The amygdala plays a central role in human social behavior. Amygdala perturbations contribute to autism, social phobia, and other psychiatric disorders, but little is known about the neural basis of its function or the genetic determinants o its role in human neural circuitry. This proposal will address these gaps by defining the microstructural changes in the amygdala of human brains from individuals with Williams syndrome (WS). WS is a neurodevelopmental disorder with a well described genotype (Korenberg et al., 2000) and a consistently altered social phenotype that includes hyperaffiliative behavior combined with poor social judgment (Semel and Rosner, 2003). Significantly, evidence from fMRI and evoked potential studies directly implicates perturbations in amygdala function in WS during socially-oriented tasks (Meyer-Lindenberg et al., 2005;Haas et al., 2009, 2010). Thus, WS provides a unique opportunity to define the neural circuitry of the social brain at the cellular level and to link it to its genetic and developmental origins. The proposed studies pave the way for understanding the neural basis of social dysfunction and for ultimately developing therapies and treatments.
Specific Aim Determine the relationship between total amygdala volume and the relative size of the four major nuclei (lateral, basal, accessory basal, central) in WS and typically developing controls. MRI studies in WS have shown increases in total amygdala volume (Reiss et al., 2004, Martens et al., 2009;Capitao, 2011), but individual nuclei have not been examined. We will examine the basolateral nuclei (lateral, basal, and accessory basal nuclei) because they have reciprocal and topographically organized connections with higher order sensory regions in the temporal lobe and with the orbitofrontal cortex (Stefanacci et al., 1996, Stefanacci and Amaral, 2002), important components of the social brain (Damasio et al., 2004, Semendeferi et al., 2010). We will also examine the central nucleus because of its importance in downstream connections to the brainstem and hypothalamus, which are key regions for marshalling species-specific behavior.
Specific Aim 2 Identify changes in neuronal size, number, and density in four major amygdala nuclei (lateral, basal, accessory basal, and central) of Williams Syndrome individuals and typically developing controls. Changes in the number of neurons in the lateral nucleus of the amygdala have been identified in autism, another disorder characterized by disruptions in social behavior. While the number of neurons in the amygdala of WS is not known, changes in density and neuronal size were reported in selected locations in the cerebral cortex of WS individuals (Hollinger et al., 2005;Galaburda et al., 2002). Our findings will reveal how the microstructure of the amygdala is disrupted in individuals who demonstrate an altered social phenotype. More broadly, we will gain new insights into the genetic contributions to the detailed cytoarchitechtonic organization of the amygdala, an essential next step for drilling down to the neurobiological and genetic targets for therapeutics of disorders of social behavior.

Public Health Relevance

The goal of the research described in this proposal is to characterize, at the cellular level, the disruptions in four amygdala nuclei in the brains of Williams syndrome individuals, who have a known genotype and a behaviorally characterized social phenotype. Our results will lead to a more comprehensive understanding about the organization of a brain region that is critical for mediating normal social behavior. This knowledge will contribute to efforts to develop novel therapies and cures for diseases characterized by outstanding social dysfunctions.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Small Research Grants (R03)
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Developmental Brain Disorders Study Section (DBD)
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Gilotty, Lisa
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University of California San Diego
Social Sciences
Schools of Arts and Sciences
La Jolla
United States
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