A dorsal hippocampus-prodynorphinergic dorsolateral septum-to-lateral hypothalamus circuit mediates contextual gating of feeding

Affiliations

¹ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; BROAD Institute of Harvard and MIT, Cambridge, MA, USA.
² Department of Pharmacology, University of Washington, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA; University of Washington Center of Excellence in Neurobiology of Addiction, Pain, and Emotion (NAPE), Seattle, WA, USA; Graduate Program in Neuroscience, University of Washington, Seattle, WA, USA.
³ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁴ BROAD Institute of Harvard and MIT, Cambridge, MA, USA.
⁵ Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA.
⁶ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; BROAD Institute of Harvard and MIT, Cambridge, MA, USA.
⁷ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA; Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA; Malone Center for Engineering in Healthcare, Johns Hopkins University, Baltimore, MD, USA.
⁸ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; BROAD Institute of Harvard and MIT, Cambridge, MA, USA. Electronic address: asahay@mgh.harvard.edu.

PMID: 41687615
DOI: 10.1016/j.neuron.2026.01.025

Free article

A dorsal hippocampus-prodynorphinergic dorsolateral septum-to-lateral hypothalamus circuit mediates contextual gating of feeding

Travis D Goode et al. Neuron. 2026.

Free article

. 2026 Feb 12:S0896-6273(26)00050-4.

doi: 10.1016/j.neuron.2026.01.025. Online ahead of print.

Authors

Affiliations

¹ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; BROAD Institute of Harvard and MIT, Cambridge, MA, USA.
² Department of Pharmacology, University of Washington, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA; University of Washington Center of Excellence in Neurobiology of Addiction, Pain, and Emotion (NAPE), Seattle, WA, USA; Graduate Program in Neuroscience, University of Washington, Seattle, WA, USA.
³ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁴ BROAD Institute of Harvard and MIT, Cambridge, MA, USA.
⁵ Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA.
⁶ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; BROAD Institute of Harvard and MIT, Cambridge, MA, USA.
⁷ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA; Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA; Malone Center for Engineering in Healthcare, Johns Hopkins University, Baltimore, MD, USA.
⁸ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; BROAD Institute of Harvard and MIT, Cambridge, MA, USA. Electronic address: asahay@mgh.harvard.edu.

PMID: 41687615
DOI: 10.1016/j.neuron.2026.01.025

Abstract

Contextual encoding in the dorsal hippocampus (DHPC) may recruit hypothalamic feeding modules to calibrate eating across environments, but the mechanistic instantiation of cells and circuits that undergird these processes is limited. Single-cell transcriptomics and transsynaptic tracing of the dorsolateral septum (DLS) identified an evolutionarily conserved prodynorphin (Pdyn)-expressing subpopulation of somatostatin (Sst)-expressing inhibitory neurons that receives dense dorsal, but not ventral, hippocampal inputs. Circuit optogenetics, electrophysiology, and in vivo calcium imaging demonstrated that DLS(Pdyn) neurons inhibit GABAergic neurons of the lateral hypothalamic area (LHA), exhibit context-dependent neural responses to food rewards and aversive stimuli, and confer contextual and internal state-dependent calibration of feeding. Viral deletion of Pdyn in the DLS impaired context-dependent food reward consumption, suggesting a role for dynorphin/kappa opioid receptor signaling in these processes. Together, our findings highlight how ancient LHA feeding circuits integrate DHPC input through DLS(Pdyn) inhibitory neurons to link context with regulation of food consumption.

Keywords: conditioned fear; context; dorsal hippocampus; feeding; kappa opioid receptors; lateral hypothalamus; lateral septum; prodynorphin; reward; somatostatin.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Update of

A dorsal hippocampus-prodynorphinergic dorsolateral septum-to-lateral hypothalamus circuit mediates contextual gating of feeding.
Goode TD, Alipio JB, Besnard A, Pathak D, Kritzer-Cheren MD, Chung A, Duan X, Sahay A. Goode TD, et al. bioRxiv [Preprint]. 2024 Aug 6:2024.08.02.606427. doi: 10.1101/2024.08.02.606427. bioRxiv. 2024. Update in: Neuron. 2026 Feb 12:S0896-6273(26)00050-4. doi: 10.1016/j.neuron.2026.01.025. PMID: 39149322 Free PMC article. Updated. Preprint.

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A dorsal hippocampus-prodynorphinergic dorsolateral septum-to-lateral hypothalamus circuit mediates contextual gating of feeding

Affiliations

A dorsal hippocampus-prodynorphinergic dorsolateral septum-to-lateral hypothalamus circuit mediates contextual gating of feeding

Authors

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Abstract

Conflict of interest statement

Update of

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