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      Distinct extended amygdala circuits for divergent motivational states

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          Summary

          The comorbidity of anxiety and dysfunctional reward processing in illnesses such as addiction 1 and depression 2 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 3, 4 , but also projects to the ventral tegmental area (VTA) 5, 6 , a region implicated in reward and aversion 713 , 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 recorded and manipulated 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. In contrast, in vivo optically-identified glutamatergic projection neurons displayed a net enhancement of activity to aversive stimuli, whereas the firing rate of identified GABAergic projection neurons was suppressed. Channelrhodopsin-2 (ChR2) 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 behavioral phenotypes. In contrast, 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 critical circuit node for bidirectionally normalizing maladaptive behaviors.

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          Most cited references23

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          Dopamine neurons modulate neural encoding and expression of depression-related behaviour.

          Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia. Dopamine neurons involved in reward and motivation are among many neural populations that have been hypothesized to be relevant, and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry.
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            Amygdala to nucleus accumbens excitatory transmission facilitates reward seeking

            The basolateral amygdala (BLA) plays a crucial role in emotional learning irrespective of valence 1–5 . While the BLA projection to the nucleus accumbens (NAc) is hypothesized to modulate cue-triggered motivated behaviors 4, 6, 7,, our understanding of the interaction between these two brain regions has been limited by the inability to manipulate neural circuit elements of this pathway selectively during behavior. To circumvent this limitation, we used in vivo optogenetic stimulation or inhibition of glutamatergic fibers from the BLA to the NAc, coupled with intracranial pharmacology and ex vivo electrophysiology. We show that optical stimulation of the BLA-to-NAc pathway in mice reinforces behavioral responding to earn additional optical stimulations of these synaptic inputs. Optical stimulation of BLA-to-NAc glutamatergic fibers required intra-NAc dopamine D1-type, but not D2-type, receptor signaling. Brief optical inhibition of BLA-to-NAc fibers reduced cue-evoked intake of sucrose, demonstrating an important role of this specific pathway in controlling naturally occurring reward-related behavior. Moreover, while optical stimulation of medial prefrontal cortex (mPFC) to NAc glutamatergic fibers also elicited reliable excitatory synaptic responses, optical self-stimulation behavior was not observed by activation of this pathway. These data suggest that while the BLA is important for processing both positive and negative affect, the BLA-to-NAc glutamatergic pathway in conjunction with dopamine signaling in the NAc promotes motivated behavioral responding.
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              Ventral tegmental area neurons in learned appetitive behavior and positive reinforcement.

              Ventral tegmental area (VTA) neuron firing precedes behaviors elicited by reward-predictive sensory cues and scales with the magnitude and unpredictability of received rewards. These patterns are consistent with roles in the performance of learned appetitive behaviors and in positive reinforcement, respectively. The VTA includes subpopulations of neurons with different afferent connections, neurotransmitter content, and projection targets. Because the VTA and substantia nigra pars compacta are the sole sources of striatal and limbic forebrain dopamine, measurements of dopamine release and manipulations of dopamine function have provided critical evidence supporting a VTA contribution to these functions. However, the VTA also sends GABAergic and glutamatergic projections to the nucleus accumbens and prefrontal cortex. Furthermore, VTA-mediated but dopamine-independent positive reinforcement has been demonstrated. Consequently, identifying the neurotransmitter content and projection target of VTA neurons recorded in vivo will be critical for determining their contribution to learned appetitive behaviors.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                29 August 2013
                20 March 2013
                11 April 2013
                11 October 2013
                : 496
                : 7444
                : 224-228
                Affiliations
                [1 ]Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
                [2 ]Neurobiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
                [3 ]Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
                [4 ]Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
                [5 ]Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
                [6 ]Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
                Author notes
                [# ]Address correspondence to: Garret D. Stuber, Ph.D., Assistant Professor, Departments of Psychiatry & Cell Biology and Physiology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Tel: +1 (919) 843-7140, Fax: +1 (919) 966-1050, gstuber@ 123456med.unc.edu
                [*]

                These authors contributed equally to this work

                Article
                NIHMS449605
                10.1038/nature12041
                3778934
                23515155
                931dd447-6ca9-4771-ab74-091dde8f0720

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                History
                Funding
                Funded by: National Institute on Drug Abuse : NIDA
                Award ID: R01 DA032750 || DA
                Funded by: National Institute on Drug Abuse : NIDA
                Award ID: F31 DA034472 || DA
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