Dorsal Medial Habenula Regulation of Mood-Related Behaviors and Primary Reinforcement by Tachykinin-Expressing Habenula Neurons

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.

Transcriptional and Spatial Resolution of Cell Types in the Mammalian Habenula

“…Visualization of canonical gene markers in UMAP space readily separated habenular neurons into 6 MHb clusters (enriched with Tac2; 2,986 cells; median UMIs/cell = 3,750, median genes/cell = 1,840) and 6 LHb clusters (enriched in Pcdh10; 2,572 cells; median UMIs/cell = 3,483, median genes/cell = 1,822) ( Figure 2B, C). Consistent with previous literature (Aizawa et al, 2012;Hsu et al, 2016;Namboodiri et al, 2016), the DEG analysis between MHb and LHb clusters revealed MHb specific (170 genes;…”

“…While less is known about the function of MHb circuitry in controlling behavior, MHb neurons play a critical role in regulating nicotine reinforcement (Fowler and Kenny, 2012;Fowler et al, 2011;Lester and Dani, 1995), novelty preference (Molas et al, 2017), and anxiety/fear related behaviors (Hsu et al, 2014(Hsu et al, , 2016Yamaguchi et al, 2013;Zhang et al, 2016). Collectively, the MHb and LHb represent two largely independent subsystems both of which importantly contribute towards regulating a variety of motivated behavioral states.…”

Specific connections of the interpeduncular subnuclei reveal distinct components of the habenulopeduncular pathway

“…The IPL is a cell‐poor region, but retrograde viral activation of a genetic reporter demonstrates that neurons surrounding the peptidergic dMHb terminals in this area have processes that extend into the habenulo‐recipient area, and that the IPL efferents are bilateral. Recent work has shown that mice with genetic ablations of the dMHb show profound defects in voluntary wheel running and changes in some but not all rodent models of mood state (Hsu et al, ). Thus the IPL efferent pathway may mediate a key link between activity and mood, and merits further investigation.…”

“…MHb efferents are directed almost entirely to the interpeduncular nucleus (IP), where the lateral subnucleus (IPL) receives dMHb input and several of the remaining subnuclei (rostral IP [IPR], caudal IP [IPC], intermediate IP [IPI], contralateral dorsolateral IP [IPDL]) receive vMHb input. Although the behavioral function of the MHb has been relatively mysterious, recent work has demonstrated a role for the dMHb in regulating voluntary wheel running and some behaviors related to mood or affect (Hsu, Morton, Guy, Wang, & Turner, ; Hsu et al, ), and a role for the vMHb and/or IP as mediating behavioral responses to nicotine, including reinforcement, aversion and withdrawal (Antolin‐Fontes, Ables, Gorlich, & Ibanez‐Tallon, ; Harrington et al, ; Salas, Sturm, Boulter, & De Biasi, ; Zhao‐Shea, Liu, Pang, Gardner, & Tapper, ; Zhao‐Shea et al, ). Recent work has also shown a role for presynpaptic vMHb CB1 receptors (Soria‐Gomez et al, ), and GABA‐B receptors (Zhang et al, ) in the regulation of conditioned fear responses.…”

Monosynaptic retrograde tracing of neurons expressing the G‐protein coupled receptor Gpr151 in the mouse brain

“…Subdivision of the habenular complex into smaller regions, defined by the expression of certain molecules or neuronal connectivity patterns, is a necessary strategy for deepening our understanding of its role in physiology and disease. This approach has been useful to target neuronal subpopulations and investigate their anatomical and functional features, especially in the medial habenula (Chou et al, ; Gardon et al, ; Hsu, Morton, Guy, Wang, & Turner, ; Hsu et al, ; Kobayashi et al, ).…”