This grant application seeks to define the genetic and neural circuit basis of the functional role of the ventromedial hypothalamus (VMH). The VMH is molecularly heterogeneous and correspondingly, it has been implicated in the regulation of diverse behaviors and physiological function: motor and visceromotor functions, neuroendocrine function, feeding, and sexually dimorphic social and emotional behaviors. One appealing possibility is that these diverse functions are controlled by discrete subsets of VMH neurons. We and others have identified a small cluster of sexually dimorphic neurons within the VMH. We hypothesize that these neurons control sexually dimorphic social and emotional behaviors.
In Aim 1, we will use a novel Cre recombinase mouse strain we have generated to genetically trace the connections of these dimorphic VMH neurons. We will also test the hypothesis that projections to different areas emanating from these dimorphic neurons are activated during distinct behaviors.
In Aim 2, we will utilize a novel Cre-dependent, pro-apoptotic gene to genetically ablate these dimorphic VMH neurons in adult males and females. These mice will subsequently be tested for deficits in dimorphic social and emotional behaviors.
In Aim 3, we will utilize a Cre- dependent heterologous receptor (DREADD) activated by a heterologous ligand (clozapine-N-oxide) to switch on activity in these VMH neurons in vivo in males and females. This experiment will test whether activity in these neurons is sufficient to elicit dimorphic socia and emotional behavior. Taken together, our molecular genetic approaches will uncover the connectivity and functional relevance of a sexually dimorphic neuronal cluster in the mammalian forebrain. Health Relatedness: The devastating clinical manifestations of common neurodegenerative conditions and psychiatric conditions often reflect dysfunction of specific neural circuits. The VMH has been implicated in the regulation of social and emotional behaviors, neuroendocrine function, feeding, and motor and visceromotor function. VMH-localized lesions such as tumors result in altered cognition, abnormal social behaviors, and metabolic changes. Our studies will provide novel mechanistic insight into the functional relevance of the VMH and the circuits in which it participates in health. These findings may ultimately allow development of more rationally-targeted diagnostic and therapeutic options for VMH dysfunction in neurological disorders. Finally, the Cre-dependent, pro-apoptotic genetically encoded reagent that we use in this proposal will be useful in developing models of "neurodegeneration" in any neuronal (or other cell) type.
Malfunctioning neural circuits often underlie the clinical manifestations of many neurodegenerative disorders, neural tumors, and mental illnesses. Our research project seeks to reveal the connectivity and behavioral functions of the ventromedial hypothalamus, a brain center implicated in the control of social and emotional behaviors, feeding, neuroendocrine function, and motor and visceromotor control. Our studies will provide new insight into the function of this important region in health, and it may suggest new diagnostic and therapeutic interventions to assess and treat disruption of these behaviors and physiological functions in neurological disease states.
|Yang, Taehong; Shah, Nirao M (2016) Molecular and neural control of sexually dimorphic social behaviors. Curr Opin Neurobiol 38:89-95|
|Delwig, Anton; Larsen, DeLaine D; Yasumura, Douglas et al. (2016) Retinofugal Projections from Melanopsin-Expressing Retinal Ganglion Cells Revealed by Intraocular Injections of Cre-Dependent Virus. PLoS One 11:e0149501|
|Bayless, Daniel W; Shah, Nirao M (2016) Genetic dissection of neural circuits underlying sexually dimorphic social behaviours. Philos Trans R Soc Lond B Biol Sci 371:20150109|
|Sokolowski, Katie; Esumi, Shigeyuki; Hirata, Tsutomu et al. (2015) Specification of select hypothalamic circuits and innate behaviors by the embryonic patterning gene dbx1. Neuron 86:403-16|
|Cheung, Clement C; Krause, William C; Edwards, Robert H et al. (2015) Sex-dependent changes in metabolism and behavior, as well as reduced anxiety after eliminating ventromedial hypothalamus excitatory output. Mol Metab 4:857-66|
|Unger, Elizabeth K; Burke Jr, Kenneth J; Yang, Cindy F et al. (2015) Medial amygdalar aromatase neurons regulate aggression in both sexes. Cell Rep 10:453-62|
|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|
|Morgan, Charles W; Julien, Olivier; Unger, Elizabeth K et al. (2014) Turning on caspases with genetics and small molecules. Methods Enzymol 544:179-213|
|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|
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