion of cells located in superficial cortical layers which provide the predominant cortical input to the hippocampus. Additionally, Sustained cells were more likely to show consistent spatial activity that reflected the location of the monkey’s gaze within the image. Notably, there was no difference in the proportion of spatial Sustained cells that showed enhanced compared to reduced firing rate at stimulus onset.
Together, these findings reveal an association between cells with an exceptionally long response decay after the appearance of an image, spatial coding, and location in the superficial cortical layers. Because the entorhinal cortex is important for memory, we speculate that these exceptionally long responses may provide necessary drive to create a sustained binding state, or memory “chunk,” linking across time spatially separate elements encountered during visual exploration of an image. Future research distinguishing these diverse cell types offers a potentially powerful, new way to enhance our understanding of the neural mechanisms that underlie memory.

1 pm – 5 pm, Halls A-C, UU11

425. Learning and Memory: Hippocampal-Parahippocampal-Limbic Interactions
Topic: H.01. Animal Cognition and Behavior

425.24 Mnemonic discrimination task in rhesus macaques


Physiol. and Biophysics, Washington Natl. Primate Res. Ctr., Univ. of Washington, Seattle, WA; Ctr. for the Neurobio. of Learning and Memory, Univ. of California Irvine, Irvine, CA; Neurobio. and Behavior, Univ. of California, Irvine, Irvine, CA; 5Intrnl. Med. Res. Unit, Pfizer, Inc., Cambridge, MA

Abstract: Pattern separation, which refers to the process of orthogonalizing overlapping inputs into distinct memory representations, has been shown to be affected in healthy elderly individuals as well as in individuals with mild cognitive impairment who may go on to develop Alzheimer’s disease. Research using functional imaging in humans has implicated substructures of the hippocampus, specifically CA3 and Dentate Gyrus (DG), as being particularly important for pattern separation, with deficits in nondemented older adults associated with increased CA3/DG activity (Lacy, et al., 2011; Yassa et al., 2010). Single unit recordings in rodents have implicated the DG in pattern separation and have suggested that CA3 representations more likely reflect pattern completion mechanisms, i.e., the retrieval of a memory with partial input (Neunuebel and Knierim, 2014). Monkeys, which can be trained to perform similar, if not identical, behavioral tasks as those used in human subjects, provide an avenue for clarifying this issue and assessing the neurobiological underpinnings of this ability at the level of cells and circuits. Here, we adapted the mnemonic discrimination task from the human literature for use with rhesus macaques. This task provides a useful behavioral assay of pattern separation. Five monkeys were trained on a sequential delayed match to sample task with centrally located images. Subjects indicated the detection of a match by touchbar release. Each trial could include repeated nonmatching stimuli (ABBA design) and extend to a potential length of six nonmatching stimuli. Human-validated distracter items from the human mnemonic discrimination task that varied parametrically across five levels of similarity to the target item were used as critical lure stimuli. All monkeys were able to perform this task successfully. Notably, monkeys displayed similar behavioral performance to humans, in that performance varied predictably along with the increasing similarity of the lure to the target. These results demonstrate the applicability of the mnemonic discrimination task as a platform for further neurophysiological studies targeting single units in specific hippocampal subregions in the primate.

1 pm – 5 pm, Halls A-C, UU12

425. Learning and Memory: Hippocampal-Parahippocampal-Limbic Interactions
Topic: H.01. Animal Cognition and Behavior

425.25 Eye movements temporally organize spatial representations in the primate hippocampus


Physiol. and Biophysics, Washington Natl. Primate Res. Ctr., Univ. of Washington, Seattle, WA

Abstract: Single unit recordings in rodents have identified place and time cells in the hippocampus that are hypothesized to support the spatial and temporal aspects of episodic memories. However, it is not fully understood the extent to which similar representations exist in the primate hippocampus. Notably, studies in monkeys have identified neurons in the hippocampus and entorhinal cortex that are modulated by gaze location rather than the monkey’s physical location (Rolls, 1999; Killian et al., 2012). In addition, saccadic eye movements modulate the activity of single hippocampal neurons (Sobotka et al., 1997) and the phase of the hippocampal local field potential (Hoffman et al., 2013; Jutras et al., 2013), suggesting that the temporal properties of active sampling of the environment via saccades plays an important role in hippocampal activity. To further explore how these representations are related to eye movements, we recorded the activity of 347 hippocampal neurons from two monkeys as they freely viewed complex images. We found that 31% of these neurons were significantly modulated by viewing location; these neurons were spatially stable across the recording session and had significant (p < 0.05) spatial information scores.(Skaggs et al., 1993) Surprisingly, each view-modulated neuron appeared to reach its maximum firing rate at a distinct time relative to the start of a fixation into the neuron’s firing field. Across the population of view-modulated neurons, the latency of the peak response tiled the full duration of a fixation (~200 msec), suggesting that these responses may reflect sequential firing. Taken together, these data provide further support for the idea that neurons in the primate hippocampus are modulated by eye movements and show selectivity for viewing location. Furthermore, these data demonstrate that eye movements temporally organize hippocampal activity across the extent of a fixation, potentially allowing information to be integrated across successive eye movements.

1 pm – 5 pm, Halls A-C, UU13

425. Learning and Memory: Hippocampal-Parahippocampal-Limbic Interactions
Topic: H.01. Animal Cognition and Behavior

425.26 Context-specific representations in monkey hippocampal neurons


Grad. Program in Neurosci., Physiol. and Biophysics, Washington Natl. Primate Res. Ctr., Inst. for Neuroengineering, Univ. of Washington, Seattle, WA

Abstract: Decades of studies have shown that the hippocampus plays an important role in memory in humans, monkeys, and rodents, but we do not yet have a full understanding of how transient neuronal activity in the hippocampus supports mnemonic function. Here, we investigated activity in the monkey hippocampus related to spatial memory performance. Monkeys were trained on a spatial delayed-alternation task in a visually rich virtual Y-Maze, in which the previous trajectory must be remembered in order to make a correct response. Hippocampal neurons were simultaneously recorded from more than 60 channels using a chronically implanted microdrive with independently movable electrodes (Gray Matter Research). The electrodes targeted the full anterior-posterior and medial-lateral extent of the hippocampus, spanning the dentate gyrus, CA3, CA1, and subliculum. Preliminary results indicate that single units show reliable responses to multiple distinct features of the task. Hippocampal neurons demonstrate discrete spiking in each phase of the task, including the center stem, choice point, reward locations, and delay period. Notably, these neural representations include place cells with consistent responses to the position of the monkey’s virtual avatar relative to maze landmarks. Over the aggregate ensemble, the observed hippocampal activity spans all task events, bridging discrete features within one network. To determine whether visual features of the maze influence network activity in addition to task structure, we compared neuronal activity across distinct environments with the same spatial dimensions. Neural responses were strikingly consistent across repeated sessions in a particular environment during a single day. When a visually distinct environment was interposed between the two repeated environments, a subpopulation of hippocampal cells showed marked shifts in response profile. These alterations included changes in whether a neuron was active in the task and in the location of a neuron’s place field. Taken together, these findings show that robust, task dependent activity in the monkey hippocampus can be elicited using a virtual reality memory paradigm. Further, environmental context biases which neural ensemble will be active, even with a consistent task structure.



Posters for Tuesday Morning, November 14

8 am – Noon, Halls A-C, DP01/A9

459. Cell Cycle Mechanisms in Neurogenesis I
Topic: A.01. Neurogenesis and Gliogenesis

459.09 Microglial cells intimately interact with multiple cell types in the proliferative zones of the fetal primate cerebral cortex.


