Distinct extended amygdala circuits for divergent motivational states

TitleDistinct extended amygdala circuits for divergent motivational states
Publication TypeJournal Article
Year of Publication2013
AuthorsJennings JH, Sparta DR, Stamatakis AM, Ung RL, Pleil KE, Kash TL, Stuber GD
JournalNature
Volume496
Issue7444
Pagination224-8
Date Published2013 Apr 11
ISSN1476-4687
KeywordsAmygdala, Animals, Anxiety, Avoidance Learning, Behavior, Animal, Channelrhodopsins, Cues, Electroshock, GABAergic Neurons, Glutamine, Male, Mice, Mice, Inbred C57BL, Motivation, Optogenetics, Phenotype, Reward, Septal Nuclei, Ventral Tegmental Area
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.

DOI10.1038/nature12041
Alternate JournalNature
PubMed ID23515155
PubMed Central IDPMC3778934
Grant ListF32 AA018610 / AA / NIAAA NIH HHS / United States
AA007573 / AA / NIAAA NIH HHS / United States
AA021043 / AA / NIAAA NIH HHS / United States
P60 AA011605 / AA / NIAAA NIH HHS / United States
R21 DA029325 / DA / NIDA NIH HHS / United States
AA011605 / AA / NIAAA NIH HHS / United States
P30 NS045892 / NS / NINDS NIH HHS / United States
T32 AA007573 / AA / NIAAA NIH HHS / United States
NS007431 / NS / NINDS NIH HHS / United States
F31 DA034472 / DA / NIDA NIH HHS / United States
DA032750 / DA / NIDA NIH HHS / United States
DA029325 / DA / NIDA NIH HHS / United States
DA034472 / DA / NIDA NIH HHS / United States
AA018610 / AA / NIAAA NIH HHS / United States
T32 NS007431 / NS / NINDS NIH HHS / United States
R01 DA032750 / DA / NIDA NIH HHS / United States
R37 DA032750 / DA / NIDA NIH HHS / United States