title: 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.
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute , Seattle, Washington 98101.
authors.forename: Yun-Wei A
authors.initials: YW
authors.lastname: Hsu
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute , Seattle, Washington 98101.
authors.forename: Glenn
authors.identifier: 0000-0002-4823-3116
authors.initials: G
authors.lastname: Morton
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute , Seattle, Washington 98101.
authors.forename: Elizabeth G
authors.identifier: 0000-0002-6842-2782
authors.initials: EG
authors.lastname: Guy
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute , Seattle, Washington 98101.
authors.forename: Si D
authors.identifier: 0000-0001-8251-1450
authors.initials: SD
authors.lastname: Wang
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute , Seattle, Washington 98101.
authors.forename: Eric E
authors.identifier: 0000-0001-5499-6788
authors.initials: EE
authors.lastname: Turner
mesh_terms: D000339:Affect / Q000502:physiology*; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D003213:Conditioning, Psychological / Q000502:physiology; D003863:Depression / Q000378:metabolism; D005239:Fear / Q000502:physiology; D015870:Gene Expression; D019262:Habenula / Q000378:metabolism*; D006380:Helplessness, Learned; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D012054:Reinforcement, Psychology; D020665:Septum of Brain / Q000378:metabolism; D013037:Spatial Behavior / Q000502:physiology; D015320:Tachykinins / Q000378:metabolism*; D046509:Tissue Culture Techniques; D050819:Transcription Factor Brn-3A / Q000172:deficiency* / Q000235:genetics
chemical_list: C494189:Pou4f1 protein, mouse; D015320:Tachykinins; D050819:Transcription Factor Brn-3A
keywords: fear conditioning; habenula; interpeduncular nucleus; learned helplessness; substance P