Psych & Behavioral Sci., UC Davis, Sacramento, CA; California Natl. Primate Res. Center, Departments of Pediatrics, Cell Biol. and Human Anat., UC Davis, Davis, CA; Univ. of California, Davis - MIND Inst., Sacramento, CA

Abstract: Microglia, the brain’s immune cells, participate in normal developmental processes in the brain, in addition to immune functions. We have shown that microglia phagocytose neural precursor cells (NPCs), including radial glia and intermediate progenitor cells, in the fetal cerebral cortex. Our previous work identified microglia and NPCs by immunolabeling microglia with the Iba1 antibody, and NPCs with the cell specific antibodies Pax6 and Tbr2. Iba1 immunostaining labels the soma and processes of microglial cells, but Pax6 and Tbr2 label only the nuclei of NPCs. To better understand cellular interactions between microglia and fetal cortical cells, we labeled the entire cell body and cellular processes of fetal cortical cells with EGFP. We performed ultrasound guided in utero intracerebral injections of a lentiviral vector in fetal rhesus macaque on gestation day 85. Tissue was harvested 5 days later, brains sectioned at 100 microns, stained with cell specific antibodies (Radial glia: Pax6 and GFAP; Intermediate progenitor cells: Tbr2; Microglia: Iba1; Mitotic cells: 4A4; Cell nuclei: DAPI), and imaged with epifluorescent and confocal microscopes. In addition to phagocytosis, we find that microglial cells intimately contact radial glia. A single radial glial cell and its cellular processes are contacted by and enveloped by multiple microglia at several points between the ventricle and the pia. Microglia contact the soma and cellular processes of radial glia in all phases of the cell cycle, and make similar contacts with intermediate progenitor cells and migrating neurons. We also show that individual microglia interact with more than one cell at a time: we observed single microglial cells phagocytosing and interacting with multiple cortical cells simultaneously. In addition, microglia exhibit unique morphological features that indicate a correlation with function. For example, microglial cells extend reticulated processes toward NPCs near the surface of the ventricle. The reticulated microglia appear to represent a specific subset of phagocytic cells. Given the multiple roles microglia play in both the immune response and postnatal neuronal development, our current findings expand the repertoire of microglial cells in monitoring, maintaining, and remodeling the neurogenic niche of the fetal primate cerebral cortex.

8 am – Noon, Halls A-C, S1

478. Preclinical Therapeutic Strategies for Neurodegenerative Disease II
Topic: C.02. Alzheimer's Disease and Other Dementias

478.12 Brain infusion of alfa-synuclein oligomers induces motor and non motor Parkinson's Disease-like symptoms in mice


UFRJ, Rio DE Janeiro, Brazil; UFRJ, Rio de janeiro, Brazil; Inst. de Ciências Biomédicas, 5Faculdade de Farmácia, UFRJ, Rio de Janeiro, Brazil; Univ. Federal do Rio de Janeiro, Rio de Janeiro, Brazil; California Natl. Primate Res. Ctr., UC Davis, Davis, CA; Federal Univ. of Rio de Janeiro, Rio De Janeiro, Brazil; UFSM, Santa Maria, Brazil; Fed Univ. Rio De Janeiro, Rio de Janeiro, Brazil; Federal Univ. of Rio De Janeiro, BALNEARIO PICARRAS, Brazil

Abstract: Parkinson’s disease (PD) is classically characterized by debilitatingmotor symptoms, which are preceded by a number of non-motor symptoms including olfactory deficits, anxiety, depression and cognitive impairment. Aggregation of α-synuclein (alfa-syn), ultimately giving rise to formation of Lewy bodies in dopaminergic neurons, is thought to play a central role in PDpathology. However, whether amyloid fibrils or pre-fibrillar soluble oligomersof alfa-syn are the main neurotoxic species in PD remains controversial. Here, we investigated the impact of a single intracerebroventricular (i.c.v.) infusion of α-syn oligomers (alfa-SYOs) on motor and non-motor symptoms of PD in mice. alfa-SYOs induced olfactory dysfunction, and decreased dopamine levels and numbers of TH-positive cells in the olfactory bulb, 4 and 8 days post infusion (dpi), respectively. The olfactory deficit persisted until 45 dpi, at which time point olfactory bulb dopamine levels had returned to control levels. alfa-SYO-infused mice had no deficit in object recognition memory, but showed increased anxiety-like behavior 20 dpi. Finally, administration of alfa-SYOs induced late motor impairment and reduction in TH-levels and dopamine content in the striatum 45 dpi. In conclusion, i.c.v. infusion of alfa-SYOs recapitulated PD-associated motor and non-motor symptoms in a temporal sequence similar to that seen in PD patients. Results point to alfa-syn oligomers as the proximal neurotoxins responsible for early non-motor and motor deficits in PD, and suggest that the i.c.v. infusion model characterized here may comprise a useful tool for identification of novel therapeutic targets and for drug screening approaches for PD

8 am – Noon, Halls A-C, JJ21

p501. Spinal Cord Injury: Training, Rehabilitation, and Recovery
Topic: E.09. Spinal Cord Injury and Plasticity

501.23 Repair of a lumbosacral ventral root avulsion injury using GDNF-releasing nerve guidance channels to bridge tissue gaps between the spinal cord and avulsed ventral roots in rhesus macaques


Dept. of Neurol., Departments of Neurol. and Neurobio., David Geffen Sch. of Med. at UCLA, Los Angeles, CA; Dept. of Materials Sci. and Engin., Dept. of Neurol. and Neurosci., Johns Hopkins Sch. of Med., Baltimore, MD; Dept. of Neuroradiology, Karolinska Hosp., Stockholm, Sweden; California Natl. Primate Res. Ctr., UC Davis, Davis, CA

Abstract: Conus medullaris (CM) and cauda equina (CE) forms of spinal cord injury commonly result in paralysis, sensory impairments, and loss of bladder, bowel, and sexual functions. There are presently no treatments to reverse these neurological deficits. The present study investigated a new approach to promote axonal regeneration to reconnect spinal cord neurons with peripheral nervous tissues in a non-human primate model of CM/CE injury. For this purpose, biodegradable and trophic factor-releasing nerve guidance channels (NGCs) were used to bridge tissue gaps. The NGCs were comprised of electrospun polycaprolactone (PCL) tubes with an inner layer of aligned PCL nanofibers for topographical guidance and a PVA-collagen gel for controlled GDNF release (300ng/tube). Adult rhesus macaques underwent a unilateral L6-S3 ventral root avulsion (VRA) injury followed by repair of the L6 and L7 ventral roots. A glial cell derived neurotrophic factor (GDNF)-releasing NGC was placed as a bridge between the spinal cord and the avulsed L6 and L7 ventral roots (n=4). NGCs without trophic factor release were used as controls (n=4). Spinal cord and nerve root tissues were collected for morphological studies at 18 months post-operatively. Morphometric analysis of plastic embedded NGCs and nerve roots was performed using the free AxonSeg software. At 18 months post-operatively, both groups showed good integration between the bridging NGCs and the spinal cord as well as with the attached ventral roots. No graft rejections were detected. Cross-sections of GDNF-releasing NGCs showed a significantly higher percentage of overall tissue occupation (91.7±2.2%) compared to control NGCs (46.5±6.3%; p<0.01). Both groups showed a large number of myelinated axons in addition to fibrous tissues, Schwann cells, and blood vessels within the NGCs. The GDNF-releasing NGCs showed 3,230±669 myelinated axons, whereas the control NGCs showed 2,033±906 axons. There was no difference in axon numbers between the groups. There was no difference in fiber size or g-ratio between the groups. Electron microscopy of NGCs from both groups confirmed myelination of axons by Schwann cells as well as the presence of several unmyelinated axons with the NGCs. We conclude that the use of GDNF-releasing NGCs was well tolerated in non-human primates and promoted axonal regeneration in long-term studies. Trophic factor-releasing NGCs may be considered as a new repair strategy for bridging tissue gaps between the spinal cord and ventral roots after CM/CE injuries.

10 am, Halls A-C, LL6

504. Early-Life Stress: Neurophysiological and Neurochemical Consequences
Theme F: Integrative Physiology and Behavior

504.11 Effects of adverse maternal care on the development of hypothalamic-pituitary-adrenal axis function in nonhuman primates.


Emory Univ., Yerkes Natl. Primate Res. Ctr., Inst. of Child Develop., Univ. of Massachusetts.

