Neurobiology of social behavior

Principal Investigator:  David G. Amaral, Ph.D.

The primate amygdaloid complex is an important component of the brain system involved in mediating appropriate species-specific behaviors such as threat and defense. This program of studies uses sophisticated neurobiological and behavioral methods to reassess the role of the primate amygdala in normal social interaction. The research is carried out in the context of a long-standing program of neuroanatomy which has demonstrated that the amygdala receives sensory information from widespread regions of the cortex. Over the last ten years, my laboratory has carried out neuroanatomical analyses of the macaque monkey amygdala. More recently both behavioral and electrophysiological studies of the macaque monkey amygdala have been inaugurated. These studies have been focused on the amygdala's role in social behavior and in the interpretation of facial expressions. This research program has been expanded to include investigations of the brain systems associated with autism. These studies will provide important insights into the neurobiology of normal social behavior and may contribute to an understanding of the pathologies of social communication in disorders such as autism.

A novel, transient inactivation technique for studying the primate social brain

Principal Investigators:  David G. Amaral, Ph.D. and Christopher J. Machado, Ph.D.

Electrophysiological recordings and brain lesions have been the most common methods used to identify and dissociate the function of brain structures in animal models. However, these techniques can result in unintended damage and compensatory functional reorganization, both of which complicate the interpretation of behavioral results. There are also methods for temporarily manipulating brain function in animal models, but all options currently available require repeated injections into the brain and/or permanent cranial implants, both of which cause physical trauma and preclude long-term study of awake, behaving animals. A new pharmacogenetic technique, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), has just emerged over the past few years and offers a minimally-invasive means to control brain function during long-term studies. Viral vectors transfect neurons in specific areas with a DREADD gene. These novel receptors are triggered by intravenous or oral administration of a nontoxic molecule called clozapine-N-oxide (CNO). Activation or inactivation of neural activity occurs within 15 minutes after CNO administration and lasts for up to 9 hours. This technique has been successfully used to study complex behavioral patterns in rodents, but has never been used in nonhuman primates, the model of choice for studying the neurobiology of social behavior. The overall objective of this study is to implement DREADD-based transient inactivation in the nonhuman primate amygdala. We plan to first demonstrate the utility of this technique by measuring the effect of the inactivation in paradigms known to be sensitive to permanent amygdala lesions, including fear learning and social interactions. We will then use eye-tracking techniques to measure how amygdala dysfunction influences visual scan paths with social stimuli.

Prenatal risk factors for schizophrenia:  An evaluation of brain neuropathology in an animal model of maternal immune activation

Principal Investigator:  Melissa D. Bauman, Ph.D.

Schizophrenia is a devastating brain disorder that affects approximately 1% of the population worldwide. While the cause of schizophrenia remains unknown, prenatal exposure to certain environmental factors may increase the risk of developing schizophrenia later in life. We know, for example, that children who are born to mothers that experience infection during pregnancy have an increased risk of developing schizophrenia. Although the association between maternal infection and an increased risk of schizophrenia is compelling, there are many unanswered questions.  How does maternal infection alter fetal brain development? Are certain gestational time points more vulnerable than others?  What steps can be taken to decrease deleterious effects if a woman becomes ill during pregnancy?  Animal models are playing an essential role in answering these questions.  This study will determine what aspects of brain development are altered following prenatal immune challenge, compare the neuropathology of the animal models to neurpathological features of human schizophrenia, and identify future preventative and/or therapeutic strategies for schizophrenia.

Efficacy of a novel neuroprotective compound in nonhuman primates

Principal Investigators:  Melissa D. Bauman, Ph.D. and Andrew Pieper, M.D., Ph.D., University of Iowa

This project is designed to provide additional support for a novel class of molecules demonstrating neuroprotective effects in rodent models.  Preclinical proof of principle in a nonhuman primate model could provide an opportunity to translate basic science into a new therapeutic approach for patients suffering from both neuropsychiatric and neurodegenerative diseases involving diminished hippocampal neurogenesis and/or broader neurodegeneration.

Translating behavioral assays from animal models of clinical populations

Principal Investigator:  Melissa D. Bauman, Ph.D.

There is a critical, and currently unmet, need for sophisticated animal models to evaluate potential pharmacologic treatments targeting the core social and communication deficits of autism spectrum disorders (ASD).  Although comparisons of efficacy across species pose a major hurdle in treatment discovery, UC Davis has the unique resources needed to develop an integrated animal model testing platform.  This project brings together a cross-discipline team needed to establish a standardized platform of ASD relevant social and behavioral assays that can be used to translate promising interventions from mouse to nonhuman primate models and ultimately to clinical populations.

Naturally hyposocial juvenile macaque monkeys: A nonhuman primate model for autism spectrum disorder treatment discovery

Principal Investigator:  Melissa D. Bauman, Ph.D.

The overarching goal of the proposed research is to develop a nonhuman primate model that can be used to evaluate novel drugs that may mitigate the social and communication impairments that characterize ASD. We anticipate that novel therapeutic agents targeting social deficits will become available in the near future and will require sophisticated animal models to evaluate drug efficacy. Although there are currently no validated nonhuman primate models of autism, we believe that natural variation in sociability of rhesus monkeys can be used to evaluate pharmacological treatment(s) designed to improve social and communication deficits.  We propose to develop protocols that will be used to identify cohorts of endogenously hyposocial monkeys and to develop high throughput behavioral assays of sociability that will be used to confirm sociability status, establish baselines for both high and low-sociable populations and ultimately provide a sensitive assay of drug efficacy.

