Valence-encoding in the lateral habenula arises from the entopeduncular region

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Abstract

Lateral habenula (LHb) neurons are activated by negative motivational stimuli and play key roles in the pathophysiology of depression. Prior reports suggested that rostral entopeduncular nucleus (rEPN) neurons drive these responses in the LHb and rostromedial tegmental nucleus (RMTg), but these influences remain untested. Using rabies viral tracers, we demonstrate disynaptic projections from the rEPN to RMTg, but not VTA, via the LHb in rats. Using in vivo electrophysiology, we find that rEPN or LHb subpopulations exhibit activation/inhibition patterns after negative/positive motivational stimuli, similar to the RMTg, while temporary inactivation of a region centered on the rEPN decreases LHb basal and burst firing, and reduces valence-related signals in LHb neurons. Additionally, excitotoxic rEPN lesions partly diminish footshock-induced cFos in the LHb and RMTg. Together, our findings indicate an important role of the rEPN, and possibly immediately adjacent hypothalamus, in driving basal activities and valence processing in LHb and RMTg neurons.

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All data generated or analyzed during this study are included in the manuscript and supporting files.

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Hao Li

Department of Neuroscience, Medical University of South Carolina, Charleston, United States

Competing interests
The authors declare that no competing interests exist.
Dominika Pullmann

Department of Neuroscience, Medical University of South Carolina, Charleston, United States

Competing interests
The authors declare that no competing interests exist.
Thomas C Jhou

Department of Neuroscience, Medical University of South Carolina, Charleston, United States

For correspondence
jhou@musc.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8811-0156

Funding

National Institutes of Health (DA037327)

Thomas C Jhou

National Institutes of Health (DA032898)

Thomas C Jhou

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (2988) of the Medical University of South Carolina. The protocol was approved by the Institutional Animal Care and Use Committee of the Medical University of South Carolina (DHHS Assurance #A3428-01). All surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.