Abstract: Early life stress (ELS) is a known risk factor for psychopathology, including anxiety and depressive disorders, substance abuse, as well as cognitive and behavioral deficits. The mechanisms underlying this association, however, remain poorly understood. A likely biological link between ELS and many psychopathologies is its impact on typical development of the hypothalamic-pituitary-adrenal (HPA) axis. Studying this relationship in humans can be challenging due to limitations in prospective studies, as well as confounding factors, such as co-morbid conditions and genetics. To circumvent these difficulties, our group used a translational and well-established ELS model of infant maltreatment by the mother in rhesus macaques. This ELS model consists of comorbid infant abuse and rejection by the mother during the first months of life. To disentangle the effects of the adverse experience from those due heritable factors, infant macaques (n=43) were cross-fostered at birth and randomly assigned to either control (n=21) or maltreating (MALT; n=22) foster mothers. We assessed the developmental impact of adverse care on HPA axis function longitudinally since birth through the juvenile period using (1) measures of hair cortisol (CORT) accumulation, (2) diurnal CORT rhythm, and (3) glucocorticoid negative feedback via dexamethasone (DEX) suppression tests. Our findings indicate that, although hair CORT levels were not different at birth, MALT infants showed significantly higher CORT accumulation than controls from birth through 6 months, with a parallel trend towards elevated plasma CORT levels. Long-term impact of adverse caregiving was detected at 12 months, with a significant interaction effect between MALT and sex on diurnal CORT rhythm, with MALT females exhibiting higher CORT levels at both the morning and afternoon time points than control females. This effect was not observed in the males. MALT subjects of both sexes showed super-suppression of CORT secretion in response to DEX challenge at 12 months. Neither of the diurnal or DEX suppression effects observed at 12 months were present at 18 months. These data suggest that alterations in HPA function due to maternal maltreatment persist past the early infant period of ELS exposure into the early juvenile period, but are ultimately temporary. Additionally, females are more sensitive to maltreatment-related HPA dysregulation than males. Although HPA axis activity seems to start to recover later in the juvenile period, chronic exposure to high levels of CORT during the first 12 months of life are expected to have long-term consequences for brain, physiological and behavioral development.

10 am, Halls A-C, RR28

514. Circuits Underlying Emotional States
Theme G: Motivation and Emotion

514.03 A robot dinosaur as a predator like stressor to highlight susceptibility versus resilience and gender difference in response to acute stress.


Yerkes Natl. Primate Res. Ctr. - Emory Un, Emory Univ.

Abstract: It is clear that stress affects emotional behavior, however each individual responds differently to adversity. Many resilient individuals display adaptive physiological responses to stress while others will develop depression or other psychiatric disorders. Moreover, there is an overwhelming wealth of evidence from the clinical literature that the prevalence of anxiety disorders is about twice as high in women compared to men. The molecular pathways underlying these differences remain unclear. Here, we used a new stressor, a robotic predator, in a 3 day paradigm (Baseline, Stress and Probe test), to induce acute stress in males (n=14) and females rats (n=12). The time spent interacting with the predator was used to assess the stress response. In males, we found that the interaction time significantly decreased during Stress compared to Baseline (18.28% vs 35.44% p<0.001 RM-ANOVA). Interestingly, during Probe about 71% of the males still displayed reduced interaction while 29% showed no difference compared to their Baseline behavior. We could not find a specific behavior during the Stress that could be correlated with the stress response during Probe, suggesting an endogenous component to the resilience. Unexpectedly, in females, a significant proportion of the animals did not display sign of stress in response to the moving predator while about 40% significantly decreased their interaction. Females with decreased interaction during Stress also showed decreased interaction during Probe while resilient animals during Stress displayed normal behavior during probe. We found a significant correlation between the behavior during Stress and Probe (Spearman r=0.7852). Previous studies have reported that the light-enhanced startle response in female rats fluctuated significantly with reproductive state. We hypothesized that the fluctuation we observed in response to the stressor might be the result of different estrogen and estrogen receptor levels. In both males and females, we then investigated the neuronal activation in response to the presentation of the stressor on D2 and D3 as well as the level of estrogen and estrogen receptors and blood cortisol. After identification of the responding neurons, we will use the TRAP technology to characterize their transcriptomic profile and potentially highlight genes involved in stress resilience.

11 am, Halls A-C, RR29

514. Circuits Underlying Emotional States
Theme G: Motivation and Emotion

514.04 Stress neuroadaptation in the bed nucleus of the stria terminalis (bnst) may underlie social defeat-induced depression-related behaviors.


Emory, Yerkes Natl. Primate Res. Ctr., Emory Univ.

Abstract: Chronic stress is a key risk factor in the development of Major Depressive Disorder (MDD), yet it is unknown why certain people develop MDD compared with others, despite reporting similar levels of stress. Corticotrophin-Releasing Factor (CRF) has emerged as a molecular substrate that may play a critical role in stress-related depression. Although, CRF’s potential role is implicated in a preponderance of preclinical and clinical reports, how stress and CRF play a pivotal role in MDD etiology is not well understood. The Bed Nucleus of the Stria Terminalis (BNST) may be in important in the interrelationship of stress and depression, as it encodes the nature and chronicity of stressful stimuli and mediates behavioral/physiological adaptive responses. Importantly, the oval nucleus of the BNST contains an enriched population of CRF postitive (BNSTovCRF) neurons that are stress responsive and serve as an attractive neuronal population to interrogate as providing a molecular link between CRF and depression. In this study, we sought to elucidate CRF neural mechanisms that underlie individual differences in stress susceptibility that arise from unmitigated chronic stress exposure. We hypothesized that individual differences in crf gene expression may correlate with an individual’s vulnerability to depression. To test this, we employed the Chronic Social Defeat Stress paradigm in mice that reliably produces stress-resilient (RES) or depressive-like (DEP) phenotypes on the basis of social interaction and sucrose preference. We discovered differential crf, crfr1, and crfr2 gene expression in the anterolateral (oval nucleus containing) region of the BNST of RES and DEP mice. Additionally, these changes in gene expression correlated with immediate early gene, cfos, activity selectively in the BNSTov, but not anteromedial or ventral BNST regions. Notably, we observed in crf-tdTomato mice, the co-localization of cfos immunofluorescence with tdTomato, suggesting these changes may be mediated by this CRF-positive neuronal subpopulation. Altogether, these findings provide evidence that the response of BNSTov CRF neurons to persistent stress may reflect individual tolerance to stress such that hypoactivity may predispose individuals to depression. Alterations in CRF neurotransmission may shift the predisposition of mice toward either stress-resiliency (RES) or stress-induced depressive-like (DEP) phenotypes. In this way, CRF transmission in the BNST may serve as a biomarker in serving to identify populations of individuals with enhanced vulnerability to depression.



Posters for Tuesday Afternoon, November 14

1 pm - 5 pm, Halls A-C, S1

572. Parkinson's Disease: Neuroprotective Therapeutic Strategies
Topic: C.03. Parkinson’s Disease

572.19 Post mortem evaluation of sympathetic neurodegeneration and neuroprotection in a nonhuman primate model of cardiac dysautonomia


Wisconsin Natl. Primate Res. Ctr., Cell. and Mol. Pathology Grad. Program, Dept. of Psychology, Dept. of Med. Physics, Univ. of Wisconsin - Madison, Madison, WI

Abstract: Cardiac dysautonomia is a common nonmotor symptom of Parkinson’s disease associated with loss of sympathetic innervation to the heart and decreased plasma catecholamines. Disease-modifying strategies are not available, and biomarkers are lacking. Systemic administration of the catecholaminergic neurotoxin 6-hydroxydopmaine (6-OHDA) recapitulates this loss of cardiac sympathetic innervation and circulating catecholamines. We recently used positron emission tomography (PET) imaging in 10 6-OHDA-treated (50mg/kg; iv) adult, male rhesus to visualize and quantify cardiac sympathetic neurodegeneration and increased inflammation and oxidative stress following neurotoxin, which were attenuated in pioglitazone treated rhesus (n=5; 5mg/kg) compared to placebo (n=5). Here we report post mortem characterization of heart and adrenal tissue in these animals compared to age and gender matched normal controls (n=5). Tissues were collected following PFA perfusion, blocked in paraffin, sectioned at 5μm, immunostained, and immunoreactivity (-ir) quantified as area above threshold (%AAT) in NIH ImageJ. In the heart, immunohistochemistry was performed for sympathetic innervation (tyrosine hydroxylase; TH) and inflammation (HLA-DR) in 3 base to apex layers and 4 regions (septal, anterior, lateral, inferior) of the left ventricle. Average TH-ir in all left ventricle nerve fascicles was significantly lower in pioglitazone (48.2%) and placebo (46.9%) groups than in healthy controls (65.6%; ANOVA p<0.001). Placebo vs pioglitazone groups showed a difference in combination with cardiac layer and region (ANOVA p=0.039). No group differences were observed for HLA-DR. Adrenal tissue was analyzed in the medulla for catecholamine production capability by TH-ir and aromatic amino acid decarboxylase (AADC)-ir. TH-ir revealed significant 6-OHDA associated loss (control 90.5%; placebo 53.6%; ANOVA p<0.0001), and preservation in the pioglitazone group compared to placebo (pioglitazone 78.9%; p<0.01). AADC-ir confirmed these findings, with a significant difference between control (86.7%) and placebo (50.0%) animals (ANOVA p<0.01), but not between control and pioglitazone (69.0%). HPLC for plasma norepinephrine (NE) showed dramatic %loss from baseline to 1wk post-6-OHDA in placebo (69.1%) and pioglitazone (57.4%) groups, which was significantly higher in placebo animals compared to pioglitazone (Mann Whitney p=0.016). Overall, these results validate in vivo findings of 6-OHDA associated cardiac sympathetic denervation and demonstrate the ability of pioglitazone to preserve enzymes critical for catecholamine production in the adrenal medulla.

