Defining brain circuits that control decisions, such as those between social interactions and asocial behaviors is an important problem in neuroscience with high relevance to human health. These neural circuits are located in evolutionarily ancient brain regions, such as the amygdala. In humans, decreased social interactions are a key symptom domain in psychiatric disorders such as autism, and are thought to involve the amygdala. The amygdala is a complex structure consisting of at least 12 distinct subregions. The amygdala circuits that control conditioned fear in the basolateral and central amygdala have been intensively studied. However a gap remains between our understanding of these circuits, and those in different amygdala subnuclei that control social interactions. The latter are thought to be located in the medial subdivision of the amygdala (MeA). To fill this gap, we will begin to dissect the function of MeA circuits that control the balance between social interactions and repetitive self-grooming, an asocial behavior. This balance is important because disorders such as autism often feature increased repetitive asocial behaviors, as well as decreased social interactions. The long-term goal is to understand the circuit-level control of this balance at a brain-wide level. The overall objective of this application is to define the roleof different MeA neuronal subpopulations that antagonistically control social interactions vs. repetitive self-grooming, and to understand the circuitry through which this antagonism is exerted. The central objective of this proposal is to study how GABAergic and glutamatergic neuronal subpopulations in the medial amygdala reciprocally regulate these opponent activities. The rationale for this research is that it will reveal fundamental mechanisms of neural circuit function in a brain region that is relevant to human health. To achieve our objective, we will map the functional projections of vGAT+ and VGLUT2+ MeApd neurons that control social interactions vs. repetitive self-grooming, respectively (Aim 1); test the hypothesis that social interactions are controlled by a dis-inhibition circuit and map that circuit (Aim 2); determine the mechanism by which vGAT+ and vGLUT2+ subpopulations exert antagonistic control of social vs. self-grooming behaviors (Aim 3); determine whether the dual functions performed by each of these subpopulations derive from common or distinct cell types (Aim 4). The contribution will be to apply state-of-the- art genetically based tools to dissect circuit-level mechanisms in MeA that control social vs. repetitive asocial behaviors. This contribution is significant because it will oen up the study of amygdala circuitry controlling social interactions, at a level of cellular specificty that has not yet been achieved. The contribution is innovative, because it investigates novel features of amygdala circuitry that we have recently uncovered involving the excitation:inhibition balance. The work proposed in this application will therefore both advance our basic understanding of neural circuit functional organization, and shed light on the particulars of amygdala neuronal subpopulations and circuitry that may relevant to human disorders affecting social interactions.

Public Health Relevance

The proposed research is relevant to public health because it addresses the study of brain circuitry that controls decisions between social interactions and repetitive, asocial behaviors. Human brain disorders such as autism often involve both a decrease in social interactions, and an increase in repetitive asocial behaviors, as if such behaviors were coupled by a see-saw like mechanism. We will study these 'see-saw circuits' in the mouse amygala, an evolutionary ancient structure that has been linked to autism in humans. Because of the conservation of this brain structure in mammalian species, the results should be relevant to understanding the human brain. The research described in this proposal will apply powerful genetic tools to the high-resolution analysis of basic neural circuit mechanisms, and is therefore relevant to NIMH's mission of achieving a 'deeper understanding of fundamental neurobiology' (Insel, T.R. and Landis, S.C., Neuron (2013)).

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH085082-09
Application #
9428455
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Vicentic, Aleksandra
Project Start
2008-12-01
Project End
2020-02-29
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
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