Autism spectrum disorder (ASD) is characterized by social impairments and affects 1 in 68 US children, but remains poorly understood. Few biomarkers of ASD have been identified, hindering the understanding of its basic biology; nor are there any medications that treat the social deficits of ASD. Progress has been impeded by: 1) the difficulty of obtaining relevant tissue samples from patients and matched controls, and 2) in mouse models, the discordance between complex human behavior and laboratory-based mouse behavior, even with shared genetic etiologies. These two limitations underscore the tremendous value in developing an animal model of social deficits with more reliable behavioral and biological correlates to the human disease. Rhesus monkeys are an ideal model organism. Like humans, they are highly social, and both species display stable and pronounced individual differences in social functioning. At the behavioral extremes, low-social compared to high-social male rhesus monkeys initiate fewer affiliative interactions and display more inappropriate social behavior, suggesting both lower social motivation and poorer social skills. Naturally occurring low-social behavior in male rhesus monkeys therefore presents an exceptional opportunity to study the biology of social impairments. This research leverages a novel statistical classification model which predicts, from infant behavior, subjects that are subsequently found to be low-social or high-social. On the basis of promising pilot data, we will collect quantitative social behavior data in a larger validation cohort of 1-5 year old male monkeys to confirm the discriminant power of this statistical model to be used as a robust high-throughput screening tool to rapidly identify social extremes in a large population. We will also test whether: our candidate biomarkers of social functioning (e.g., oxytocin and arginine-vasopressin; kinase signaling) correctly classify monkeys as low- social vs. high-social; the degree of biomarker dysregulation co-varies with the degree of social deficits; and cerebrospinal fluid and blood measures are equally informative. Because exclusion of females may impede identification of important disease mechanisms, we will also test, for the first time, whether our statistical classification model can be used to identify social extremes in female monkeys, and whether the same or different biomarkers predict social deficits in low-social females. Finally, we will create the first primate social behavior test battery to better characterize the impairments of low-social monkeys with direct relevance to core autism symptoms (e.g., deficits in joint attention, face recognition, social learning, social competence, theory of mind, peer preferences). Creation of this battery will also allow us to test which biomarker measurements most robustly predict low-social monkey test performance to identify the most promising targets for therapeutic intervention. We are optimistic that further development of this model will accelerate the discovery of autism biomarkers and novel druggable targets, provide non-behavioral biometrics for treatment response, and streamline the development of the first effective autism therapeutics.

Public Health Relevance

This project will: 1) validate the efficacy of a high-throughput screening tool to rapidly identify individuals with naturally occurring social impairments in a lare monkey population; 2) create the first standardized primate social behavior test battery with face validity to core autism symptoms; 3) confirm that abnormal neurochemical signaling implicated in autism patients is also associated with monkey social deficits; and 4) identify which biomarker measurements most robustly predict test performance in socially impaired monkeys. Further development of this model will allow us to identify the most promising biological targets for intervention and to test novel medications to improve social functioning in monkeys that ultimately stand to benefit autism patients.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD087048-04
Application #
9606378
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Kau, Alice S
Project Start
2015-12-15
Project End
2020-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Parker, Karen J; Garner, Joseph P; Oztan, Ozge et al. (2018) Arginine vasopressin in cerebrospinal fluid is a marker of sociality in nonhuman primates. Sci Transl Med 10:
Capitanio, John P (2017) Naturally Occurring Nonhuman Primate Models of Psychosocial Processes. ILAR J 58:226-234
Sclafani, Valentina; Del Rosso, Laura A; Seil, Shannon K et al. (2016) Early Predictors of Impaired Social Functioning in Male Rhesus Macaques (Macaca mulatta). PLoS One 11:e0165401