2 pm, Halls A-C, V25

575. Animal Models of Huntington’s Disease
Theme C: Neurodegenerative Disorders and Injury

575.10 Microstructural alterations of corpus callosum in developing brains of macaques with Huntington’s disease.


Yerkes Natl. Primate Res. Ctr., Emory Univ. Sch. of Med., Yerkes Natl. Primate Res. Ctr., Emory Univ. Sch. Of Med., Yerkes Natl. Primate Res. Ctr.

Abstract: It is poorly understood when corpus callosum (CC) changes emerge during development with Huntington’s disease (HD). HD rhesus monkeys (male, n=3) were generated using lentiviral-mediated transgenesis (Yang et al., Nature, 2008) and four age-matched wild-type non-transgenic rhesus macaques (2 males and 2 females) were used as controls. Animals were anesthetized with 1.0% isoflurane mixed with 100% O2. Diffusion tensor imaging (DTI) was conducted on a Siemens 3T Trio with parallel echo planar imaging (EPI) sequence with isotropic voxel size 1.3 mm and a single b-value of 1000 s/mm2 with 30 gradient directions. T1-weighted images acquired were used for structural identification and template construction. FA maps were nonlinearly registered to a population-specific template and then skeletonised with TBSS toolbox (FMRIB, Oxford). FA in the skeleton was averaged for each of the seven CC segments (from CC1 to CC7: rostrum, genu, rostral body, anterior mid-body, posterior mid-body, isthmus, and splenium) (Witelson et al., Brain, 1989). A multivariate analysis of variance (MANOVA) was performed to examine group difference in FA of each CC segments with significant level 0.05. No significant group differences in FA were noted in any CC segments before 18 months (p>0.2) (Fig. 1). Group differences were shown in rostrum from 18 months (p <0.02) and in genu from 30 months (p<0.05). From 36 months, splenium began showing group differences. At 48 months, most CC segments of the HD monkeys (p<0.05) except anterior mid-body (p=0.22) had FA values significantly different from controls. Altered rostrum and genu connect inter-hemispheric prefrontal cortical areas, paralleling the impairment in motor planning skills reported previously in the same HD animals at 36 months (Chan et al., PLOS One, 2015). CC alterations were observed as early as at 18 months and became more severe with ages. They parallel the findings in patients with progressive HD stages (Rosas et al., Neuroimage, 2010). The results suggest that DTI may provide valuable early neural markers for the pre-diagnosis of HD.

1 pm, Halls A-C, FF12

588. Visual Cortex: Development and Plasticity
Theme D: Sensory Systems

588.25 Development of social-visual engagement in rhesus macaques (Macaca mulatta).


Emory Univ., Yerkes Natl. Primate Res. Ctr., Marcus Autism Ctr., Emory Sch. of Med., Yerkes Natl. Primate Res. Ctr., Yerkes Natl. Primate Ctr.

Abstract: Autism Spectrum Disorder (ASD) is characterized by altered engagement with the social world and is apparent at early stages of the disorder. A theory in ASD etiology is that neonatal visual function is reflexive, but undergoes an important shift towards voluntary reward-based functioning involving affective neurocircuits. Disruptions in this transition are believed to be involved in ASD pathogenesis (Klin, Shultz & Jones, 2015). Given the critical nature of this transition, illuminating its neurobehavioral underpinnings through a nonhuman primate model will be essential to understanding the pathophysiology of ASD. Twenty-seven mother-reared infant male rhesus macaques living in social groups were eye-tracked longitudinally from birth to 6 months while viewing semi-naturalistic videos of macaque social interactions and full-faced videos of unfamiliar adult and juvenile males and females. Novel stimuli were presented each session with a subset repeated in following sessions to control for novelty across the longitudinal design. Using procedures similar to human studies, 14 sessions were conducted for each infant across the 6 months. The figure demonstrates that monkeys’ fixation to the eye region shows an inflection in developmental trajectory, increasing from birth to 8 weeks, decreasing slowly to a trough between 14-18 weeks, before increasing again. Different developmental patterns were observed in fixation on the mouth and body. The results indicate a critical period for social skills refinement around 4-8 weeks of age that parallels the developmental trajectory of eye looking in human infants (Jones & Klin, 2013), and suggest ethologically relevant species differences in the development of mouth and body looking. Importantly, the data suggest the presence of a switch in critical networks supporting these developing social skills. Further analyses of neuroimaging data collected on these animals during this developmental period will allow us to identify neural networks mediating this shift in behavior and will be aid in our understanding of ASD pathophysiology.

1 pm – 5 pm, Halls A-C, FF13

588. Visual Cortex: Development and Plasticity
Topic: A.08. Development of Motor, Sensory, and Limbic Systems

588.26 Developmental changes in visual processing of faces: A combined eye-tracking and structural MRI study in infant rhesus macaques


Yerkes Natl. Primate Res. Ctr., Dept. of Psychology, Emory Univ., Atlanta, GA; Dept. of Pediatrics, Dept. of Psychiatry and Behavioral Sci., Emory Univ. Sch. of Med., Atlanta, GA; Marcus Autism Ctr., Children’s Healthcare of Atlanta, Atlanta, GA; Dept. of Psychiatry, Univ. of North Carolina, Chapel Hill, NC

Abstract: Reading others’ facial cues (i.e. trustworthiness) in social interactions is crucial to understand their intentions and emotions, and is impaired in individuals with Autism Spectrum Disorder (ASD). Characterizing the emergence and development of this skill and supporting brain regions may further broaden our understanding of impaired socioemotional development observed in children with ASD. Rhesus macaques, a highly translational nonhuman primate model of early socioemotional development allow for densely sampled longitudinal neuroimaging studies not feasible in human infants. Therefore, this study aims to characterize early development of social and facial feature perception and the underlying brain regions in rhesus infants.
We conducted preliminary analyses of eye tracking and MRI data collected longitudinally in 6 male macaques (1 week - 6 months) living with their mothers in complex social groups. Each session included trials of 2 human faces representing extreme levels of trustworthiness. Looking behavior, including fixation to eye and mouth regions was characterized for trustworthy and untrustworthy faces. Structural MRI scans (T1 MPRAGE sequences (TR/TE = 2600/3.46msec, voxel size: 0.5x0.5x0.5mm)) acquired using a 3T scanner were used to characterize volumetric changes of the amygdala (AMY) and cortical grey matter of the insula, superior temporal sulcus, prefrontal cortex (BA46 & BA9) and inferotemporal area (TE), all areas involved in visual processing of “trust” in faces, and associations with looking behavior were assessed. At 2 weeks of age, monkeys did not distinguish between the faces, looking equally to them (p=0.07), although greater looking to the trustworthy face correlated with smaller right AMY volumes (r2=-0.98, p=.01). The ability to distinguish the faces emerged by 8 weeks, when infants looked more at trustworthy faces (p=0.04), explained by greater looking to trustworthy than untrustworthy eyes, and greater looking to eyes than mouth of trustworthy faces (p=0.05). At this age, there was a trend for an association between looking to trustworthy mouths and increased TE volume (left TE: r2=0.79, p=.059; right TE: r2=0.79, p=.061). This behavioral pattern was observed at 6 months, with no significant behavior-volume correlations.
Our results show a protracted development in the ability to distinguish between facial features that is predicted by different brain regions across age (AMY and potentially TE). They parallel the developmental trajectories of social visual engagement in human infants (Jones & Klin, 2013), and further validate rhesus monkeys as a translational model of early socioemotional development.

