title: Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons.
abstract: Ventral tegmental area (VTA) dopamine neurons in the brain's reward circuit have a crucial role in mediating stress responses, including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities. VTA dopamine neurons show two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing. Phasic firing of the neurons, which is well known to encode reward signals, is upregulated by repeated social-defeat stress, a highly validated mouse model of depression. Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no apparent change in firing rate in resilient individuals. However, direct evidence--in real time--linking dopamine neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here we took advantage of the temporal precision and cell-type and projection-pathway specificity of optogenetics to show that enhanced phasic firing of these neurons mediates susceptibility to social-defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons of mice undergoing a subthreshold social-defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social-defeat stress. Furthermore, we show differences in projection-pathway specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to social-defeat stress. Conversely, optogenetic inhibition of the VTA-NAc projection induced resilience, whereas inhibition of the VTA-mPFC projection promoted susceptibility. Overall, these studies reveal novel firing-pattern- and neural-circuit-specific mechanisms of depression.
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Dipesh
authors.initials: D
authors.lastname: Chaudhury
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Walsh
authors.forename: Allyson K
authors.initials: AK
authors.lastname: Friedman
authors.forename: Barbara
authors.initials: B
authors.lastname: Juarez
authors.forename: Stacy M
authors.initials: SM
authors.lastname: Ku
authors.forename: Ja Wook
authors.initials: JW
authors.lastname: Koo
authors.forename: Deveroux
authors.initials: D
authors.lastname: Ferguson
authors.forename: Hsing-Chen
authors.initials: HC
authors.lastname: Tsai
authors.forename: Lisa
authors.initials: L
authors.lastname: Pomeranz
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Christoffel
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Nectow
authors.forename: Mats
authors.initials: M
authors.lastname: Ekstrand
authors.forename: Ana
authors.initials: A
authors.lastname: Domingos
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Mazei-Robison
authors.forename: Ezekiell
authors.initials: E
authors.lastname: Mouzon
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Lobo
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Friedman
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Russo
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.forename: Ming-Hu
authors.initials: MH
authors.lastname: Han
mesh_terms: D000818:Animals; D003863:Depression / Q000209:etiology / Q000503:physiopathology*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D005518:Food Preferences; D008297:Male; D008636:Mesencephalon / Q000166:cytology*; D051379:Mice; D009434:Neural Pathways; D009714:Nucleus Accumbens / Q000502:physiology; D062308:Optogenetics; D010641:Phenotype; D017397:Prefrontal Cortex / Q000502:physiology; D012919:Social Behavior; D013315:Stress, Psychological / Q000150:complications / Q000503:physiopathology*; D013395:Sucrose / Q000008:administration & dosage; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000502:physiology
chemical_list: D013395:Sucrose