title: Role of the dorsal medial habenula in the regulation of voluntary activity, motor function, hedonic state, and primary reinforcement.
abstract: The habenular complex in the epithalamus consists of distinct regions with diverse neuronal populations. Past studies have suggested a role for the habenula in voluntary exercise motivation and reinforcement of intracranial self-stimulation but have not assigned these effects to specific habenula subnuclei. Here, we have developed a genetic model in which neurons of the dorsal medial habenula (dMHb) are developmentally eliminated, via tissue-specific deletion of the transcription factor Pou4f1 (Brn3a). Mice with dMHb lesions perform poorly in motivation-based locomotor behaviors, such as voluntary wheel running and the accelerating rotarod, but show only minor abnormalities in gait and balance and exhibit normal levels of basal locomotion. These mice also show deficits in sucrose preference, but not in the forced swim test, two measures of depression-related phenotypes in rodents. We have also used Cre recombinase-mediated expression of channelrhodopsin-2 and halorhodopsin to activate dMHb neurons or silence their output in freely moving mice, respectively. Optical activation of the dMHb in vivo supports intracranial self-stimulation, showing that dMHb activity is intrinsically reinforcing, whereas optical silencing of dMHb outputs is aversive. Together, our findings demonstrate that the dMHb is involved in exercise motivation and the regulation of hedonic state, and is part of an intrinsic reinforcement circuit.
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: Si D
authors.identifier: http://orcid.org/0000-0001-8251-1450
authors.initials: SD
authors.lastname: Wang
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California 92037.
authors.forename: Shirong
authors.initials: S
authors.lastname: Wang
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98101.
authors.forename: Glenn
authors.identifier: http://orcid.org/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: Hatim A
authors.initials: HA
authors.lastname: Zariwala
authors.affiliation: Department of Biology, University of Washington, Seattle, Washington 98195-1800.
authors.forename: Horacio O
authors.initials: HO
authors.lastname: de la Iglesia
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98101, Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, and Center on Human Development and Disability, University of Washington, Seattle, Washington 98195 eric.turner@seattlechildrens.org.
authors.forename: Eric E
authors.identifier: http://orcid.org/0000-0001-5499-6788
authors.initials: EE
authors.lastname: Turner
mesh_terms: D000818:Animals; D000075402:Channelrhodopsins; D003216:Conditioning, Operant; D005518:Food Preferences; D019262:Habenula / Q000166:cytology / Q000502:physiology*; D008124:Locomotion / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009042:Motivation / Q000235:genetics / Q000502:physiology*; D009043:Motor Activity / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D062308:Optogenetics; D012054:Reinforcement, Psychology; D012653:Self Stimulation; D013550:Swimming / Q000502:physiology; D050857:Synaptotagmins / Q000235:genetics; D050819:Transcription Factor Brn-3A / Q000172:deficiency / Q000235:genetics; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D000075402:Channelrhodopsins; C494189:Pou4f1 protein, mouse; C494300:Syt6 protein, mouse; D050819:Transcription Factor Brn-3A; D050857:Synaptotagmins; D001616:beta-Galactosidase
keywords: exercise motivation; interpeduncular nucleus; intracranial self-stimulation; medial habenula; optogenetics