Our Research

Major Projects

Project 1 – Understanding addiction through tetrapartite synapses

This project expands on our recent discovery that relapse in the reinstatement model requires the rapid induction of transient synaptic potentiation (t-SP) in accumbens spiny cells. When an animal experiences a drug-conditioned cue t-SP occurs and this is correlated with the intensity of the behavioral response. Transient-SP occurs regardless of whether the animal was trained to self-administer cocaine, heroin or nicotine. Following up on this finding has resulted in establishing the model shown below, whereby down-regulated glutamate transport in astroglia and a retraction of astroglial processes adjacent to synapses causes synaptic glutamate spillover to stimulate nNOS interneurons, which activates matrix metalloproteases (MMPs). The activated MMPs create ligands for integrin receptors that signal postsynaptic insertion of AMPA receptors and dendritic spine enlargement (e.g. how we measure t-SP). In addition to clarifying details of this model, in future studies we are examining whether we can manipulate this microcircuit and thereby turn a biological reinforcer into a drug-like compulsive reinforcer and vice versa. 

Project 2 – Understanding subcircuits that regulate addiction

Another project is to examine circuitry distal to the nucleus accumbens mediating relapse to addictive drugs. For this project we have characterized the cell subtypes in the ventral pallidum and the subtypes of accumbens cells that provide afferents. Additionally, we find enduring drug-induced synaptic plasticity selectively in some ventral pallidal subcircuitry and only in certain subtypes of nucleus accumbens neurons.  To make these discoveries we use transgenic rodents coupled with viral transgenes to study the physiology, morphology and function of each subcircuit. This includes measurements of calcium transients using miniscopes attached to implanted lenses, electrophysiology electrophysiology in brain slices, high resolution confocal microscopy and behavior.

Project 3 – Understanding how PTSD correlates with substance abuse

We have a model of PTSD comorbidity with substance use disorder, with a focus on heroin and cannabis abuse.  Acute restraint stress leads to long term plasticity in cortico-accumbens projections and tetrapartite accumbens synaptic plasticity that strongly resembles the tetrapartite plasticity produced by drug self-administration (as outlined in Project 1). Moreover, associating stress with a conditioning odor causes odor induces tetrapartite synaptic plasticity and alters cue-induced seeking of cocaine, heroin and cannabis.

Project 4 – Neuropsychiatric disorders

We collaborate with clinicians at MUSC to evaluate N-acetylcysteine in clinical trials for regulating neuropsychiatric disorders characterized in part by intrusive thinking. We hypothesize that dysregulation of the circuitry outlined above creates a vulnerability to thoughts becoming intrusive and difficult to control, which is a characteristic of addiction (e.g. craving), anxiety disorders (e.g. PTSD), major depression and OCD. N-acetylcysteine normalizes drug induced changes in the circuit by restoring glutamate transport, and we have successfully used N-acetylcysteine to reduce cocaine craving and PTSD.