PT  - JOURNAL ARTICLE
AU  - Yun-Wei A. Hsu
AU  - Glenn Morton
AU  - Elizabeth G. Guy
AU  - Si D. Wang
AU  - Eric E. Turner
TI  - Dorsal medial habenula regulation of mood-related behaviors and primary reinforcement by tachykinin-expressing habenula neurons
AID  - 10.1523/ENEURO.0109-16.2016
DP  - 2016 Jul 01
TA  - eneuro
PG  - ENEURO.0109-16.2016
4099  - http://www.eneuro.org/content/early/2016/07/01/ENEURO.0109-16.2016.short
4100  - http://www.eneuro.org/content/early/2016/07/01/ENEURO.0109-16.2016.full
AB  - 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, while 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 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.Significance Statement Our current understanding of neural circuits regulating mood states such as fear and depression is fragmentary. Recently, interest has grown in how the habenula, a poorly understood nucleus providing decending inputs to the tegmentum and raphe, may affect these behavioral states. We have employed mouse genetic models to study part of this system, the dorsal medial habenula (dMHb). Here we report that the dMHb is not, as previously proposed, required for normal acquisition of a conditioned fear response. Mice with genetic lesions of the dMHb show some profound effects in mood-related tests, but cannot be described strictly as “depressed” or “resilient”, suggesting that at the circuit level, models of affective states are complex and do not report identical phenomena.