1 pm – 5 pm, Halls A-C, FF13

588. Visual Cortex: Development and Plasticity
Topic: A.08. Development of Motor, Sensory, and Limbic Systems

588.27 Developmental changes in visual processing of faces: A combined eye-tracking and resting state functional connectivity study in infant rhesus macaques


Yerkes Natl. Primate Res. Ctr., Dept. of Psychology, Emory Univ., Atlanta, GA; Dept. of Pediatrics, Dept. of Psychiatry and Behavioral Sci., Emory Univ. Sch. of Med., Atlanta, GA; Marcus Autism Ctr., Children's Healthcare of Atlanta, Atlanta, GA; Dept. of Behavioral Neurosci., Oregon Hlth. and Sci. Univ., Portland, OR; Dept. of Psychiatry, Univ. of North Carolina, Chapel Hill, GA

Abstract: The ability to attribute intentions and emotions in social interactions based on facial features (i.e. trustworthiness) is impaired in children with Autism Spectrum Disorder (ASD). Understanding the early developmental trajectories of this skill and the underlying brain circuits may further clarify the impaired socioemotional development in children with ASD. Due to limitations of repeated experiments of human infants, we are using a highly translational nonhuman primate model to characterize the early development of social and facial feature perception in parallel with the maturation of the underlying brain networks.
Eye-tracking (ET) data was collected longitudinally (14 times) from 1 week to 6 months in 16 male rhesus infants; here we are only presenting preliminary findings on those with MRI scans (n=6). In each session, monkeys were shown pairs of human faces, one with trustworthy (TW) and one with untrustworthy (UTW) facial features. Fixations to eyes, mouth and whole face were compared across TW or UTW faces. Structural and resting-state fMRI (rsfMRI) scans were acquired 7 times using a 3T MRI scanner. We mapped developmental changes in functional connectivity (FC) between insula (INS), amygdala (AMY), dorso-lateral prefrontal cortex, superior temporal sulcus and inferotemporal cortex (TE). Associations between ET and rsfMRI data were assessed via Pearson’s correlations.
At 2 weeks, there were no significant differences between fixations to TW and UTW regions; however greater looking to the TW faces was correlated with weaker FC between left INS and TE (r2=-0.99, p=.005). The ability to distinguish TW and UTW emerged by 8 weeks, when infants looked more to TW than UTW faces (p=0.04), effect driven by more fixation time to the TW than either UTW eyes (p=0.05) or TW mouth (p=0.05). Greater looking to the TW faces correlated with stronger FC between INS and AMY in the left hemisphere (r2=0.85, p=.003), whereas greater looking to the UTW faces correlated with stronger FC between these regions in the right hemisphere (r2=0.82, p=.047). This pattern was stable through 6 months of age, although at that age greater looking to UTW eyes was associated with weaker FC between right TE and INS (r2=-0.97, p=.002).
Our results suggest a protracted development in social and facial feature perception in infant rhesus macaques and underlying neural networks. These changes parallel typical development of preferential looking abilities in human infants (Jones & Klin, 2013). Results also showed a high conservation of brain regions responsible for facial feature perception in humans and macaques, further validating this model of early socioemotional development.

3 pm, Halls A-C, NN16

602. Adolescent Stress: Neurological and Neurobehavioral Outcomes
Theme F: Integrative Physiology and Behavior

602.07 Adolescent stress leads to enduring enrichment of inflammatory pathways in the hippocampus without peripheral immune consequences.


Emory Univ., Yerkes Natl. Primate Res. Ctr., Virginia Commonwealth Univ.

Abstract: Chronic adolescent stress (CAS) has previously been shown to prime the hippocampal inflammatory response in adult male rats; however, the underlying mechanism and origin are undefined. Here we tested the hypothesis that CAS exaggerates induction of the pro-inflammatory NF-kappa-B pathway in adult rat hippocampus without compromising the peripheral immune response. Male and female adolescent rats underwent a mixed-modality CAS paradigm or received no stress. Five weeks following the last stressor all rats received a single, systemic injection of either a low dose of lipopolysaccharide (LPS) or vehicle to unmask possible priming effects of CAS. Total RNA from the hippocampus was used to perform RNA-Seq and enriched transcriptional pathways were identified using gene set enrichment analysis. NF-kappa-B emerged as the most enriched pathway in CAS males and females compared to non-stressed controls following LPS. Targeted qPCR experiments further confirmed that CAS exaggerated the expression of I-kappa-B (F(1,105)=4.209, p=0.043), p65 (F(1,105)=5.262, p=0.024), and p52 (F(1,105)=8.186, p=0.005). To explore the underlying mechanisms of CAS-potentiated neuroinflammation, we tested whether CAS impaired glucocorticoid-mediated anti-inflammatory gene expression. Interestingly, CAS led to a marginal increase in the induction of the anti-inflammatory gene DUSP1 (F(1,105)=3.253, p=0.074), indicating partial anti-inflammatory compensation in CAS rats. CAS impacted neither LPS-induced NF-kappa-B activity in the spleen (F(1,57)=0.256, p>0.05) nor plasma IL-6 (F(1,58)=1.083, p>0.05) and TNF-alpha (F(1,43)=0.60, p>0.05), suggesting that the central effects of CAS on the NF-kappa-B pathway are independent of changes to the peripheral immune response. Collectively, our results indicate that chronic stress experienced during adolescence leads to long-lasting changes to the hippocampal genomic profile, and that the inflammatory consequences of CAS are specific to the brain.

1 pm – 5 pm, Halls A-C, TT18

614. Learning and Memory: Molecules and Mechanisms II
Topic: H.01. Animal Cognition and Behavior

614.06 Adolescent corticosteroid exposure disrupts decision-making, trkB, and cortico-limbic anatomy in adulthood

E. T. BARFIELD1,2,3,4, K. J. GERBER5, S. L. GOURLEY1,2,3,4 1

Yerkes NPRC, 2Dept. of Pediatrics, 3Grad. Program in Neurosci., 4Dept. of Psychiatry & Behavioral Sci., 5Mol. & Systems Pharmacol., Emory Univ., Atlanta, GA

Abstract: Prolonged exposure to elevated glucocorticoids, as occurs with chronic stress, disrupts the structure and function of cortico-limbic brain regions involved in decision-making, planning, and motivation, and impairs neurotrophin signaling that supports dendritic spine growth and plasticity. However, neurodevelopmental factors remain largely uncharacterized, despite evidence that adverse experiences during adolescence may be particularly impactful. Here, we tested the hypothesis that adolescents are vulnerable to the long-term neurobehavioral consequences of prolonged, elevated glucocorticoid levels. We exposed mice to the primary glucocorticoid, corticosterone (CORT), for 11 days and found that CORT exposure in early adolescence, but not adulthood, impaired goal-directed decision-making, biasing behavior towards stimulus-elicited habits, in adulthood. CORT exposure also disrupted the ratio of tyrosine receptor kinase B (trkB) isoforms throughout multiple cortico-limbic brain regions. Further, dendritic spine densities on excitatory pyramidal neurons in the orbital prefrontal cortex (oPFC) were reduced in adult animals with a history of adolescent CORT exposure. Additionally, goal-directed behavior was positively correlated with the density of mature, mushroom-shaped spines in the oPFC. Stimulation of trkB during adolescence blocked decision-making deficits in CORT-exposed mice. Finally, we examined how CORT±trkB stimulation impacted inputs to the oPFC, in particular those from the ventral hippocampus. Our findings indicate that adolescent CORT exposure induces long-term alterations in neuronal structure, function, and decision making. Pharmacological interventions that augment trkB signaling may be particularly efficacious in blocking enduring neurobehavioral deficits in adolescents exposed to chronic stress.



Posters for Wednesday Morning, November 15

8 am – noon, Halls A-C, D1

655. Limbic System Development
Topic: A.08. Development of Motor, Sensory, and Limbic Systems

655.10 Developmental outcomes of early adverse care on Amygdala functional connectivity and structure in nonhuman primates


1Neurosci., 2Yerkes Natl. Primate Res. Ctr., 3Ctr. for Translational Social Neurosci., Emory Univ., Atlanta, GA; 4Dept. of Psychiatry & Behavioral Sci., Emory Univ. Sch. of Med., Atlanta, GA; 5Univ. of Minnesota, Inst. of Child Develop., Minneapolis, MN; 6Dept. Of Behavioral Neurosci., Oregon Hlth. & Sci. Univ., Portland, OR; 7Section on Integrative Neuroimaging, NIH, Bethesda, MD; 8Dept. of Psychiatry, Univ. of North Carolina, Chapel Hill, NC

