Abstract
Animal models have been developed to investigate aspects of stress, anxiety, and depression, but our understanding of the circuitry underlying these models remains incomplete. Prior studies of the habenula, a poorly understood nucleus in the dorsal diencephalon, suggest that projections to the medial habenula (MHb) regulate fear and anxiety responses, whereas the lateral habenula (LHb) is involved in the expression of learned helplessness, a model of depression. Tissue-specific deletion of the transcription factor Pou4f1 in the dorsal MHb (dMHb) results in a developmental lesion of this subnucleus. These dMHb-ablated mice show deficits in voluntary exercise, a possible correlate of depression. Here we explore the role of the dMHb in mood-related behaviors and intrinsic reinforcement. Lesions of the dMHb do not elicit changes in contextual conditioned fear. However, dMHb-lesioned mice exhibit shorter immobility time in the tail suspension test, another model of depression. dMHb-lesioned mice also display increased vulnerability to the induction of learned helplessness. However, this effect is not due specifically to the dMHb lesion, but appears to result from Pou4f1 haploinsufficiency elsewhere in the nervous system. Pou4f1 haploinsufficiency does not produce the other phenotypes associated with dMHb lesions. Using optogenetic intracranial self-stimulation, intrinsic reinforcement by the dMHb can be mapped to a specific population of neurokinin-expressing habenula neurons. Together, our data show that the dMHb is involved in the regulation of multiple mood-related behaviors, but also support the idea that these behaviors do not reflect a single functional pathway.
Footnotes
The authors report no conflict of interest.
This work was supported by National Institute Health Awards R01 MH093667 and R01 DA035838 to E.E.T; Y.-W.A.H. was supported by NIMH Training Award F32MH098498; and E.G.G. was supported by T32-DA007278. We thank Dr. Susan Ferguson for helpful comments on the experimental results and paper, Dr. Fritz Henn for helpful discussions, and Lely Quina for technical assistance. BAC transgenic mice were generated by the Gene Expression Nervous System Atlas (GENSAT) Project, NINDS Contracts N01NS02331 & HHSN271200723701C to The Rockefeller University (New York, NY). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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