“High Profile Diseases” are written by individual NPRC Core Scientists who are experts in the specific subject of each article. Before publication on the website, each article is reviewed by representatives of all seven NPRCs.
Melissa Bauman, Kathy West and Jeff Roberts (CNPRC)
I. Autism Spectrum Disorder
Autism spectrum disorder (ASD) refers to the wide range of symptoms, skills, and levels of impairment or disability that individuals with ASD can have. Symptoms can include persistent deficits in social communication and social interaction across multiple contexts and/or restricted, repetitive patterns of behavior, interests, or activities. There remains relatively little understanding of the underlying cause(s) and few options for therapeutic interventions, and there is a critical need for preclinical animal models to evaluate risk factors and develop novel therapeutic interventions for ASD.
Developing valid animal models has proven exceptionally challenging for complex behaviorally-defined disorders such as ASD, where the varied symptoms are difficult to model. However, a number of the National Primate Research Centers are developing nonhuman primate models to investigate the diverse causes of ASD, and to develop and test the safety and efficacy of novel treatments.
II. Evaluating Prenatal Risk Factors for Autism and Other Neurodevelopmental Disorders
Laboratories at the California and Wisconsin National Primate Research Centers (NPRC) are directly evaluating prenatal risk factors for neurodevelopmental disorders.
1. Maternal Immune Activation Models
Epidemiological studies reveal that women exposed to viral, bacterial or parasitic infections during pregnancy have an increased risk of having a child that later develops a neurodevelopmental disorder, such as autism or schizophrenia. The diversity of maternal infections reported in the human studies suggests that the maternal immune response to infection, rather than a specific pathogen, is the critical link between sickness in the mother and altered neurodevelopment in her child.
Investigators at the Wisconsin NPRC report that rhesus offspring born to mothers exposed to influenza in the early third trimester demonstrate reduced gray matter volume throughout the cortex and increased white matter in the parietal cortex at 1 year of age (1). This research team has also described brain enlargement and increased behavioral and cytokine reactivity in infant monkeys following acute prenatal endotoxemia (i.e., the presence of bacterially-derived endotoxins in the blood) (2).
At the California NPRC, investigators have evaluated the effects of stimulating the maternal immune response with a viral nucleci acid mimic, polyIC, at the end of the first or second trimester. The macaque offspring exposed to prenatal immune challenge in utero differ from control offspring in measures of the core diagnostic symptoms of ASD: repetitive behaviors, vocal communication and social interactions. The treated offspring also failed to attend to salient social cues in an eye-tracking study, which closely parallels clinical findings from human with ASD (3, 4, 5).
Collectively, these studies suggest that prenatal exposure to immune challenge can result in long lasting brain and behavioral changes in the offspring. Translational animal models provide a powerful tool to systematically examine the consequences of prenatal immune challenge on brain and behavioral development of the offspring.
2. Maternal Antibody Model
Investigators at the California NPRC have evaluated one immune-based mechanism implicated in ASD – maternal autoantibodies directed towards proteins in the developing fetal brain. Approximately 23% of mothers who have given birth to a child with ASD produce autoantibodies to fetal brain proteins that are critical for neurodevelopment, raising the possibility that maternal autoantibodies cross the placenta during gestation, interact with fetal brain protein targets, alter neurodevelopment, and lead to one form of ASD. Macaque offspring prenatally exposed to the autism-specific maternal antibodies taken from the human mothers of children with ASD developed abnormal social behavior that paralleled features of human ASD symptomatology. The male monkeys prenatally exposed to autism-specific maternal antibodies had larger total brain volume compared to control males, a finding that parallels neuroimaging data from human children prenatally exposed to these same maternal antibodies. Efforts are underway to identify the mechanism of prenatal insult as well as the resulting cellular and molecular neuropathology accompanying prenatal exposure to the brain-reactive maternal autoantibodies (6).
III. Developing Novel Therapeutic or Pharmacological Interventions
While intensive behavioral intervention delivered early in life improves social functioning for some children with ASD, current pharmacological treatments are limited to targeting only peripheral symptoms such as aggression, anxiety, and depression. Novel pharmacological interventions specifically targeting social behavior delivered in parallel with behavioral intervention holds the promise of improving quality of life for many individuals with ASD. Development of pro-social pharmacological treatments will depend upon the successful translation of basic neuroscience research into safe and effective medicines and will require the use of sophisticated animal models. While current ASD drug discovery efforts have relied primarily upon mouse models to evaluate compound efficacy, pharmacological interventions targeting the complex social and communication deficits of ASD may ultimately require the use of an animal model more closely related to humans.
Although nasal oxytocin therapy is being promoted as a “safe and promising” therapy for ASD, we know very little about the safety, efficacy or mechanism of oxytocin treatment in humans. Investigators at the California NPRC are currently exploring the safety of long-term intranasal oxytocin pediatric use using another nonhuman primate species – the titi monkey (Callicebus cupreus). These monkeys live in monogamous family groups that consist of the parents and their offspring. The CNPRC titi monkeys are the only laboratory colony in the world. The preliminary results (from studies in rodents) of the research-to-date show a potentially adverse effect on the long-term health with chronic pediatric use of intranasal oxytocin (7).
Investigators at Yerkes NPRC are exploring the effects of intranasal oxytocin on social perception in rhesus monkeys. This line of research suggests that intranasal oxytocin alters the evaluation of social stimuli in rhesus monkeys, similar to humans (8,9).
