Scientific Understanding of Consciousness
Amygdala Involved in Anxiety State
Nature 496, 219–223 (11 April 2013)
Diverging neural pathways assemble a behavioural state from separable features in anxiety
Department of Bioengineering, Stanford University, Stanford, California 94305, USA
Sung-Yon Kim, Avishek Adhikari, Soo Yeun Lee, James H. Marshel, Christina K. Kim, Caitlin S. Mallory, Maisie Lo, Sally Pak, Joanna Mattis, Melissa R. Warden, Kay M. Tye & Karl Deisseroth
Neurosciences Program, Stanford University, Stanford, California 94305, USA
Sung-Yon Kim, Christina K. Kim, Caitlin S. Mallory, Joanna Mattis & Karl Deisseroth
CNC Program, Stanford University, Stanford, California 94305, USA
Soo Yeun Lee & Karl Deisseroth
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305, USA
Byung Kook Lim, Robert C. Malenka & Karl Deisseroth
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Rachael Neve & Kay M. Tye
Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA
Behavioural states in mammals, such as the anxious state, are characterized by several features that are coordinately regulated by diverse nervous system outputs, ranging from behavioural choice patterns to changes in physiology (in anxiety, exemplified respectively by risk-avoidance and respiratory rate alterations). Here we investigate if and how defined neural projections arising from a single coordinating brain region in mice could mediate diverse features of anxiety.
Integrating behavioural assays, in vivo and in vitro electrophysiology, respiratory physiology and optogenetics, we identify a surprising new role for the bed nucleus of the stria terminalis (BNST) in the coordinated modulation of diverse anxiety features.
First, two BNST subregions were unexpectedly found to exert opposite effects on the anxious state: oval BNST activity promoted several independent anxious state features, whereas anterodorsal BNST-associated activity exerted anxiolytic influence for the same features.
Notably, we found that three distinct anterodorsal BNST efferent projections—to the lateral hypothalamus, parabrachial nucleus and ventral tegmental area—each implemented an independent feature of anxiolysis: reduced risk-avoidance, reduced respiratory rate, and increased positive valence, respectively. Furthermore, selective inhibition of corresponding circuit elements in freely moving mice showed opposing behavioural effects compared with excitation, and in vivo recordings during free behaviour showed native spiking patterns in anterodorsal BNST neurons that differentiated safe and anxiogenic environments.
These results demonstrate that distinct BNST subregions exert opposite effects in modulating anxiety, establish separable anxiolytic roles for different anterodorsal BNST projections, and illustrate circuit mechanisms underlying selection of features for the assembly of the anxious state.
Here, we have mapped the role of BNST circuit elements in the assembly and modulation of the anxious behavioural state.
Many complexities are involved in anxiety, including brain regions, hormonal changes, and physiological manifestations beyond those investigated here. For example, none of our manipulations altered heart rate, consistent with a previous report suggesting the BNST does not modulate this feature of anxiety and pointing to the need for further exploration of sympathetic pathways. Moreover, the anxious state may be parsed still further to delineate additional features, such as changes in exploratory drive or in novelty seeking, which could involve networks not explored here. It is likely that complex circuit structure and dynamics are required to assemble behavioural states in animals with highly diverse repertoires of internal states and adaptations to the environment.
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Nature 496, 224–228 (11 April 2013)
Distinct extended amygdala circuits for divergent motivational states
Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
Joshua H. Jennings, Dennis R. Sparta, Alice M. Stamatakis, Randall L. Ung & Garret D. Stuber
Neurobiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
Joshua H. Jennings, Alice M. Stamatakis, Thomas L. Kash & Garret D. Stuber
Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
Dennis R. Sparta, Kristen E. Pleil, Thomas L. Kash & Garret D. Stuber
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
Kristen E. Pleil & Thomas L. Kash
Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
Thomas L. Kash & Garret D. Stuber
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
Garret D. Stuber
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.
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