title: Dopamine neurons modulate neural encoding and expression of depression-related behaviour.
abstract: Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia. Dopamine neurons involved in reward and motivation are among many neural populations that have been hypothesized to be relevant, and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry.
authors.affiliation: Picower Institute for Learning and Memory, Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Department of Bioengineering, Stanford University, Stanford, California 94305, USA.
authors.forename: Kay M
authors.initials: KM
authors.lastname: Tye
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California 94305, USA.
authors.forename: Julie J
authors.initials: JJ
authors.lastname: Mirzabekov
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California 94305, USA.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Warden
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California 94305, USA.|Neurosciences Program, Stanford University, Stanford California 94305, USA.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Ferenczi
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California 94305, USA.|Neurosciences Program, Stanford University, Stanford California 94305, USA.
authors.forename: Hsing-Chen
authors.initials: HC
authors.lastname: Tsai
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California 94305, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Finkelstein
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California 94305, USA.|Neurosciences Program, Stanford University, Stanford California 94305, USA.
authors.forename: Sung-Yon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California 94305, USA.
authors.forename: Avishek
authors.initials: A
authors.lastname: Adhikari
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California 94305, USA.
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Thompson
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California 94305, USA.
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Andalman
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California 94305, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Gunaydin
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California 94305, USA.
authors.forename: Ilana B
authors.initials: IB
authors.lastname: Witten
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California 94305, USA.|Neurosciences Program, Stanford University, Stanford California 94305, USA.|Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305, USA.|Howard Hughes Medical Institute, Stanford University, Stanford California 94305, USA.|CNC Program, Stanford University, Stanford, California 94305, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
mesh_terms: D000818:Animals; D003863:Depression / Q000139:chemically induced / Q000503:physiopathology*; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D005260:Female; D008297:Male; D051379:Mice; D008959:Models, Neurological; D009714:Nucleus Accumbens / Q000378:metabolism; D062308:Optogenetics; D010641:Phenotype; D051381:Rats; D020318:Rats, Long-Evans; D013315:Stress, Psychological / Q000503:physiopathology; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000166:cytology
chemical_list: D004298:Dopamine