title: Synaptic potentiation onto habenula neurons in the learned helplessness model of depression.
abstract: The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.
authors.affiliation: Center for Neural Circuits and Behavior, Department of Neuroscience, University of California at San Diego, La Jolla, California 92093, USA. bli@cshl.edu
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Joaquin
authors.initials: J
authors.lastname: Piriz
authors.forename: Martine
authors.initials: M
authors.lastname: Mirrione
authors.forename: ChiHye
authors.initials: C
authors.lastname: Chung
authors.forename: Christophe D
authors.initials: CD
authors.lastname: Proulx
authors.forename: Daniela
authors.initials: D
authors.lastname: Schulz
authors.forename: Fritz
authors.initials: F
authors.lastname: Henn
authors.forename: Roberto
authors.initials: R
authors.lastname: Malinow
mesh_terms: D000818:Animals; D001362:Avoidance Learning; D046690:Deep Brain Stimulation; D003863:Depression / Q000473:pathology* / Q000503:physiopathology* / Q000628:therapy; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006380:Helplessness, Learned; D008297:Male; D008959:Models, Neurological; D056347:Neuroanatomical Tract-Tracing Techniques; D009474:Neurons / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission; D013788:Thalamus / Q000378:metabolism / Q000473:pathology*; D017557:Ventral Tegmental Area / Q000502:physiology
chemical_list: D004298:Dopamine