In the last fiscal year, the Neuromodulation and Synaptic Integration Unit was established and our group has equipped the laboratory with in-vivo imaging, whole-cell patch clamp electrophysiology, transgenic and viral approaches, and various behavioral assays to dissect the impact of stress and neuromodulators on motivational circuits. Using the interdisciplinary approaches described above, our group has started to dissect the function of the dynorphin / KOR system in regulating prefrontal cortex (PFC) circuit dynamics and the role of this system in the PFC in shaping stress reactivity. We have identified that dynorphin, the endogenous ligand of the KOR, is expressed in a subset of inhibitory GABAergic PFC neurons that control synaptic integration in projection neurons. Moreover, dynorphin is expressed in excitatory glutamatergic projection neurons that make functional synaptic connections in multiple limbic regions, including the ventral tegmental area (VTA), nucleus accumbens (NAcc), and paraventricular nucleus of the thalamus (PVT). This is of interest as these are all brain regions with heavy kappa-opioid receptor expression. Furthermore, we have also started to delineate how stress recruits different PFC dynorphin-expressing neuronal populations to promote mal-adaptive physiological responses to threats utilizing in-vivo imaging approaches. On-going work is aimed at determining the role of dynorphin release and subsequent kappa-opioid receptor activation in mediating physiological and behavioral arousal induced by stress utilizing a novel fluorescence-based kappa-opioid receptor sensor and genetic/viral approaches to ablate prodynorphin gene expression. Overall, this last fiscal year our group has laid the foundation to deconstruct the role of the dynorphin/kappa-opioid receptor system in mediating the effects of stress on PFC circuits critical for emotion, motivation, and cognition.