Abstract: Early life stress, including adverse caregiving experiences, is a major risk factor for psychopathology, and social and cognitive deficits. How maltreatment affects neurobehavioral development is not well understood and challenging to disentangle from heritable factors. This study utilized a well-established nonhuman primate model of spontaneous maternal maltreatment (MALT) leading to infant distress. In this model, the highest rates of abuse and rejection co-occur with rapid brain development and limbic maturation, leading to long-term effects on socioemotional behavior, and alterations in amygdala (AMYG) and white matter development. To disentangle the effects of experience from inheritance we used a unique cross-fostering design with random assignment of infants to control or maltreating foster mothers. This study delves into neurodevelopmental alterations underlying behavioral and stress outcomes, focusing on AMYG functional connectivity and structural development in the juvenile period. We collected (1) structural MRI in 42 infant rhesus (20 Control (11 F, 9 M), 22 MALT (8 F, 14 M)) during infancy (2 wks, 3, 6 mo) and juvenile period (12, 18 mo), and (2) resting state functional MRI to examine AMYG functional connectivity (FC) in a subset (13 MALT (6 F, 7 M) and 13 Controls (7 F, 6 M)). We have reported weaker prefrontal cortex-AMYG FC in MALT during development - we extend these studies to examine alterations in AMYG FC to other regions, performing a voxel-wise AMYG seed-based FC analysis at the group level. Stronger positive FC was found in MALT with regions regulating fear and processing socioemotional stimuli: right-left AMYG FC, periamygdaloid ctx, piriform ctx and superior temporal gyrus; brainstem- locus coeruleus, laterodorsal/dorsal tegmental areas, parabrachial complex, Inferior cerebellar peduncle and spinal vestibular nuclei. Stronger negative FC detected with the cerebellum in MALT (all results p<0.005, cluster threshold >2 voxels, uncorrected for multiple comparisons). Stronger FC between these regions in MALT suggest increased processing of socioemotional stimuli, especially related to fear-learning. Fear-potentiated startle studies in these animals, now adolescents, are consistent with this interpretation - MALT show elevated fear potentiated startle, and impaired discrimination of fear and safety cues, suggesting impaired fear regulation. Our group reported larger AMYG volumes in MALT during adolescence associated with increased emotional reactivity - we are extending these studies to examine the emergence of these effects on total brain, gray and white matter, cortical, and hippocampal and AMYG volumes.

11 am, Halls A-C, V2

668. Parkinson’s Disease: Circuit Mechanisms
Theme C: Neurodegenerative Disorders and Injury

668.16 Reduction of SPN firing by NMDAR blockade or DREADDs activation normalizes motor responses to dopamine in animal models of Parkinson’s disease.


Yerkes Natl. Primate Res. Ctr., Yerkes Natl. Primate Res. Center, Emory Univ., Emory Univ.

Abstract: Dopamine replacement is an effective treatment for motor dysfunction of Parkinson’s disease (PD). However, long-term dopaminergic therapy is associated with changes in motor responses and the development of involuntary movements known as L-Dopa-induced dyskinesia (LID). Studies in rodent and nonhuman primate (NHP) models, as well as in patients with PD, have shown that striatal projection neurons (SPNs) are hyperactive at the baseline parkinsonian state (“off” state). These neurons respond to dopaminergic stimulation with unstable firing changes at the peak of the response, which are associated with the expression of LID. This study was aimed at examining whether decreasing the baseline SPN firing rates towards the low activity found in normal conditions would reduce LID. The SPN activity was reduced “acutely” using local NMDAR blockade in NHP. A selective NMDAR antagonist (LY235959) was infused into one side of the putamen of advanced parkinsonian NHPs (n=3). In addition, the SPN activity was reduced “chronically” by expressing inhibitory DREADDs (designer receptor exclusively activated by designer drugs), hM4Di, in hemiparkinsonian rats. hM4Di is an engineered version of the M4 muscarinic receptor selectively activated by clozapine-N-oxide (CNO), which leads to hyperpolarization in neurons. We injected rAAV-hSyn-hM4D(Gi)-mCherry or the control virus rAAV-hSyn-GFP into the left striatum of rats with 6-hydroxydopamine lesions of the left medial forebrain bundle (n=9). The whole motor response and LID or AIMs (abnormal involuntary movements) were assessed using standardized rating scales for primates and rodents. Results showed that the striatal injection of NMDAR antagonist in the “off” state of NHP significantly reduced LID scores on the contralateral side without affecting the antiparkinsonian action of L-Dopa acutely. Also, activation of inhibitory DREADDs in rats significantly reduced AIMs during the chronic testing period of two weeks with daily treatment of L-dopa plus CNO. Virus transduction in the rat striatum was confirmed with histological examination. These results indicate that therapeutic strategies to reduce the hyperactivity of SPNs may help to control dyskinesias and improve motor responses to dopamine in patients with PD.

8 am – noon, Halls A-C, DD24

680. Somatosensory Cortex
Topic: D.04. Somatosensation: Touch

680.10 Functional tract tracing with intracortical microstimulation and intrinsic optical imaging can reveal distinct intracortical neural circuits within somatosensory cortex.


Div. of Neurosci., Oregon Hlth. & Sci. Univ. - ONPRC, Beaverton, OR; Interdisciplinary Inst. of Neurosci. and Technol., Zhejiang Univ., Hangzhou, China

Abstract: Electrical microstimulation has been used to modulate behavior, study the functional organization of the brain, and drive human brain-machine interfaces. However, how local and distant neural circuits are activated by electrical microstimulation is not well understood. We previously demonstrated that intrinsic optical imaging (IOI) can reveal cortical activity produced by intracortical microstimulation (ICMS) in primate somatosensory cortex (SI) (Brock et al. 2013, J Neurophys) and known anatomical projections between somatomotor cortical areas (Stepniewska et al. 2011 PNAS; Kudyba et al. 2013 SFN Abstr #495.21). Here, we report on the patterns of activation in finer detail. Data were obtained from rhesus and squirrel monkey SI. Following IOI mapping of digit representation in response to vibrotactile stimulation of the finger pads, an electrode was placed tangentially to the surface of cortex (20-30 degrees) and advanced in superficial layers across the digit representation in 200-300 μm steps. Trains of electrical stimulation (bipolar, 0.4 ms pulse width, 250 Hz, 250 ms, 15-100 μA) were applied and optical images were acquired. We found that small advances in the electrode position within the same cortical finger pad cortical representation could evoke different patterns of activation. These patterns are consistent with anatomical tracer studies which show clustering of anatomical connections in areas 3b and 1 (Négyessy et al. 2013 J Comp Neurol; Ashaber et al. 2014 J Comp Neurol; Negyessy et al. 2015 SFN Abstr #515.09). In summary, patterns of cortical activity evoked by ICMS are consistent with the idea that distinct modality specific intracortical networks underlie tactile feature extraction in SI.

8 am – noon, Halls A-C, SS63

707. Learning: From Model Systems to Modeling
Topic: H.01. Animal Cognition and Behavior


707.07 Impaired cognitive flexibility after neonatal perirhinal lesions in rhesus macaques


A.R. WEISS1,2, J. B. WHITE2, R. RICHARDSON2, J. BACHEVALIER2 1Oregon Hlth. and Sci. University/Onprc, Beaverton, OR; 2Emory University/YNPRC, Atlanta, GA

Abstract: Previous research showed that monkeys with neonatal perirhinal lesions (Neo-PRh) were impaired on working memory tasks that generated proactive interference, but performed normally on working memory tasks devoid of interference (Weiss et al., 2016, Front Sys Neurosci, 9:179), suggesting that working memory processes were spared after the Neo-PRh lesions. However, these findings also showed that Neo-PRh lesions may have disrupted cognitive processes important for resolving proactive interference, such as behavioral inhibition and/or cognitive flexibility. For example, increases in perseverative errors observed in the Neo-PRh animals could be due to failure to suppress the influence of previously acquired stimulus-reward associations (behavioral inhibition), resulting in repetitive tendencies. However, a second interpretation is that the impairment could be due to difficulty shifting attention towards new stimulus-reward associations (cognitive flexibility), resulting in a tendency to choose the previously rewarded stimulus. Lesion studies in monkeys have already demonstrated a double-dissociation between behavioral inhibition supported by the orbitofrontal cortex (OFC), and cognitive flexibility supported by the ventrolateral prefrontal cortex (vlPFC) (Dias et al., 1997, J Neurosci, 17:9285). Given that the PRh has interconnections with both of these cortical areas (Suzuki, 1996, Op Neurobiol, 6:179), it is possible that the PRh also may play a role in mechanisms underlying behavioral inhibition and/or cognitive flexibility. To distinguish between these two possible explanations, we characterized the ability of the same Neo-PRh monkeys to perform a task that taps both capacities: the Intradimensional-Extradimensional set-shifting paradigm. The results indicated that Neo-PRh monkeys completed the simple and compound discrimination stages, the intradimensional shift stage, and all reversal stages (measuring behavioral inhibition) comparably to controls, but made significantly more errors on the extradimensional shift stage of the task (measuring cognitive flexibility) as compared to age- and experience-matched controls [t(9)=-2.320, p=0.045]. These data demonstrate that impaired cognitive flexibility is the likely source of increased perseverative errors made by the same Neo-PRh monkeys when performing WM tasks, rather than impaired behavioral inhibition, and imply that the perirhinal cortex may play a unique and critical role in the development of attentional set shifting abilities supported by the vlPFC. This work was supported by grants MH-58846 and NSF-GRFP DGE-1444932.