IV. Comparative neuroanatomy in human and nonhuman primates
Another line of research at the CNPRC being conducted is with a novel protocol developed to understand the biology and etiology of ASD. The method uses selective oxytocin receptor ligands to locate and map oxytocin receptors in rhesus monkey and human brain samples. The oxytocin receptor and the closely related vasopressin 1a receptor have also been mapped in brain tissue from the titi monkey.
These two nonhuman primate species have been found to express the oxytocin receptor in areas that are important for visual, auditory, and multimodal sensory processing. This distribution is distinct from rodent brain tissue, where oxytocin receptors are concentrated in areas that process olfactory information. This research provides insights into the neural mechanisms by which oxytocin modulates social cognition and behavior in primates, which, like humans, uses vision and audition as the primary modalities for social communication.
The information gained from the titi monkey studies has led to further studies using the same novel techniques in identifying receptor locations in post-mortem brain tissue from individuals with autism and matched neurotypical controls. The titi monkeys are also being used to evaluate an innovative protocol to noninvasively map the oxytocin receptors in living animals using PET scanning technology. These techniques will for the first time inform us where the human brain has these important receptors and will validate and vastly increase our understanding of primate models for treatment and causes of autism (10,11).
1. Short SJ, Lubach GR, Karasin AI, Olsen CW, Styner M, Knickmeyer RC, et al. (2010): Maternal influenza infection during pregnancy impacts postnatal brain development in the rhesus monkey. Biol Psychiatry. 67:965-973. PMCID: PMC3235476
2. Willette AA, Lubach GR, Knickmeyer RC, Short SJ, Styner M, Gilmore JH, et al. (2011): Brain enlargement and increased behavioral and cytokine reactivity in infant monkeys following acute prenatal endotoxemia. Behavioural brain research. 219:108-115. PMCID: PMC3662233
3. Bauman MD, Iosif AM, Smith SE, Bregere C, Amaral DG, Patterson PH (2014): Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring. Biol Psychiatry. 2014 Feb 15;75(4):332-41. doi: 10.1016/j.biopsych.2013.06.025. Epub 2013 Sep 5. PMID: 24011823
4. Weir, RK, Forghany, R., McAllister, AK, Smith, S.E., Patterson, P.H., Schumann, CM, and Bauman, MD (2015). Preliminary evidence of neuropathology in nonhuman primates prenatally exposed to maternal immune activation. Brain Behav Immun. Aug;48:139-46. doi: 10.1016/j.bbi.2015.03.009. Epub 2015 Mar 24. PMID: 25816799
5. Machado, CJ, Whitaker, AW, Smith, SEP, Patterson, PH and Bauman, MD (2014). Maternal immune activation in nonhuman primates alters social attention in juvenile offspring. Biol Psychiatry. May 1;77(9):823-32. doi: 10.1016/j.biopsych.2014.07.035. Epub 2014 Aug 30. PMID: 25442006
6. Bauman MD, Iosif AM, Ashwood P, Braunschweig D, Lee A, Schumann CM, Van de Water, J, Amaral, DG. (2013): Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey. Transl Psychiatry. Jul 9;3:e278. doi: 10.1038/tp.2013.47. PMCID: PMC3731783
7. Miller M, Bales KL, Taylor SL, Yoon J, Hostetler CM, Carter CS, and Solomon M. Oxytocin and vasopressin in children and adolescents with autism spectrum disorders: sex differences and associations with symptoms. Autism Res 6: 91-102, 2013. PMCID: PMC3657571, PMID 23413037
8. Modi ME, Connor-Stroud F, Landgraf R, Young LJ, Parr LA. Aerosolized oxytocin increases cerebrospinal fluid oxytocin in rhesus macaques. Psychoneuroendocrinology. 2014 Jul;45:49-57. doi: 10.1016/j.psyneuen.2014.02.011. Epub 2014 Mar 3. PMID 24845176
9. Parr LA, Modi M, Siebert E, Young LJ. Intranasal oxytocin selectively attenuates rhesus monkeys' attention to negative facial expressions. Psychoneuroendocrinology. 2013 Sep;38(9):1748-56. doi: 10.1016/j.psyneuen.2013.02.011. Epub 2013 Mar 13. PMID:23490074
10. Freeman SM, Inoue K, Smith AL, Goodman MM, Young LJ. The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta). Psychoneuroendocrinology, July:45:128-141, 2014. PMCID: PMC4043226
11. Freeman SM1, Walum H2, Inoue K2, Smith AL3, Goodman MM3, Bales KL4, Young LJ2. . Neuroanatomical distribution of oxytocin and vasopressin 1a receptors in the socially monogamous coppery titi money (Calicebus cupreus). Neuroscience. 2014 Jul 25;273:12-23. doi: 10.1016/j.neuroscience.2014.04.055. Epub 2014 May 9. PMCID: PMC4083847
Andari E, Nishitani S, Kaundinya G, Caceres GA, Morrier MJ, Ousley O, Smith AK, Cubells JF, Young LJ
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Bauman MD, Van de Water J
Translational opportunities in the prenatal immune environment: Promises andlimitations of the maternal immune activation model.
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Liu J, Shelkar GP, Gandhi PJ, Gawande DY, Hoover A, Villalba RM, Pavuluri R, Smith Y, Dravid SM
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