Saturday, May 10, 2025
5/10/2025
Inhibitory Cell Types and Circuits in the Lateral Hypothalamus - PROJECT SUMMARY/ABSTRACT The goal of this proposal is to define the cellular diversity, connectivity and function of inhibitory neurons in the lateral hypothalamic area (LHA). The LHA is a linchpin in the orchestration of fundamental aspects of behavior owing to its unique position at the intersection of multiple neural and humoral systems. LHA GABAergic neurons in particular have emerged as potent actuators of arousal, goal-directed behavior as well as both negative and positive valence behavior. Within this broad class of inhibitory LHA neurons lie poorly resolved but functionally important subpopulations, which may differentially determine behavioral output. Important among these is a population of putative inhibitory neurons that express the neuropeptide melanin-concentrating hormone (MCH). LHA MCH-expressing neurons (LHAMCH) display remarkable functional diversity, sending extensive projections throughout the brain and coordinating a broad range of physiological functions and behaviors, including the modulation of sleep-wake states, feeding, motivated behavior, stress and memory. However, experimental manipulations of LHAMCH neurons are largely interpreted in the context of LHAMCH neurons being a monolithic, neuromodulatory projection system, creating a profound knowledge gap as to the source of their functional diversity. There is, therefore, a critical need to delineate the unique cellular, circuit-level and behavioral impact of LHAMCH diversity. In the previous grant cycle, we made significant progress towards our long-term goal of defining the population structure of LHA GABAergic neurons, including the generation of the most comprehensive cellular taxonomy to date of molecularly distinct LHA cell types in the mouse. Here, we will build upon that progress through our investigation of: 1) two transcriptomically-distinct LHAMCH subpopulations that differentially express the neurokinin 3 receptor (NK3R), the receptor for neurokinin B (NKB); 2) and a novel projection from NKB neurons in the central extended amygdala to the LHA. In Aim 1, we will determine whether distinct LHAMCH subpopulations give rise to functional sub-circuits that project to different targets in the brain and release different neurochemicals using a precise intersectional viral strategy based on the enrichment of NK3R in one LHAMCH subpopulation over the other. In Aim 2, we will explore whether differential engagement of LHAMCH subpopulations elicits distinct behavioral repertoires using two parallel intersectional strategies for optogenetically targeting LHAMCH subpopulations and then subjecting animals to a suite of behavioral assessments. In Aim 3, we will investigate the biological mechanisms underlying NKB/NK3R signaling in the central extended amygdala–LHA circuit through a detailed electrophysiological investigation of NKB/GABA co- transmission onto LHAMCH neurons, and by studying the behavioral impact of these projections. Together, the proposed experiments will address outstanding questions concerning the cellular and circuit-level functions of LHAMCH neuron diversity, which is necessary both for a mechanistic understanding of LHA circuit function, and as a critical precursor for identifying therapeutic targets for neuropsychiatric, sleep and metabolic disorders.
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