title: Distinct extended amygdala circuits for divergent motivational states.
abstract: The co-morbidity of anxiety and dysfunctional reward processing in illnesses such as addiction and depression suggests that common neural circuitry contributes to these disparate neuropsychiatric symptoms. The extended amygdala, including the bed nucleus of the stria terminalis (BNST), modulates fear and anxiety, but also projects to the ventral tegmental area (VTA), a region implicated in reward and aversion, thus providing a candidate neural substrate for integrating diverse emotional states. However, the precise functional connectivity between distinct BNST projection neurons and their postsynaptic targets in the VTA, as well as the role of this circuit in controlling motivational states, have not been described. Here we record and manipulate the activity of genetically and neurochemically identified VTA-projecting BNST neurons in freely behaving mice. Collectively, aversive stimuli exposure produced heterogeneous firing patterns in VTA-projecting BNST neurons. By contrast, in vivo optically identified glutamatergic projection neurons displayed a net enhancement of activity to aversive stimuli, whereas the firing rate of identified GABAergic (γ-aminobutyric acid-containing) projection neurons was suppressed. Channelrhodopsin-2-assisted circuit mapping revealed that both BNST glutamatergic and GABAergic projections preferentially innervate postsynaptic non-dopaminergic VTA neurons, thus providing a mechanistic framework for in vivo circuit perturbations. In vivo photostimulation of BNST glutamatergic projections resulted in aversive and anxiogenic behavioural phenotypes. Conversely, activation of BNST GABAergic projections produced rewarding and anxiolytic phenotypes, which were also recapitulated by direct inhibition of VTA GABAergic neurons. These data demonstrate that functionally opposing BNST to VTA circuits regulate rewarding and aversive motivational states, and may serve as a crucial circuit node for bidirectionally normalizing maladaptive behaviours.
authors.affiliation: Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Joshua H
authors.initials: JH
authors.lastname: Jennings
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Sparta
authors.forename: Alice M
authors.initials: AM
authors.lastname: Stamatakis
authors.forename: Randall L
authors.initials: RL
authors.lastname: Ung
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Pleil
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Kash
authors.forename: Garret D
authors.initials: GD
authors.lastname: Stuber
mesh_terms: D000679:Amygdala / Q000502:physiology*; D000818:Animals; D001007:Anxiety / Q000503:physiopathology; D001362:Avoidance Learning; D001522:Behavior, Animal / Q000502:physiology; D000075402:Channelrhodopsins; D003463:Cues; D004597:Electroshock; D059330:GABAergic Neurons / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009042:Motivation / Q000502:physiology*; D062308:Optogenetics; D010641:Phenotype; D012201:Reward; D012686:Septal Nuclei / Q000502:physiology; D017557:Ventral Tegmental Area / Q000502:physiology
chemical_list: D000075402:Channelrhodopsins; D005973:Glutamine