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bioRxiv · 10.1101/2023.09.25.559435

Regulation of the mouse ventral tegmental area by melanin-concentrating hormone

Spencer, C. D.·Miller, P. A.·Williams-Ikhenoba, J. G.·Nikolova, R. G.·Chee, M. J.
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Abstract

Melanin-concentrating hormone (MCH) acts via its sole receptor MCHR1 in rodents and is an important regulator of homeostatic behaviors like feeding, sleep, and mood to impact overall energy balance. The loss of MCH signaling by MCH or MCHR1 deletion produces hyperactive mice with increased energy expenditure, and these effects are consistently associated with a hyperdopaminergic state. We recently showed that MCH suppresses dopamine release in the nucleus accumbens, which principally receives dopaminergic projections from the ventral tegmental area (VTA), but the mechanisms underlying MCH-regulated dopamine release are not clearly defined. MCHR1 expression is widespread and includes dopaminergic VTA cells. However, as the VTA is a neurochemically diverse structure, we assessed Mchr1 gene expression at glutamatergic, GABAergic, and dopaminergic VTA cells and determined if MCH inhibited the activity of VTA cells and/or their local microcircuit. Mchr1 expression was robust in major VTA cell types, including most dopaminergic (78%) or glutamatergic cells (52%) and some GABAergic cells (38%). Interestingly, MCH directly inhibited dopaminergic and GABAergic cells but did not regulate the activity of glutamatergic cells. Rather, MCH produced a delayed increase in excitatory input to dopamine cells and a corresponding decrease in GABAergic input to glutamatergic VTA cells. Our findings suggested that MCH may acutely suppress dopamine release while disinhibiting local glutamatergic signaling to restore dopamine levels. This indicated that the VTA is a target of MCH action, which may provide bidirectional regulation of energy balance. Significance StatementRole of melanin-concentrating hormone (MCH) on energy balance may converge on the dopamine system via the mesolimbic pathway, as loss of MCH or MCH receptor (MCHR1) signaling increases hyperactivity and energy expenditure associated with a hyperdopaminergic state. MCH can suppress dopamine release within the mesolimbic pathway, but its underlying mechanism is not known. We thus determined if MCH could inhibit dopamine release through direct actions within the ventral tegmental area (VTA). We found that MCH directly inhibited dopaminergic VTA cells, but MCH also disinhibited excitatory input to dopamine cells. Therefore, we showed that the VTA is a putative target site supporting dopamine-dependent actions of MCH.

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Spencer, C. D., Miller, P. A., Williams-Ikhenoba, J. G., Nikolova, R. G., Chee, M. J.. 2023-09-26. Regulation of the mouse ventral tegmental area by melanin-concentrating hormone. https://doi.org/10.1101/2023.09.25.559435

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