1. Neural Circuitry of Sign- and Goal-Tracking Phenotypes
Pavlovian conditioning procedures can be used to distinguish “sign-tracking” rats that tend to attribute high levels of motivational significance to discrete predictive cues while largely ignoring context, from “goal-tracking” rats that make more use of context to appropriately modify their emotional responses. Sign-tracking individuals are more prone to both addiction- and PTSD-like behaviors than goal-trackers. We are exploring the neurobiological basis of these behavioral traits by using viral vectors to manipulate growth factor expression and epigenetic mechanisms in order to test for a causal influence on conditioned motivational responses. We are also using electrophysiological measures of connectivity and synaptic efficiency within limbic pathways of interest. These experiments are designed to test the hypothesis that goal-trackers have an increased capacity to use contextual information, derived from hippocampal inputs and relayed through the medial prefrontal cortex, to appropriately modify subcortical responses to cues associated with emotionally salient events.
2. Drug Discovery
The ultimate impetus behind most of our research efforts is a desire to reduce the burden of human illness. In contrast to most other psychiatric disorders, animal models of addiction generally have good construct and predictive validity, and several effective pharmacologic treatments for addiction have been developed directly from animal research. We are screening compounds for an ability to selectively reduce the motivational salience of conditioned cues, in the hope that they might be useful for reducing symptoms of addiction, PTSD, and other related disorders. We have found promising results from a number of different classes of drugs that can be systemically administered, including cannabinoid agonists and NMDA-receptor antagonists, and we are currently pursuing neuroimmune modulators as a potential new avenue for treating psychiatric disorders.
3. Translation of Sign- and Goal Tracking Research to Human Subjects
Sign-tracking captures several core features of addiction and predicts the development of addiction-like behaviors in animals. Though sign-tracking behavior has been studied in dozens of organisms from primates to invertebrates, there have as yet been few published attempts to measure sign- and goal-tracking in humans. We have now developed behavioral procedures that can capture individual variability in human sign- and goal-tracking. We are developing more tasks that will be compatible with different types of clinical research techniques. These experiments will open the door to a number of clinical studies that could facilitate translation of findings from animal research into effective treatments and preventative strategies for human patients.