Unit of Neuromodulation and Synaptic Integration

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

In the last fiscal year, the Neuromodulation and Synaptic Integration Unit has dissected 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 generated an anatomical framework for how the dynorphin / KOR system is embedded in the PFC. This includes mapping the outputs of dynorphin-containing PFC cells to the rest of the brain, identifying the laminar organization of various excitatory projection and local-circuit inhibitory dynorphin-expressing cells, as well as the electrophysiological and morphological properties of dynorphin-expressing neurons. Furthermore, we have demonstrated that local-circuit PFC cells and afferents inputs expressing the KOR display a laminar organization. Since the laminar organization of cortical circuits is integral for information processing and execution of PFC-dependent behaviors, these data suggest that laminar organization of PFC dynorphin cell and KOR-expressing afferent inputs and PFC KOR cells, may contribute to information processing in ways not currently understood. Furthermore, we have delineated how stress recruits different PFC dynorphin-expressing neuronal populations and mobilizes dynorphin/KOR signaling utilizing in-vivo imaging approaches. We have demonstrated that PFC dynorphin-expressing cells show more threat-related changes in activity relative to dynorphin-lacking counterparts. We have also identified threat-induced changes in activity of excitatory and inhibitory PFC dynorphin cells. Further, we have elucidated 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. These studies advance our understanding of how cells that constitute the PFC dynorphin / KOR system are engaged by threats and utilize this peptidergic transmitter to change emotionally-charged behavior. Finally, we have demonstrated that dynorphin release has functional effects on cortical circuits via KOR signaling utilizing a combination of patch clamp electrophysiology and optogenetics. Dyn / KOR signaling inhibits excitatory synaptic transmission coming into the PFC from the thalamus and amygdala by directly acting on the presynaptic terminals of these afferents. Interestingly, other limbic inputs like the hippocampus are not regulated by the dynorphin / KOR system. Despite KORs decreasing excitatory inputs to the PFC in an input-specific manner, the net result of dynorphin signaling is a massive loss of feedforward/feedback inhibition (disinhibition), as dynorphin decreases excitatory drive of inhibitory interneurons. Even inputs that are KOR insensitive, like those coming from the hippocampus, are disinhibited by dynorphin/KOR signaling, emphasizing a local circuit mechanism by which dynorphin / KOR signaling shuts down feedforward/feedback inhibition. We find very sparse KOR expression in GABAergic interneurons and no evidence of direct actions of dynorphins on GABAergic interneurons, emphasizing that dynorphins indirectly depress excitatory drive of GABAergic circuits to limit PFC inhibition. We are currently utilizing cell-type specific pharmacology and knockout of KOR expression to further dissect the microcircuits through which dynorphin/KOR disintegrates inhibitory signaling in the PFC. 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. These findings are of relevance as 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, KOR ligands are being developed for the treatment of addictive and mood disorders, and this work may elucidate the mechanism by which KOR ligands may have therapeutic effects in treating neuropsychiatric disorders and reveal novel approaches to target this system to treat these disorders.