Computational model of extracellular glutamate in the nucleus accumbens predicts neuroadaptations by chronic cocaine

Notice: this is the author's version of a work that was accepted for publication in Neuroscience. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Neuroscience, Vol. 158, Issue #4 (2008) doi:10.1016/j.neuroscience.2008.11.014 . http://journals.elsevier.com/03064522/neuroscience/Chronic cocaine administration causes instability in extracellular glutamate in the nucleus accumbens that is thought to contribute to the vulnerability to relapse. A computational framework was developed to model glutamate in the extracellular space, including synaptic and nonsynaptic glutamate release, glutamate elimination by glutamate transporters and diffusion, and negative feedback on synaptic release via metabotropic glutamate receptors (mGluR2/3). This framework was used to optimize the geometry of the glial sheath surrounding excitatory synapses, and by inserting physiological values, accounted for known stable extracellular, extrasynaptic concentrations of glutamate measured by microdialysis and glutamatergic tone on mGluR2/3. By using experimental values for cocaine-induced reductions in cystine-glutamate exchange and mGluR2/3 signaling, the computational model successfully represented the experimentally observed increase in glutamate that is seen in rats during cocaine-seeking. This model provides a mathematical framework for describing how pharmacological or pathological conditions influence glutamate transmission measured by microdialysis

Amygdala inputs to prefrontal cortex guide behavior amid conflicting cues of reward and punishment

Orchestrating appropriate behavioral responses in the face of competing signals that predict either rewards or threats in the environment is crucial for survival. The basolateral nucleus of the amygdala (BLA) and prelimbic (PL) medial prefrontal cortex have been implicated in reward-seeking and fear-related responses, but how information flows between these reciprocally connected structures to coordinate behavior is unknown. We recorded neuronal activity from the BLA and PL while rats performed a task wherein competing shock- and sucrose-predictive cues were simultaneously presented. The correlated firing primarily displayed a BLA→PL directionality during the shock-associated cue. Furthermore, BLA neurons optogenetically identified as projecting to PL more accurately predicted behavioral responses during competition than unidentified BLA neurons. Finally photostimulation of the BLA→PL projection increased freezing, whereas both chemogenetic and optogenetic inhibition reduced freezing. Therefore, the BLA→PL circuit is critical in governing the selection of behavioral responses in the face of competing signals.National Institutes of Health (U.S.) (Award 1R25-MH092912-01)National Institute of Mental Health (U.S.) (Grant R01- MH102441-01)National Institutes of Health (U.S.) (Award DP2- DK-102256-01