Cortex-basal ganglia interactions in drug addiction and motivated behavior

A main theme of the lab is studying how interactions between the hippocampus, nucleus accumbens, and prefrontal cortex underlie both physiological reward valuation and the pathological overvaluation of drugs of abuse. Our previous work characterized the role of interactions between hippocampus and nucleus accumbens in cocaine conditioned place preference, finding evidence that selective potentiation of specific hippocampal inputs to accumbens stores information linking certain spatial contexts to drug use. This provides a possible mechanistic substrate for the well-known phenomenon by which relapse is triggered by exposure to “people, places, and things” previously associated with drug use. Our current work expands upon this using a range of sophisticated approaches.

The foundation of most of our experiments is carefully-designed behavioral tasks that isolate the variables of interest and allow them to be measured quantitatively. We are currently using freely-moving and head-fixed versions of tasks in which an animal chooses between different options with reward values that change unpredictably.

One of our main experimental approaches is multi-site silicon optoprobe recordings in transgenic mice performing behavioral tasks. We perform these recordings in both freely-moving and head-fixed mice using many probe configurations ranging from multishank μLED optoprobes to Neuropixels probes. These large-scale recordings generate many terabytes of data, and we rely heavily on dimensionality reduction and machine learning approaches to characterize and understand the population-level coordination of neuronal activity between the striatum, hippocampus, and PFC during decision making or drug self-administration. In order to test the function of various circuit elements, we also use closed-loop optogenetic manipulations triggered on real-time analysis of local field potentials, spiking activity, and behavioral events. When combined with well-designed behavioral tasks, this allows us to make both precise perturbations and sensitive measurements of the behavioral effects.

Another major theme of the lab is linking transcriptomically-defined cell classes to their functional roles during decision-making and addiction-related behaviors. In addition to using optotagging to identify known genetically-identified cell populations, we use activity-dependent labeling to mark cells that are active during specific behavioral or neurophysiological events. We then determine the transcriptomic cell type of labeled cells using pciSeq, a technique developed by our collaborator Jens Hjerling-Leffler. pciSeq uses hundreds of simultaneously applied hybridization probes that each contain a unique barcode that is sequenced in situ. A custom algorithm then counts the transcripts associated with each nucleus in the image and maps each cell to a transcriptomic cluster previously identified using scRNA-seq.

Developing novel translational strategies for treating drug addiction

Drug addiction represents a large public health burden for which few effective biologically-based treatments exist. A second theme of the lab is developing novel gene-based tools and validating anatomical targets for future translational studies in human subjects. Our previous work in this area has focused on using DREADDs to modulate nucleus accumbens and suppress alcohol consumption in a model of binge drinking.

Our current work focuses on opioid and cocaine use disorders, using novel DREADD variants we have developed to target and manipulate several parts of the canonical basal ganglia-VTA circuit. We are also developing a viral vector system to express these DREADDs reversibly in wild type animals for primate testing in collaboration with the laboratory of Emad Eskandar.

Our work has been generously supported by these organizations:

The Peter F. McManus Charitable Trust