The goal of our grant application is a functional and anatomic dissection of the neural pathways emanating from the mouse medial amygdala (MeA). This nucleus regulates many behaviors, including social memory, the response to predators and other stressors, and mating and aggression. The MeA is heterogeneous and contains many neuronal pools with distinct identities. One hypothesis to account for the functional diversity of the MeA is that different MeA neuronal pools serve distinct functions. Our previous work (funded by the prior grant period) and that of others has identified a small collection of aromatase-expressing neurons located in the posterodorsal component of the MeA. Both aromatase and the MeA are essential for the display of mating and aggression. Intriguingly, our work shows that there are more aromatase+ neurons in the MeA in males compared to females. We therefore hypothesize that aromatase+ MeA neurons influence the dimorphic displays of mating and aggression.
In Aim 1, we will use c-Fos expression to identify the behavioral and chemosensory stimuli that activate these neurons;our studies will be performed in an aromatase reporter mouse we have previously generated to allow sensitive co-labeling for c-Fos and aromatase.
In Aim 2, we will trace the connections of aromatase+ MeA neurons. We will use a Cre-dependent pseudorabies virus for trans-synaptic retrograde labeling, and a novel Cre-dependent neural tracer encoding virus we have developed for labeling the projections of aromatase+ neurons. These studies will be performed using a novel aromatase-Cre mouse strain we have engineered. We will also combine c-Fos labeling with cholera toxin B, a retrograde tracer, to determine if aromatase+ neurons activated by different stimuli project to distinct targets.
In Aim 3, we will use powerful optogenetic effectors to stimulate (channelrhodopsin2) and inhibit (halorhodopsin3) aromatase+ MeA neurons to determine the functional relevance of these cells to dimorphic displays of mating and aggression. Thus, our studies will provide insight into the neural pathways emanating from aromatase+ MeA neurons and their functional relevance in vivo. Health Relatedness: Neuro-psychiatric conditions often reflect dysfunction of neural circuitry at a gross or microscopic level, and these remain poorly understood and therapeutically intractable. The human amygdala is critical for recognition of social and emotional cues, and amygdalar dysfunction is thought to contribute to post-traumatic stress disorder and autism spectrum disorders. Our proposed work will shed light on the connectivity and functions of a subset of amygdalar neurons, thereby leading to an advance in basic scientific understanding of this region and the neural circuits within which it functions in health, and it may ultimately help guide future therapeutic or diagnostic applications for disorders of the amygdala.

Public Health Relevance

Dysfunction of neuronal circuits is thought to underlie many devastating neuro-psychiatric conditions. Our basic research is focused on elucidating the connections and functions of the amygdala, a brain region that has been implicated in post-traumatic stress disorder and autism spectrum disorders. Our work will shed light on how the amygdala functions in health, and ultimately may help guide future therapeutic and diagnostic applications for amygdalar dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS049488-08
Application #
8512807
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Gnadt, James W
Project Start
2004-07-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
8
Fiscal Year
2013
Total Cost
$326,140
Indirect Cost
$115,046
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Fraser, Eleanor J; Shah, Nirao M (2014) Complex chemosensory control of female reproductive behaviors. PLoS One 9:e90368
Morgan, Charles W; Julien, Olivier; Unger, Elizabeth K et al. (2014) Turning on caspases with genetics and small molecules. Methods Enzymol 544:179-213
Nelson, Alexandra B; Hammack, Nora; Yang, Cindy F et al. (2014) Striatal cholinergic interneurons Drive GABA release from dopamine terminals. Neuron 82:63-70
Yang, Cindy F; Shah, Nirao M (2014) Representing sex in the brain, one module at a time. Neuron 82:261-78
Yang, Cindy F; Chiang, Michael C; Gray, Daniel C et al. (2013) Sexually dimorphic neurons in the ventromedial hypothalamus govern mating in both sexes and aggression in males. Cell 153:896-909
Manoli, Devanand S; Fan, Pu; Fraser, Eleanor J et al. (2013) Neural control of sexually dimorphic behaviors. Curr Opin Neurobiol 23:330-8
Xu, Xiaohong; Coats, Jennifer K; Yang, Cindy F et al. (2012) Modular genetic control of sexually dimorphic behaviors. Cell 148:596-607
Wu, Melody V; Shah, Nirao M (2011) Control of masculinization of the brain and behavior. Curr Opin Neurobiol 21:116-23
Cavanaugh, Daniel J; Chesler, Alexander T; Bráz, Joao M et al. (2011) Restriction of transient receptor potential vanilloid-1 to the peptidergic subset of primary afferent neurons follows its developmental downregulation in nonpeptidergic neurons. J Neurosci 31:10119-27
Cavanaugh, Daniel J; Chesler, Alexander T; Jackson, Alexander C et al. (2011) Trpv1 reporter mice reveal highly restricted brain distribution and functional expression in arteriolar smooth muscle cells. J Neurosci 31:5067-77

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