To deconstruct a hypothalamic neural circuit pathway for feeding and compulsive behaviors

University Of Texas Hlth Sci Ctr Houston, Houston TX

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Abstract

? DESCRIPTION (provided by applicant): Eating disorders and obsessive-compulsive disorders are two commonly co-occurring, severe neuropsychiatric diseases that affect millions of Americans. Patients with these diseases similarly experience recurrent obsessions followed by compulsive behaviors aimed at reducing distressing thoughts. These debilitating, complex symptoms severely impair a patient's daily life functioning, and current available treatments may reduce the severity of symptoms but do not cure these life-long disorders. To date, the neural pathways underlying these disorders are poorly understood, highlighting a critical need for uncovering the precise neural circuit interactions behind destructive behaviors seen in these diseases. This proposal seeks to achieve a circuit-level understanding of hypothalamic pathways that control feeding and self-grooming in mice, two behaviors that are maladaptive in human eating and obsessive-compulsive disorders, respectively. Optogenetics, a technology that combines genetics with properties of light-activated channels, allows for precise control of specific neural circuit activity. Preliminary experiments utilized optogenetic approaches combined with unique animal models to map and characterize neural circuit projections from the lateral hypothalamus to the paraventricular hypothalamus, two important regions previously implicated in feeding and self-grooming behaviors. The proposal's preliminary data shows that lateral hypothalamic neurons send excitatory and inhibitory monosynaptic input to paraventricular hypothalamic neurons, and light activation of this circuit projection in live animas produces voracious feeding and repetitive grooming behaviors. Importantly, evoked feeding depends on release of the neurotransmitter gamma-aminobutyric acid (GABA), and loss of GABA in LH neurons results in uncontrolled grooming upon light stimulation of the same circuit projection. Additionally, optogenetic activation of PVH neurons induces repetitive grooming. These observations led to the hypothesis that separable, competing inhibitory and excitatory lateral hypothalamic neuron populations control feeding and grooming by modulating paraventricular hypothalamus neuron activity. The experiments proposed in this application will identify the specific neural circuit pathways within the hypothalamus controlling these two important behaviors, allowing for insight into the neural basis for eating disorders and obsessive-compulsive disorders and development of novel therapeutic strategies.