Monday, January 20, 2025
1/20/2025
PROJECT SUMMARY/ABSTRACT This exploratory project is a collaboration between researchers studying arousal-related behavioral states and BRAIN tool developers and will utilize novel interventional tools for changing neural circuit dynamics to elucidate the hierarchical organization of hypocretin (Hcrt) circuits with respect to arousal and reward. Motivated behaviors are fundamentally linked to arousal; however, little is known about the neural mechanisms that couple motivational processes with sleep/wake regulation. The hypothalamic Hcrt neurons play a central role as a hub integrating sensory and physiological information to tune arousal-related behavioral states, and deficiencies in these circuitries contribute to a variety of neuropsychiatric disorders. Hcrt neurons project throughout the brain, with specially dense excitatory projections to brain areas regulating arousal (e.g., locus coeruleus, LC) and reward (e.g., ventral tegmental area, VTA). To understand the relevance of individual projections in arousal and reward we will functionally interrogate projection-selective subsets of Hcrt neurons. Our hypothesis is that selective manipulation of synaptic drive of Hcrt neurons towards subpopulations of neurons in key brain structures mediating arousal (LC) versus reward (VTA) will reveal functional diversity rather than dichotomy. Our major goal will be to determine if lateral hypothalamus Hcrt projections to noradrenergic LC neurons are sufficient to enhance brain reward (Aim 1) and projections to dopaminergic VTA neurons are sufficient for arousal state transitions (Aim 2). For manipulation of neuronal activity this project will employ the bioluminescent optogenetic (BL-OG) platform that employs light emitting luciferases to activate light sensing opsins. Using a novel trans- synaptic bioluminescent optogenetic strategy, Interluminescence, Hcrt neurons will express a presynaptic vesicle targeted luciferase, while opsin expression is restricted to specific postsynaptic neurons in target areas. In this “optical synapse” light emission from luciferases by peripheral luciferin administration will modulate the synaptic activity of highly selective projections. The impact of projection-specific interventions on reward behavior and sleep-to-wake transition will be evaluated using established behavioral tests. A deeper understanding of how the outputs of Hcrt neurons are functionally organized and their individual effects on behavioral transitions will be highly significant as several Hcrt receptor antagonists have been approved for the treatment of insomnia and are being tested in clinical trials to reduce cravings in substance abuse disorder. Learning about the relative weight of Hcrt projections to LC compared with VTA may lead to optimization of these treatments and to therapeutic opportunities in substance abuse, eating and panic disorders, cognitive disruption and emotion- related disorders including anxiety, MDD and PTSD.
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