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      Amygdala to nucleus accumbens excitatory transmission facilitates reward seeking

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          Abstract

          The basolateral amygdala (BLA) plays a crucial role in emotional learning irrespective of valence 15 . 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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          Most cited references 14

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          Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning.

          Natural rewards and drugs of abuse can alter dopamine signaling, and ventral tegmental area (VTA) dopaminergic neurons are known to fire action potentials tonically or phasically under different behavioral conditions. However, without technology to control specific neurons with appropriate temporal precision in freely behaving mammals, the causal role of these action potential patterns in driving behavioral changes has been unclear. We used optogenetic tools to selectively stimulate VTA dopaminergic neuron action potential firing in freely behaving mammals. We found that phasic activation of these neurons was sufficient to drive behavioral conditioning and elicited dopamine transients with magnitudes not achieved by longer, lower-frequency spiking. These results demonstrate that phasic dopaminergic activity is sufficient to mediate mammalian behavioral conditioning.
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            Channelrhodopsin-2 and optical control of excitable cells.

            Electrically excitable cells are important in the normal functioning and in the pathophysiology of many biological processes. These cells are typically embedded in dense, heterogeneous tissues, rendering them difficult to target selectively with conventional electrical stimulation methods. The algal protein Channelrhodopsin-2 offers a new and promising solution by permitting minimally invasive, genetically targeted and temporally precise photostimulation. Here we explore technological issues relevant to the temporal precision, spatial targeting and physiological implementation of ChR2, in the context of other photostimulation approaches to optical control of excitable cells.
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              Subsecond dopamine release promotes cocaine seeking.

              The dopamine-containing projection from the ventral tegmental area of the midbrain to the nucleus accumbens is critically involved in mediating the reinforcing properties of cocaine. Although neurons in this area respond to rewards on a subsecond timescale, neurochemical studies have only addressed the role of dopamine in drug addiction by examining changes in the tonic (minute-to-minute) levels of extracellular dopamine. To investigate the role of phasic (subsecond) dopamine signalling, we measured dopamine every 100 ms in the nucleus accumbens using electrochemical technology. Rapid changes in extracellular dopamine concentration were observed at key aspects of drug-taking behaviour in rats. Before lever presses for cocaine, there was an increase in dopamine that coincided with the initiation of drug-seeking behaviours. Notably, these behaviours could be reproduced by electrically evoking dopamine release on this timescale. After lever presses, there were further increases in dopamine concentration at the concurrent presentation of cocaine-related cues. These cues alone also elicited similar, rapid dopamine signalling, but only in animals where they had previously been paired to cocaine delivery. These findings reveal an unprecedented role for dopamine in the regulation of drug taking in real time.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                29 August 2013
                29 June 2011
                17 September 2013
                : 475
                : 7356
                : 377-380
                Affiliations
                [1 ]Departments of Psychiatry & Cell and Molecular Physiology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
                [2 ]Ernest Gallo Clinic and Research Center, Department of Neurology, Wheeler Center for the Neurobiology of Drug Addiction, University of California San Francisco, San Francisco, CA USA
                [3 ]Departments of Bioengineering & Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA USA
                [4 ]Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD USA
                Author notes
                [* ]Address correspondence to: Garret D. Stuber, Ph.D., Assistant Professor, Departments of Psychiatry & Cell and Molecular 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
                Article
                NIHMS313003
                10.1038/nature10194
                3775282
                21716290

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                Funding
                Funded by: National Institute on Drug Abuse : NIDA
                Award ID: R21 DA029325 || DA
                Funded by: National Institute on Drug Abuse : NIDA
                Award ID: R01 DA032750 || DA
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