Prefrontal cortical dynorphin peptidergic transmission constrains threat-driven behavioral and network states.

Prefrontal cortical (PFC) circuits provide top-down control of threat reactivity. This includes ventromedial PFC (vmPFC) circuitry, which plays a role in suppressing fear-related behavioral states. Dynorphin (Dyn) has been implicated in mediating negative affect and maladaptive behaviors induced by severe threats and is expressed in limbic circuits, including the vmPFC. However, there is a critical knowledge gap in our understanding of how vmPFC Dyn-expressing neurons and Dyn transmission detect threats and regulate expression of defensive behaviors. Here, we demonstrate that Dyn cells are broadly activated by threats and release Dyn locally in the vmPFC to limit passive defensive behaviors. We further demonstrate that vmPFC Dyn-mediated signaling promotes a switch of vmPFC networks to a fear-related state. In conclusion, we reveal a previously unknown role of vmPFC Dyn neurons and Dyn neuropeptidergic transmission in suppressing defensive behaviors in response to threats via state-driven changes in vmPFC networks.

Prefrontal cortical dynorphin peptidergic transmission constrains threat-driven behavioral and network states.

Prefrontal cortical (PFC) circuits provide top-down control of threat reactivity. This includes ventromedial PFC (vmPFC) circuitry, which plays a role in suppressing fear-related behavioral states. Dynorphin (Dyn) has been implicated in mediating negative affect and mal-adaptive behaviors induced by severe threats and is expressed in limbic circuits, including the vmPFC. However, there is a critical knowledge gap in our understanding of how vmPFC Dyn-expressing neurons and Dyn transmission detect threats and regulate expression of defensive behaviors. Here, we demonstrate that Dyn cells are broadly activated by threats and release Dyn locally in the vmPFC to limit passive defensive behaviors. We further demonstrate that vmPFC Dyn-mediated signaling promotes a switch of vmPFC networks to a fear-related state. In conclusion, we reveal a previously unknown role of vmPFC Dyn neurons and Dyn neuropeptidergic transmission in suppressing defensive behaviors in response to threats via state-driven changes in vmPFC networks.

Neuropeptide System Regulation of Prefrontal Cortex Circuitry: Implications for Neuropsychiatric Disorders.

Neuropeptides, a diverse class of signaling molecules in the nervous system, modulate various biological effects including membrane excitability, synaptic transmission and synaptogenesis, gene expression, and glial cell architecture and function. To date, most of what is known about neuropeptide action is limited to subcortical brain structures and tissue outside of the central nervous system. Thus, there is a knowledge gap in our understanding of neuropeptide function within cortical circuits. In this review, we provide a comprehensive overview of various families of neuropeptides and their cognate receptors that are expressed in the prefrontal cortex (PFC). Specifically, we highlight dynorphin, enkephalin, corticotropin-releasing factor, cholecystokinin, somatostatin, neuropeptide Y, and vasoactive intestinal peptide. Further, we review the implication of neuropeptide signaling in prefrontal cortical circuit function and use as potential therapeutic targets. Together, this review summarizes established knowledge and highlights unknowns of neuropeptide modulation of neural function underlying various biological effects while offering insights for future research. An increased emphasis in this area of study is necessary to elucidate basic principles of the diverse signaling molecules used in cortical circuits beyond fast excitatory and inhibitory transmitters as well as consider components of neuropeptide action in the PFC as a potential therapeutic target for neurological disorders. Therefore, this review not only sheds light on the importance of cortical neuropeptide studies, but also provides a comprehensive overview of neuropeptide action in the PFC to serve as a roadmap for future studies in this field.

Characterizing Different Strategies for Resolving Approach-Avoidance Conflict.

The ability of animals to maximize benefits and minimize costs during approach-avoidance conflicts is an important evolutionary tool, but little is known about the emergence of specific strategies for conflict resolution. Accordingly, we developed a simple approach-avoidance conflict task in rats that pits the motivation to press a lever for sucrose against the motivation to step onto a distant platform to avoid a footshock delivered at the end of a 30 s tone (sucrose is available only during the tone). Rats received conflict training for 16 days to give them a chance to optimize their strategy by learning to properly time the expression of both behaviors across the tone. Rats unexpectedly separated into three distinct subgroups: those pressing early in the tone and avoiding later (Timers, 49%); those avoiding throughout the tone (Avoidance-preferring, 32%); and those pressing throughout the tone (Approach-preferring, 19%). The immediate early gene cFos revealed that Timers showed increased activity in the ventral striatum and midline thalamus relative to the other two subgroups, Avoidance-preferring rats showed increased activity in the amygdala, and Approach-preferring rats showed decreased activity in the prefrontal cortex. This pattern is consistent with low fear and high behavioral flexibility in Timers, suggesting the potential of this task to reveal the neural mechanisms of conflict resolution.

Individual variability in behavior and functional networks predicts vulnerability using an animal model of PTSD.

Only a minority of individuals experiencing trauma subsequently develop post-traumatic stress disorder (PTSD). However, whether differences in vulnerability to PTSD result from a predisposition or trauma exposure remains unclear. A major challenge in differentiating these possibilities is that clinical studies focus on individuals already exposed to trauma without pre-trauma conditions. Here, using the predator scent model of PTSD in rats and a longitudinal design, we measure pre-trauma brain-wide neural circuit functional connectivity, behavioral and corticosterone responses to trauma exposure, and post-trauma anxiety. Freezing during predator scent exposure correlates with functional connectivity in a set of neural circuits, indicating pre-existing circuit function can predispose animals to differential fearful responses to threats. Counterintuitively, rats with lower freezing show more avoidance of the predator scent, a prolonged corticosterone response, and higher anxiety long after exposure. This study provides a framework of pre-existing circuit function that determines threat responses, which might directly relate to PTSD-like behaviors.

Long-range GABAergic neurons in the prefrontal cortex modulate behavior.

Cortical glutamatergic projections are extensively studied in behavioral neuroscience, whereas cortical GABAergic projections to downstream structures have been overlooked. A recent study by Lee and colleagues (Lee AT, Vogt D, Rubenstein JL, Sohal VS. J Neurosci 34: 11519-11525, 2014) used optogenetic and electrophysiological techniques to characterize a behavioral role for long-projecting GABAergic neurons in the medial prefrontal cortex. In this Neuro Forum, we discuss the potential implications of this study in several learning and memory models.

Prelimbic and infralimbic neurons signal distinct aspects of appetitive instrumental behavior.

It is thought that discrete subregions of the medial prefrontal cortex (mPFC) regulate different aspects of appetitive behavior, however, physiological support for this hypothesis has been lacking. In the present study, we used multichannel single-unit recording to compare the response of neurons in the prelimbic (PL) and infralimbic (IL) subregions of the mPFC, in rats pressing a lever to obtain sucrose pellets on a variable interval schedule of reinforcement (VI-60). Approximately 25% of neurons in both structures exhibited prominent excitatory responses during rewarded, but not unrewarded, lever presses. The time courses of reward responses in PL and IL, however, were markedly different. Most PL neurons exhibited fast and transient responses at the delivery of sucrose pellets, whereas most IL neurons exhibited delayed and prolonged responses associated with the collection of earned sucrose pellets. We further examined the functional significance of reward responses in IL and PL with local pharmacological inactivation. IL inactivation significantly delayed the collection of earned sucrose pellets, whereas PL inactivation produced no discernible effects. These findings support the hypothesis that PL and IL signal distinct aspects of appetitive behavior, and suggest that IL signaling facilitates reward collection.