title: Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience.
abstract: Typical therapies try to reverse pathogenic mechanisms. Here, we describe treatment effects achieved by enhancing depression-causing mechanisms in ventral tegmental area (VTA) dopamine (DA) neurons. In a social defeat stress model of depression, depressed (susceptible) mice display hyperactivity of VTA DA neurons, caused by an up-regulated hyperpolarization-activated current (I(h)). Mice resilient to social defeat stress, however, exhibit stable normal firing of these neurons. Unexpectedly, resilient mice had an even larger I(h), which was observed in parallel with increased potassium (K(+)) channel currents. Experimentally further enhancing Ih or optogenetically increasing the hyperactivity of VTA DA neurons in susceptible mice completely reversed depression-related behaviors, an antidepressant effect achieved through resilience-like, projection-specific homeostatic plasticity. These results indicate a potential therapeutic path of promoting natural resilience for depression treatment.
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Allyson K
authors.initials: AK
authors.lastname: Friedman
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Walsh
authors.forename: Barbara
authors.initials: B
authors.lastname: Juarez
authors.forename: Stacy M
authors.initials: SM
authors.lastname: Ku
authors.forename: Dipesh
authors.initials: D
authors.lastname: Chaudhury
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Xianting
authors.initials: X
authors.lastname: Li
authors.forename: David M
authors.initials: DM
authors.lastname: Dietz
authors.forename: Nina
authors.initials: N
authors.lastname: Pan
authors.forename: Vincent F
authors.initials: VF
authors.lastname: Vialou
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yue
authors.forename: Ming-Hu
authors.initials: MH
authors.lastname: Han
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003863:Depression / Q000503:physiopathology*; D059290:Dopaminergic Neurons / Q000502:physiology*; D055724:Electrophysiological Phenomena; D006706:Homeostasis; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D000077213:Lamotrigine; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D062308:Optogenetics; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism; D055500:Resilience, Psychological; D012919:Social Behavior; D013315:Stress, Psychological / Q000503:physiopathology*; D014227:Triazines / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000502:physiology*
chemical_list: D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D014227:Triazines; D000077213:Lamotrigine
references.citation: Science. 2009 Nov 20;326(5956):1127-30
references.pmid: 19965435
references.citation: J Neurosci. 2011 Jun 22;31(25):9084-92
references.pmid: 21697359
references.citation: Cell. 2007 Oct 19;131(2):391-404
references.pmid: 17956738
references.citation: Nat Neurosci. 2010 Jun;13(6):745-52
references.pmid: 20473292
references.citation: Nat Neurosci. 2009 Feb;12(2):200-9
references.pmid: 19151710
references.citation: Annu Rev Neurosci. 2011;34:89-103
references.pmid: 21438687
references.citation: Nat Neurosci. 2012 Nov;15(11):1475-84
references.pmid: 23064380
references.citation: Science. 2012 Oct 5;338(6103):79-82
references.pmid: 23042887
references.citation: N Engl J Med. 2011 Jan 6;364(1):51-9
references.pmid: 21208108
references.citation: Science. 1994 May 13;264(5161):974-7
references.pmid: 8178157
references.citation: Nat Rev Neurosci. 2009 Jun;10(6):446-57
references.pmid: 19455174
references.citation: J Pharmacol Sci. 2013;123(2):203-6
references.pmid: 24096830
references.citation: Neuron. 2012 Dec 20;76(6):1133-46
references.pmid: 23259949
references.citation: Nat Rev Neurosci. 2013 Dec;14(12):820-1
references.pmid: 24201182
references.citation: Biol Psychiatry. 2006 Jun 15;59(12):1151-9
references.pmid: 16566899
references.citation: Nat Protoc. 2011 Jul 21;6(8):1183-91
references.pmid: 21799487
references.citation: Science. 2006 Feb 10;311(5762):864-8
references.pmid: 16469931
references.citation: Science. 2009 May 22;324(5930):1080-4
references.pmid: 19389999
references.citation: J Neurosci. 2002 Feb 15;22(4):1290-302
references.pmid: 11850457
references.citation: Nat Neurosci. 2002 Aug;5(8):767-74
references.pmid: 12118259
references.citation: J Neurosci. 2008 Sep 3;28(36):8908-13
references.pmid: 18768684
references.citation: J Neurosci. 2010 Dec 8;30(49):16453-8
references.pmid: 21147984
references.citation: Nature. 2013 Jan 24;493(7433):537-541
references.pmid: 23235822
references.citation: J Physiol. 2008 Apr 15;586(8):2157-70
references.pmid: 18308824
references.citation: Nature. 2004 Oct 14;431(7010):789-95
references.pmid: 15483600
references.citation: Cognit Ther Res. 2008 Aug 1;32(4):507-525
references.pmid: 20360998
references.citation: Nat Neurosci. 2014 Jan;17(1):27-9
references.pmid: 24270188
references.citation: Physiol Rev. 2009 Jul;89(3):847-85
references.pmid: 19584315
references.citation: Nature. 2006 Sep 7;443(7107):81-4
references.pmid: 16929304
references.citation: Nature. 2012 Nov 8;491(7423):212-7
references.pmid: 23064228
references.citation: Neuron. 2008 Mar 13;57(5):760-73
references.pmid: 18341995
references.citation: Clin Psychol Rev. 2011 Mar;31(2):236-48
references.pmid: 20447745
references.citation: Science. 2012 Oct 5;338(6103):124-8
references.pmid: 23042896