Posters for Wednesday Afternoon, November 15

1 pm – 5 pm, Halls A-C, N10

757. Cellular Mechanisms of Parkinson's Disease I
Topic: C.03. Parkinson’s Disease

757.10 Synaptic Inputs to GABAergic Interneurons in the ventral motor thalamus of nonhuman primates: A comparative analysis between control and MPTP-treated parkinsonian monkeys.


1Yerkes Natl. Primate Res. Ctr., 2Neurol., Emory Univ., Atlanta, GA; 3Udall Ctr. of Excellence for Parkinson's Dis. at Emory Univ., Atlanta, GA

Abstract: Local circuit GABAergic interneurons comprise nearly one third of all neurons in the primate motor thalamus, while they are almost non-existent in the rodent motor thalamus. Despite their abundance in primates, almost nothing is known about their synaptic connectivity and functional role in thalamic processing. Defining the source(s) of their presynaptic inputs is a prerequisite to a deeper understanding of the cellular mechanisms through which they integrate and regulate the thalamic microcircuitry and thalamocortical systems. Although there is evidence for dysregulation of motor thalamic activity in MPTP-treated parkinsonian monkeys and Parkinson’s disease patients, the underlying substrate of these changes remains poorly understood. Thus, to determine if changes in the innervation of thalamic interneurons might potentially contribute to these pathophysiological changes, we used electron microscopy to quantify the numbers, types and potential sources of axon terminals in contact with dendrites of interneurons in the ventral motor thalamus of healthy and parkinsonian (MPTP-treated) rhesus macaques. Interneuron dendrites were defined by their ultrastructural features (i.e. presence of synaptic vesicles) and immunoreactivity for GABA. For this study, we focused on both the basal ganglia- and cerebellar-receiving territories of the motor thalamus, which were analyzed separately in both healthy and MPTP-treated conditions. The bulk of axon terminals in these thalamic nuclei include: (1) AS1: small-sized, putative glutamatergic, single asymmetric synapse, mostly from the cerebral cortex, (2) AS2: large-sized, putative glutamatergic, multiple asymmetric synapses, mostly from the cerebellum (3) S1: GABAergic, single symmetric synapse, likely from the reticular nucleus and GABAergic interneurons (4) S2: GABAergic, multiple symmetric synapses, from GPi. Preliminary data from control monkeys indicate that dendrites of GABAergic interneurons are frequently contacted by AS1 terminals and more rarely by S1 and S2 boutons, suggesting a dense innervation from corticothalamic cells. This ongoing work highlights GABAergic interneurons as a target of extrinsic glutamatergic and GABAergic inputs to the primate ventral motor thalamus. As interneurons are likely to functionally contribute to the regulation of motor thalamic processing in primates, their absence in rodents raises important species differences in thalamic function and dysfunction in normal and diseased states.

4 pm, Halls A-C, N12

757. Cellular Mechanisms of Parkinson’s Disease I
Theme C: Neurodegenerative Disorders and Injury

757.12 Structural plasticity of GABAergic and glutamatergic inputs to the ventral motor and caudal intralaminar thalamic nuclei in MPTP-treated Parkinsonian monkeys.


Yerkes Natl. Primate Res. Ctr., Emory Univ., Sch. of Med.

Abstract: In primates, the parvocellular part of the ventral anterior nucleus (VApc) and the centromedian nucleus (CM) are the main thalamic targets of sensorimotor inputs from the internal globus pallidus (GPi). Cortical glutamatergic terminals, as well as GABAergic inputs from the reticular nucleus and interneurons are other major sources of afferents to these nuclei. In MPTP-treated parkinsonian monkeys, thalamic cells in VApc display significant alterations in their rate, pattern, and oscillatory firing properties. In other component nuclei of the basal ganglia-thalamocortical circuitry, parkinsonism-related functional changes are associated with substantial remodeling of specific synaptic microcircuits. Thus, to examine whether such structural alterations also affect the thalamic components of the circuitry, we used light- and electron microscopy as well as tract tracing methods to assess potential changes in the GABAergic and glutamatergic synaptic networks of the VApc and CM in parkinsonian monkeys. At the light microscopic level, the intensity of immunostaining for GABAergic markers, vGAT and GAD67, in VApc and CM was not significantly different between normal and parkinsonian monkeys. At the electron microscopic level, we identified 3 major types of terminals in VApc and CM: (1) terminals forming putatively glutamatergic, asymmetric synapses (AS), which originate mostly from the cerebral cortex, (2) terminals forming single symmetric synapses (S1), likely representing GABAergic inputs from the reticular nucleus and GABAergic interneurons, and (3) terminals forming multiple symmetric synapses (S2), likely associated with GABAergic inputs from GPi. The density of AS terminals far outnumbered that of S1 and S2 terminals in VApc and CM of normal and parkinsonian monkeys. The density of AS terminals was significantly decreased in the VApc of MPTP-treated monkeys, while the density of S1 and S2 terminals remained unchanged. The pattern of synaptic connectivity of these terminals with thalamocortical (TC) neurons was not significantly different between control and parkinsonian monkeys. In addition to TC cells, the three types of terminals targeted vesicle-filled dendrites of GABAergic interneurons. Individual S2 terminals often formed synapses with dendrites of both TC cells and interneurons. Analysis of these relationships in parkinsonian monkeys is in progress. In line with data from the striatum and the subthalamic nucleus, our findings suggest that plasticity of the corticothalamic system may also contribute to the pathophysiology of the basal ganglia-thalamocortical systems in parkinsonism.

1 pm – 5 pm, Halls A-C, II24

782. Neural Control of Social Interactions: Parental Behavior
Topic: F.02. Behavioral Neuroendocrinology

782.18 Deserted prairie vole mothers: Unaltered maternal investment but increased emotionality due to heightened brain CRF system activity.


1Univ. of Regensburg, Regensburg, Germany; 2Yerkes NPRC and Ctr. for Translational Social Neurosci., Emory Univ., Atlanta, GA

Abstract: Human families often consist of a bonded couple in which the pair cooperate in rearing the offspring. When the father leaves the family, the prevalence of depression and anxiety disorders in mothers increases perhaps due to increased childcare responsibilities and reduced social support. To study the behavioral and emotional consequences of mate desertion we used biparental, socially monogamous prairie voles. Previous work has shown that sudden separation of the bonded partners leads to increased passive stress-coping, indicative of depressive-like behavior, and signs of chronic stress in both female and male prairie voles (Bosch et al., 2009 NPP; 2016 PNEC; McNeal et al., 2014 Auton Neurosci). However, the emotional and behavioral consequences of separation in lactating prairie vole mothers are unknown. Here, sexually naïve prairie vole pairs were cohoused over 18 days, after which half of the pairs (n = 6 / group) were separated by removing the male. All females became pregnant and gave birth. Following parturition, there were no group differences in pup directed behaviors, e.g., arched back nursing or licking / grooming the pups. However, anxiety-related behavior on the elevated plus maze (p = 0.035) as well as passive stress-coping behavior in the forced swim test (p = 0.028) were significantly elevated in separated mothers. In situ hybridization revealed that CRF mRNA was increased in the PVN after separation under basal conditions (p = 0.047). In a second cohort of animals, females were fitted with an intracerebroventricular guide cannula on the day of separation. On the experimental days, females were acutely infused with vehicle (2 μl Ringer’s solution; paired (n = 6) and separated females (n = 7)) or the nonspecific CRF receptor antagonist D-Phe (2 μg / 2 μl; separated females (n = 7)) 10 min prior to behavioral testing. The brief restraining during acute treatment infusion led to a significant decrease in arched back nursing in both paired and separated vehicle-treated groups compared to the separated D-Phe-treated group (p < 0.01), in which the behavior was unchanged compared to pre-treatment levels. Furthermore, in the separated females the increased anxiety-related behavior (p < 0.01) and passive stress-coping (p < 0.01) was back to normal levels (paired, vehicle-treated) after treatment with D-Phe. In conclusion, maternal investment is robust enough to withstand loss of a pair bonded partner, whereas the mothers’ emotionality is negatively impaired and potentially mediated by a CRF-dependent mechanism. This animal model has potential for mechanistic studies of the behavioural and physiological consequences of partner loss in single mothers.

