Unit of Neuromodulation and Synaptic Integration

National Institute Of Mental Health

Investigators

Linked publications & trials

Abstract

In the last fiscal year, the Neuromodulation and Synaptic Integration Unit has dissected the function of endogenous opioids and dopamine in regulating limbic circuits to control emotional behaviors and motivation. In one major project, we dissected the role of endogenous opioid systems in the prefrontal cortex in orchestrating defensive behaviors in response to threats. Using in-vivo imaging approaches, we demonstrated that stress recruits prefrontal cortical cells expressing dynorphin- and mobilizes dynorphin/kappa-opioid receptor signaling. We have demonstrated that prefrontal cortical dynorphin-expressing cells show more threat-related changes in activity relative to dynorphin-lacking counterparts. We also identified threat-induced changes in activity of excitatory and inhibitory prefrontal cortical dynorphin cells. Using viral-mediated knockdown of dynorphin expression we have shown the dynorphin/kappa-opioid receptor signaling is required to mount adaptive responses to threats and limit the expression of passive fear states. We delineated the cellular and microcircuit basis by which dynorphin/kappa-opioid receptor signaling can shape prefrontal cortical circuits using electrophysiological procedures. We demonstrated that select afferent inputs express kappa-opioid receptors on presynaptic terminals innervating the prefrontal cortex. At synapses from kappa-opioid receptor positive inputs to the prefrontal cortex, dynorphin signaling limits how much these excitatory inputs can recruit prefrontal neuronal ensembles. Additionally, dynorphin/kappa-opioid receptor signaling inhibits the ability of afferent inputs to recruit inhibitory microcircuits, potentiating the ability of afferent inputs lacking presynaptic kappa-opioid receptors to engage prefrontal cortical circuits. This provides a physiological framework by which dynorphin/kappa-opioid receptor signaling can shift how excitatory limbic pathways control prefrontal cortical circuits. Lastly, using single cell calcium imaging in mice with prefrontal cortical dynorphin knockdown, we demonstrated that threats are not as efficacious at exciting, and to a lesser extent inhibiting, prefrontal cortical ensembles. Loss of prefrontal dynorphin/kappa-opioid receptor signaling also dramatically disrupted population-level encoding of threat states by prefrontal cortical circuits, suggesting that dynorphin/kappa-opioid receptor signaling may be critical for shifting the prefrontal cortical network to a state conducive for mounting adaptive behaviors in the face of threats. These studies advance our understanding of how cells that constitute the prefrontal dynorphin / kappa-opioid receptor system are engaged by threats and use this peptidergic transmitter to change emotionally-charged behavior. In sum, over 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 prefrontal circuits critical for emotion, motivation, and cognition. These findings are relevant because disinhibition of cortical circuits is implicated in mediating disruptions in cognition in various neuropsychiatric disorders, including schizophrenia, and kappa-opioid receptor activation produces cognitive disruptions and psychotomimetic effects in humans. Furthermore, kappa-opioid receptor ligands are being developed for the treatment of addictive and mood disorders, and this work may elucidate the mechanism by which kappa-opioid receptor ligands can have therapeutic effects in treating neuropsychiatric disorders, revealing the targeting of this system as a potential novel approach for treatment of these disorders. In another study, our laboratory has made significant progress in eludcidating the role of distinct dopamine receptors in the ventral striatum in regulating dissociable features of reward function; motivation and reinforcement. Dopamine release in striatal circuits, including the nucleus accumbens (NAc), tracks separable features of reward such as motivation and reinforcement. However, the cellular and circuit mechanisms by which dopamine receptors transform dopamine release into distinct constructs of reward remain unclear. Here, our lab demonstrated that dopamine D3 receptor (D3R) signaling in the NAc drives motivated behavior by regulating local NAc microcircuits. Furthermore, D3Rs co-express with dopamine D1 receptors (D1Rs), which regulate reinforcement, but not motivation. Paralleling dissociable roles in reward function, we report non-overlapping physiological actions of D3R and D1R signaling in NAc neurons. Our results establish a novel cellular framework wherein dopamine signaling within the same NAc cell type is physiologically compartmentalized via actions on distinct dopamine receptors. This structural and functional organization provides neurons in a limbic circuit with the unique ability to orchestrate dissociable aspects of reward-related behaviors that are relevant to the etiology of neuropsychiatric disorders.