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Channelrhodopsin co-expression on tyrosine hydroxlase neurons in the substantia nigra

Research in the Carelli Lab incorporates a multidisciplinary approach in rodent models to examine how the brain processes information about rewards, how that information is used to guide goal-directed actions, and how it is altered in drug addiction. At the core of all our work is the development of sophisticated behavioral tasks that enable us to examine discrete aspects of reward processing. We then combine our behavioral tasks with various methodologies including: multi-neuron recording (single unit/multi-site and local field potential), electrochemistry (fast scan cyclic voltammetry, FSCV), optogenetics (alone and in combination with electrophysiology), calcium imaging methods, and a preclinical model of non-invasive brain stimulation. A brief overview of some topics currently under investigation in my lab are available below.

Neurobiological Investigation of Decision-Making

Dopamine signaling in the NAc scales with the costs associated with actions, placing this neural substrate in a critical juncture in the decision-making process. We use electrochemical methods to examine dopamine release dynamics in ‘real time’ during cue periods in our tasks when rats are evaluating their options and making decisions to act. We have shown that dopamine release scales with more preferred options in decision making tasks involving, effort, delay and risk. Ongoing research seeks to provide insight into how NAc circuitry encodes and controls decision-making under normal conditions using electrochemistry, electrophysiology and optogenetics, and determine how a history of cocaine can alter aspects of this processing. The latter is clinically relevant since several psychiatric diseases, including drug addiction, are believed to reflect maladaptive decision making linked with altered dopamine function.

Unraveling Neurobiological Mechanisms of Cocaine Addiction

The DSM-V recognizes the emergence of negative affect (e.g., dysphoria, irritability, anhedonia) in addiction, where prior rewarding experiences (e.g., food, job) become devalued as the addict continues to seek and use drug despite harmful outcomes. We continue working with a novel behavioral model we developed of natural reward devaluation by cocaine where we showed that a drug-associated cue elicits a conditioned aversive state that is quantifiable in terms of behavior, neural and chemical processing and, critically, predicts subsequent cocaine consumption. Other related lines of research are examining the neurobiological consequences in the NAc of drug removal (abstinence, known to exert numerous neuroadaptations linked to relapse), how a history of cocaine alters aspects of associative learning, and the role of reward choice in normal versus addicted states. In addition, we are examining processing within the larger neural circuit in which the NAc is embedded, including for example reward-processing within the insula and prefrontal (prelimbic and infralimbic) cortex. Additional studies are examining the role the ‘anti-reward’ system (e.g., RMTg and LHb) in these processes.

Preclinical Model of Non-Invasive Brain Stimulation

While it has proven extremely difficult to develop effective therapies to treat substance use disorders, one exciting approach that holds great promise is Non-Invasive Brain Stimulation (NIBS). Although studies using NIBS in humans are encouraging, virtually no information is known about how any form of NIBS can modulate maladaptive brain pathologies linked to repeated drug use, since rodent models of NIBS are lacking. Working with an expert in NIBS, Dr. Flavio Frohlich, the Carelli lab developed a rat model of one form of NIBS, transcranial alternating current stimulation (tACS). Ongoing studies are using this approach to: 1) determine if tACS can reverse cocaine-induced deficits in neural signaling and one aspect of associative learning (behavioral flexibility) and 2) if it can modulate drug taking/seeking behavior and underlying neuroadaptations. Since this approach is ‘noninvasive’ (i.e., electrical stimulation is applied to screws mounted on the skull, not in brain), it holds great translational value.

Stimulated rapid dopamine release in the nucleus accumbens measured with Fast Scan Cyclic VoltammetryGCaMP expression in prefrontal cortexChannelrhodopsin co-expression (green) on tyrosine hydroxlase (red) neurons