1 pm – 5 pm, Halls A-C, II26

782. Neural Control of Social Interactions: Parental Behavior
Topic: F.02. Behavioral Neuroendocrinology

782.20 Fatherhood alters gene expression within the MPOA

A. M. SEELKE1, J. M. BOND1, D. STOLZENBERG1, M. RHEMTULLA1, K. L. BALES1,2 1Dept. of Psychology, Univ. of California Davis, Davis, CA; 2California Natl. Primate Res. Ctr., Univ. of California, Davis, Davis, CA

Abstract: Parental care, and especially maternal care, is a common behavioral characteristic of mammals. Female parenting is obligate because mammalian offspring need to nurse, but fathering behavior among mammals is rare. Only 3-5% of mammalian species exhibit biparental care. A great deal is known about the neural and hormonal mechanisms underlying maternal behavior, but the mechanisms of fathering behavior are less clear. Here we attempt to identify new targets involved in the regulation of fathering behavior using RNA sequencing. Subjects were male prairie voles that experienced one of three social conditions: virgin males, pair bonded males, and males with fathering experience. Tissue punches were taken from the medial preoptic area (MPOA) and RNA was extracted. The RNA was sequenced, and sequences were compared between groups to identify genes that were differentially expressed in fathers. The top 500 differentially expressed genes from each comparison (i.e., Virgin vs Paired, Virgin vs Fathers, and Paired vs Fathers) were evaluated using the Gene Ontology enrichment analysis. Further analysis entailed the use of Kegg Pathways to reveal metabolic pathways associated with specific differentially expressed genes. Using these tools, we identified 23 genes within the MPOA that are differentially expressed in voles with fathering experience, including Adora2a, Chrm1, Gabrd, Grin2a and Grin2b, and Kcnj2 and Kcnj4. These genes are involved in a variety of processes ranging from immune function and metabolism to learning and memory and the remodeling of dendritic spines. The identification of these genes will lead to novel insights into the biological basis of fathering behavior.

1 pm to 5 pm, Halls A-C, JJ13

783. Neural Control of Social Interactions: Role of Oxytocin and Vasopressin
Topic: F.02. Behavioral Neuroendocrinology

783.11 Peripheral methylation of macaque OXT and OXTR genes, oxytocin levels in cerebrospinal fluid, and social behavior

D. DE LEON1, S. NISHITANI1, H. WALUM1, K. MCCORMACK2, J. ROGERS3, M. WILSON1, A. SMITH1, L. YOUNG1, M. SANCHEZ1 1Yerkes NPRC, Emory Univ., Atlanta, GA; 2Spelman, Atlanta, GA; 3Baylor Col. of Med., Houston, TX

Abstract: Oxytocin (OXT) is a neuropeptide well-known to modulate social behavior across many mammalian species. The action of OXT is mediated by its receptor, which is encoded by the gene OXTR. DNA methylation of the OXT and OXTR genes is variable in humans, and peripheral measures of their methylation have been linked to variability in social behaviors and neural endophenotypes. Because OXTR on hypothalamic OXT neurons can regulate OXT release, here we examine the relationship between OXTR and OXT methylation on concentrations of OXT in cerebrospinal fluid (CSF) and social behavior in rhesus macaques. Behavioral, genetic, and physiological data (in blood and CSF) were collected from 192 socially-housed rhesus macaques. For the first time, we report a similar pattern of CpG sites in the promoter region of the OXT gene and the MT2 region of the OXTR gene of rhesus macaque and human. Using regression analyses, we did not detect a statistically significant association between methylation of individual OXT or OXTR CpG sites and CSF OXT concentration that survived correction for multiple comparisons. Before corrections, methylation of one OXTR CpG site (-717bp from transcription start site), explained less than 1.69% of the variance in OXT CSF levels (p=0.013). This site was also associated initially with some measures of social behavior (increased proximity to other animals and decreased anxiety) before multiple comparison corrections. Two other CpG sites (-778 and -999bp from transcription start site) explained 1.75% of the variance (p=0.025), such that increased methylation was associated with increased OXT CSF levels but had no associations with social behavior. Because none these associations survive correction for multiple comparisons, if there is any relationship between methylation of these genes in blood and OXT CSF or social behavior, the effect size is too small to be detected reliably with this sample size and would need to be replicated in additional studies. These results do not support the hypothesis that blood methylation of OXT or OXTR are associated with CSF OXT concentration or social behavior in rhesus macaques. It is possible, though, that methylation of these loci in the hypothalamus or in cheek epithelia may be associated with central OXT release and behavior.

2 pm, Halls A-C, MM8

786. Sexual Differentiation
Theme F: Integrative Physiology and Behavior

786.30 Estradiol modulates hypothalamic POMC neurotransmssion.


Oregon Hlth. & Sci. Univ., Oregon Natl. Primate Res. Ctr.

Abstract: Compared to men, women face a reduced risk of developing metabolic disorder. However, around menopause this benefit is lost, suggesting that 17β-estradiol confers a protective effect. Energy balance is regulated by the anorexigenic proopiomelanocortin (POMC) and orexigenic neuropeptide Y/agouti-related protein (NPY/AgRP) neurons of the hypothalamic arcuate nucleus (ARH). These two populations respond differentially to circulating factors such as blood glucose, insulin, and leptin. Reciprocal connections also enable them to modulate each other’s excitability; yet, little is known about POMC inputs to NPY/AgRP. Considering POMC neurons release both excitatory (glutamate and α-MSH) and inhibitory (GABA and β-endorphin) neurotransmitters, they are well positioned to maintain homeostasis. We used optogenetic stimulation of POMC neurons in hypothalamic slices to examine evoked release onto NPY/AgRP neurons. POMCCre and Ai32 mice were crossed to produce cell-type specific expression of a channelrhodopsin/fluorophore fusion protein (ChR2::EYFP) in POMC neurons. Female mice were ovariectomized (OVX) 7-10 days prior to experiments and given oil or 17β-estradiol benzoate (EB) injections while males were left intact. NPY/AgRP cells were targeted for recording based on location within the ARH, soma size and electrophysiological characteristics. At the end of recording, cells were harvested and identified posthoc based on single cell RT-PCR. GABA, glutamate, and mixed postsynaptic currents were measured in response to paired pulses (PPR, 50 ms interstimulus interval). Outward GABA currents were antagonized by bicuculline and glutamatergic inward currents by CNQX and AP5. Interestingly, the release probability was elevated in EB-treated versus OVX female mice, as indicated by a significant decrease in the paired pulse ratio (p<0.01). Males exhibited an intermediate response, not significantly different from the PPR of either female group. As high frequency-mediated glutamate release inhibits NPY/AgRP neurons via activation of group II metabotropic glutamate receptors (Nestor et al., Mol Endo 2016), these results suggest that estradiol enhances the efficacy of POMC projections, contributing to the anorexigenic effects of estrogens.

4 pm, Halls A-C, NN23

788. Reward: Dopamine, Pharmacology, and Pathophysiology
Theme G: Motivation and Emotion

788.08 Dopamine release reflects both predictive value of a discriminative stimulus and satiety state.


Univ. of North Carolina at Chapel Hill, Oregon Natl. Primate Res. Center, OHSU, Albert Einstein Col. of Med.

Abstract: Binge eating disorder (BED) is the most prevalent eating disorder in epidemiologic studies in the U.S and has been strongly associated with obesity. People with BED eat non-nutritious food in large quantities outside of regular meal times. Understanding the neural foundations of hedonic processes is particularly relevant for BED, but a pertinent question to understanding both eating disorders and obesity remains unanswered: how do stimuli associated with high-calorie food drive consumption in the absence of homeostatic need? To address that question, we used a simple task involving two discriminative stimuli: one (DS+) predicting availability of high-caloric food and the other not (DS-). Animals learned to approach the reward cup for an aliquot of unsweetened heavy cream when the DS+, but not the DS-, was presented. After training, fast-scan cyclic voltammetry was used to follow dopamine dynamics in the nucleus accumbens core during the DS task. Preliminary results found that dopamine transients occurred at the onset of the DS+ but not the DS-. Moreover, dopamine release to the food-predictive DS+ was higher when rats were food restricted than when the same rats were sated; in contrast, the lack of dopamine response to the DS- was unaffected by satiety status. These results indicate that cue-evoked dopamine is modulated by satiety state. Further analyses are underway to examine the relationship between cue-evoked dopamine and the probability of behavioral responding to the DS+.



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