A Dorsal Hippocampus-Prodynorphinergic Dorsolateral Septum-to-Lateral Hypothalamus Circuit Mediates Contextual Gating of Feeding

Adaptive regulation of feeding depends on linkage of internal states and food outcomes with contextual cues. Human brain imaging has identified dysregulation of a hippocampal-lateral hypothalamic area (LHA) network in binge eating, but mechanistic instantiation of underlying cell-types and circuitry is lacking. Here, we identify an evolutionary conserved and discrete Prodynorphin (Pdyn)-expressing subpopulation of Somatostatin (Sst)-expressing inhibitory neurons in the dorsolateral septum (DLS) that receives primarily dorsal, but not ventral, hippocampal inputs. DLS(Pdyn) neurons inhibit LHA GABAergic neurons and confer context- and internal state-dependent calibration of feeding. Viral deletion of Pdyn in the DLS mimicked effects seen with optogenetic silencing of DLS Pdyn INs, suggesting a potential role for DYNORPHIN-KAPPA OPIOID RECEPTOR signaling in contextual regulation of food-seeking. Together, our findings illustrate how the dorsal hippocampus has evolved to recruit an ancient LHA feeding circuit module through Pdyn DLS inhibitory neurons to link contextual information with regulation of food consumption.

Note:
Funding Information: T.D.G is a recipient of Brain & Behavior Research Foundation Young Investigator Award, a Harvard Brain Initiative Travel Grant, and a NIH K99/R00 Pathway to Independence Award (K99MH132768). A.S. acknowledges support from the Simons Collaboration on Plasticity and the Aging Brain, NIH R01MH111729, NIH R01MH131652, NIH R01MH111729-04S1, NIH R01AG076612, NIH R01AG076612-S1 diversity supplement, the James and Audrey Foster MGH Research Scholar Award, and the Department of Psychiatry at MGH.

Declaration of Interests: None.

Ethical Approval Statement: All experiments were conducted in accordance with approved procedures by the Institutional Animal Care and Use Committees (IACUC) at Massachusetts General Hospital and following NIH guidelines (IACUC Protocol # 2011N000084).

Keywords: context, dorsal hippocampus, dorsolateral septum, eating disorder, feeding, GABA, kappa opioid receptors, lateral hypothalamus, prodynorphin, somatostatin

Suggested Citation: Suggested Citation

Goode, Travis David and Alipio, Jason Bondoc and Besnard, Antoine and Pathak, Devesh and Kritzer, Michael and Chung, Ain and Duan, Xin and Sahay, Amar and Administrator, Sneak Peek, A Dorsal Hippocampus-Prodynorphinergic Dorsolateral Septum-to-Lateral Hypothalamus Circuit Mediates Contextual Gating of Feeding. Available at SSRN: https://ssrn.com/abstract=4923432

This version of the paper has not been formally peer reviewed.