16p11.2 deletion mice: autism-relevant phenotypes

Principal Investigators:  Jacqueline Crawley, Ph.D. and Ricardo Dolmetsch, Ph.D., Stanford University

Deletions and duplications within the 16p11.2 chromosomal locus are associated with autism spectrum disorders (ASDs), as well as with developmental delays, language impairments, intellectual disabilities, schizophrenia, motor deficits, seizures, macroencephaly and obesity.  The goal of this project is to understand the behavioral, anatomical, and cellular phenotypes caused by a heterozygous deletion of the mouse homolog of 16p11.2.  We are conducting comprehensive behavioral phenotyping of heterozygous 16p11.2 knockout mice and their wild type littermate controls on measures of social interaction, social communication, motor stereotypies, repetitive behaviors, developmental milestones, learning and memory, seizures, hyperactivity, anxiety, sensory sensitivity, sensorimotor gating, and motor functions, relevant to the human 16p11.2 syndrome.  Our collaborator Ricardo Dolmetsch is analyzing 16p11.2 knockout mice on measures of brain development, neuroanatomy, neurochemistry, electrophysiology, and downstream gene expression.

Engrailed2 regulates forebrain monoamines and behavior

Principal InvestigatorsJacqueline Crawley, Ph.D. and Emanuel DiCicco-Bloom, M.D., UMDNJ-Robert Wood Johnson Medical School

Engrailed2 is a homeodomain transcription factor that regulates embryonic hindbrain development.  Single nucleotide polymorphisms in EN2, the gene coding for Engrailed2, have been associated with autism in five independent genetic studies, implicated EN2 genetic variants as a likely autism susceptibility gene.   This project investigates monoamine levels and behavioral phenotypes relevant to the symptoms of autism in En2 knockout mice.   We are conducting behavioral assays relevant to sociability, cognition, and depression.  Pharmacological treatments that reverse the noradrenergic abnormalities discovered by our collaborator Manny DiCicco-Bloom are being evaluated for reversal of behavioral phenotypes in En2 knockout mice.

Gene discovery and neurodevelopmental analysis in a mouse model of autism

Principal Investigators:  Jacqueline Crawley, Ph.D., and Elliott Sherr, M.D., UC San Francisco

This project is a genetic investigation of BTBR mice, an inbred strain that displays low sociability, high repetitive behaviors, and corpus callosum absence.  We are conducting behavioral assays of sociability and repetitive behaviors in 400 F2 mice from the BTBR x B6 intercross, to identify significant quantitative trait loci (QTL) and generate a list of high probability candidate genes within those chromosomal loci.   Our collaborator Elliorr Sherr is simultaneously conducting corpus callosum assays in the same F2 mice, to identify genetic loci mediating the acallosal syndrome in BTBR.  20x sequencing coverage of the BTBR genome is being employed to identify candidate genes for both commissural anatomy and autism-relevant behaviors revealed by the QTL screen.  The overarching aim of these studies is to identify background genes mediating biological pathways that regulate autism-relevant behaviors in mice, which may inform the search for susceptibility and protective genes in autism.

Characterization of brain and behavior in 7q11.23 duplication syndrome

Principal Investigators:  Jacqueline Crawley, Ph.D., and Lucy Osborne, Ph.D., University of Toronto

Duplication of the Williams syndrome region on chromosome 7q11.23 (Dup7q11.23) has recently been identified as a possible autism-associated copy number variant.  Four Dup7q11.23 de novo cases of autism were identified during screening of the Simons Simplex Collection.  We are characterizing a Dup7q11.23 mouse model, employing our constellations of behavioral assays relevant to the diagnostic and associated symptoms of autism.  Our collaborator Lucy Osborne is characterizing the biological properties of mouse and human Dup7q11.3 cell reprogrammed to become neurons.   Collaborators Jacob Ellegood and Mark Henkelman are conducting brain morphology and diffusion tensor imaging of this mouse model of 7q11.23 duplication syndrome.

Functional magnetic resonance imaging of the nonhuman primate social brain

Principal Investigator:  Christopher J. Machado, Ph.D.

This project is the latest extension of a series of noninvasive functional neuroimaging experiments that began in 2008. Those initial studies used high-resolution positron emission tomography (microPET) and radio-labeled glucose analogs to noninvasively measure epoch-related brain activity related to social information processing in nonhuman primates. However, the low temporal (on the order minutes) and spatial (~2.5 mm3) resolution of microPET limits its ability to study many aspects of social cognition that occur on a second-by-second basis and in structures that are composed of multiple heterogeneous subregions, such as the amygdala and orbitofrontal cortex. Therefore, the current studies are utilizing functional magnetic resonance imaging (fMRI), with its higher temporal (on the order of seconds) and spatial (0.5 - 1 mm3) resolution, and a small group of nonhuman primates to study the neurobiology of social information processing. Specifically, we aim to study the neural network responsible for social and nonsocial recognition memory. The primary advantage of fMRI experiments with nonhuman primates is that follow-up studies can be performed with the same animals using methods that manipulate brain activity, like pharmacogenetic transient activation/inactivation techniques.