Focus. This laboratory investigates the interface of pharmacology, molecular neuroscience, and behavior. We use strategies that span several levels of organization from RNA regulation, protein translation, cellular plasticity, and neural circuit level analysis of complex behaviors relating to stress and addiction models. We use rat and mouse behavioral models as well as in vitro cultures of cell lines and primary neurons to study components of intracellular signaling pathways.
Why are some individuals vulnerable to stress while others are resilient? How can we enhance resilience and recovery? Can we reverse compulsively learned behaviors? Can we reduce the impact of opioid or alcohol withdrawal and the relapse to drug seeking?
Methods. We use intersectional genetic manipulations in rats and mice to manipulate neural activity and plasticity with DREADD chemogenetic receptors, RiboTag analysis of RNAs under active translation, and a variety of behavioral strategies to understand how neural circuits adapt to stress, develop compulsive behaviors, and exposure to addictive drugs in the hopes of identifying new targets for therapeutics. We are now adapting Crispr gene editing to test whether discrete mutations of key proteins in specific target cells will elucidate the function of these circuits. We use a wide variety of operant conditioning models to investigate drug taking and seeking, memory function, compulsivity, as well as a range of behavioral tests for stress responses, anxiety, and hedonic regulation.
1. Stress-induced plasticity in serotonin neurons: vulnerability and resilience. This is a part of the UW Conte Center for Basic or Translational Mental Health Research. We are using a variety of molecular strategies and behavior in transgenic mice to investigate how adaptations in serotonin neurons confer vulnerability or resilience to repeated stress exposure.
2. Lateral habenula in stress and resilience. This tiny brain region plays a profound role in mediating aversive information processing in the brain. We are studying how manipulating the discrete outputs from this nucleus regulates modulates stress responses that are relevant to conditions such as depression and PTSD. We are also using translatome analysis with RiboTag expressed in the discrete output projections from this nucleus to identify molecular targets for manipulating the activity of these neurons during exposure to aversive stimuli. We also investigate these circuits in relation to cocaine addiction with our colleague Sunila Nair, Ph.D.
3. The role of direct and indirect pathway medium spiny neurons in cocaine self-administration and the incubation of craving. The laboratory is also exploring the role of neural inflammation involving microglia in the brain using similar molecular and behavioral strategies.
4. 5-HT receptors in striatum. We are investigating the role of 5-HT1B and 5-HT6 receptors in regulating cocaine seeking using self-administration and cell culture strategies using overexpression and knockdown of these receptors in specific neuron populations to understand the intracellular signaling cascades that mediate serotonin actions.
5. Microglia in opioid and alcohol withdrawal. We are using mice expressing RiboTag in microglia to understand the changes in these inflammatory cells that occur with opioid tolerance and withdrawal.
Our research is supported by Grants from NIMH and NIDA.