PROJECT SUMMARY
The brain serotonin (5-HT) system has been a target for multiple weight loss therapies. Compounds that elevate
5-HT content reduce food intake and body weight. Our previous and current findings show that 5-HT acts on two
postsynaptic 5-HT receptors, Htr2c and Htr1b in the arcuate nucleus of the hypothalamus (ARH) to suppress
food intake. Within the ARH, 5-HT reciprocally inhibits the orexigenic AgRP neurons (via Htr1b) while activating
the anorectic POMC neurons (via Htr2c). Moreover, we have demonstrated that Htr2c and Htr1b in these neurons
are necessary for the anorectic effects of 5-HT agents including the once-popular diet pill Fen/Phen.
However, despite these significant findings, the precise source of the presynaptic 5-HT inputs to ARH neurons
remains largely elusive. This has posed a considerable challenge due to the heterogeneity of 5-HT neurons in
the midbrain dorsal raphe nucleus (DRN), comprising multiple subpopulations with distinct projection patterns
and physiological functions. Consequently, our current proposal aims to unravel the neural circuit mechanism by
which 5-HT regulates satiety.
To accomplish this, we propose a multidisciplinary approach to isolate the 5-HT neurons that innervate the ARH
(5-HTARH neurons). Our central hypothesis posits that these neurons provide direct synaptic inputs to the ARH
and play a critical role in feeding regulation. To investigate this, we will use in vivo calcium imaging to determine
the activity patterns of 5-HTARH neurons during hunger and satiety in behaving mice [Aim 1a]. Furthermore, we
will manipulate the activity of these neurons in live mice by either stimulating or inhibiting them, aiming to uncover
their specific contributions to food intake [Aim 1b]. Finally, we have developed a new intersectional genetic
approach that enables us to selectively deplete 5-HT inputs to the ARH in adult mice and evaluate their
physiological impact on energy homeostasis [Aim 2].