Elyssa Margolis, PhD

Associate Professor

Neurology

415-353-4793

Behavior is energized by motivations and shaped by either positive (rewarding) or negative

(punishing) outcomes. Opioids in the CNS play a major role in motivation and can drive experiences of either reward or punishment. Understanding how opioid receptors and release of endogenous opioid peptides contribute to these processes requires identifying the neural circuits responsible for these processes and then determining how the opioid receptors act on the component neurons of the relevant circuits. At the center of the circuits we study are the ventral tegmental area (VTA) and the lateral habenula (LHb). The VTA is the source of dopamine in the reward circuitry of the brain, while activity in the LHb is strongly associated with negative affect. We are investigating how these brain regions change anatomically and physiologically following exposure to drugs of abuse, stress, and/or painful injury, with the goal of identifying a target for a treatment for alcohol use disorder, substance use disorder, and pain.

We also use ex vivo extracellular and whole cell electrophysiological approaches to characterize differences in GPCR drug pharmacologies. The VTA neurons are rich in neuropeptide receptors, especially opioid receptors, enabling us to utilize acute brain slices to differentiate GPCR pharmacologies that have been difficult to detect in heterologous systems. We also compare pharmacological profiles across several brain regions in order to find parallels to behavioral effects. This method of testing compound pharmacology in real brain tissue at the single neuron physiological level gives us the opportunity to more accurately predict in vivo activity at the behavioral level than heterologous systems.

Together, this ongoing research informs our understanding of the normal and compromised function of the motivational circuits through the VTA and LHb, with the goal of identifying new therapeutic approaches to modulating these circuits.