Neural signatures of opioid-induced risk-taking behavior in the prelimbic prefrontal cortex.

Opioid use disorder occurs alongside impaired risk-related decision-making, but the underlying neural correlates are unclear. We developed a novel approach-avoidance conflict model using a modified conditioned place preference paradigm to study neural signals of risky opioid seeking in the prefrontal cortex, a region implicated in executive decision making. Upon establishment of morphine conditioned place preference, rats underwent a subsequent conflict test in which fear-inducing cat odor was introduced in the previously drug-paired side of the apparatus. While the saline control group avoided the cat odor side, the morphine group maintained preference for the paired side despite the presence of cat odor. K-means clustering identified two subsets of morphine-treated rats that exhibited either persistent drug seeking (Risk-Takers) or increased avoidance (Risk-Avoiders) during conflict. Single-unit recordings from the prelimbic cortex (PL) revealed decreased neuronal firing rates upon acute morphine exposure in both Risk-Takers and Risk-Avoiders, but this firing rate suppression was absent after repeated administration. Risk-Avoiders also displayed distinct post-morphine excitation in PL which persisted across conditioning. During the preference test, subpopulations of PL neurons in all groups were either excited or inhibited when rats entered the paired side. Interestingly, while this inhibitory signal was lost during the subsequent conflict test in both saline and Risk-Avoider groups, these inhibitory responses persisted in Risk-Takers. Our results suggest that loss of PL inhibition after opioid conditioning is associated with the formation of contextual reward memory. Furthermore, persistent PL inhibitory signaling in the drug-associated context during conflict may underlie increased risk taking following opioid exposure.

Enhancing Associative Learning in Rats With a Computationally Designed Training Protocol.

Background: Learning requires the activation of protein kinases with distinct temporal dynamics. In Aplysia, nonassociative learning can be enhanced by a computationally designed learning protocol with intertrial intervals (ITIs) that maximize the interaction between fast-activated PKA (protein kinase A) and slow-activated ERK (extracellular signal-regulated kinase). Whether a similar strategy can enhance associative learning in mammals is unknown. Methods: We simulated 1000 training protocols with varying ITIs to predict an optimal protocol based on empirical data for PKA and ERK dynamics in rat hippocampus. Adult male rats received the optimal protocol or control protocols in auditory fear conditioning and fear extinction experiments. Immunohistochemistry was performed to evaluate pCREB (phosphorylated cAMP response element binding)\protein levels in brain regions that have been implicated in fear acquisition. Results: Rats exposed to the optimal conditioning protocol with irregular ITIs exhibited impaired extinction memory acquisition within the session using a standard footshock intensity, and stronger fear memory retrieval and spontaneous recovery with a weaker footshock intensity, compared with rats that received massed or spaced conditioning protocols with fixed ITIs. Rats exposed to the optimal extinction protocol displayed improved extinction of contextual fear memory and reduced spontaneous recovery compared with rats that received standard extinction protocols. Moreover, the optimal conditioning protocol increased pCREB levels in the dentate gyrus of the dorsal hippocampus, suggesting enhanced induction of long-term potentiation. Conclusions: These findings demonstrate that a computational model-driven behavioral intervention can enhance associative learning in mammals and may provide insight into strategies to improve cognition in humans.

Positioning the brainstem within the neural network of threat prediction.

In a recent study, Strickland and McDannald dissected the role of brainstem networks in threat prediction. Using probabilistic threat discrimination in rats, the authors demonstrated that brainstem neurons estimate threat probability and generate positive aversive prediction errors after unexpected outcomes. Their findings suggest that, beyond organizing defensive behaviors, brainstem neurons are involved in threat prediction computations.

Mild Traumatic Brain Injury Decreases Spatial Information Content and Reduces Place Field Stability of Hippocampal CA1 Neurons.

Both clinical and experimental studies have reported that mild traumatic brain injury (mTBI) can result in cognitive impairments in the absence of overt brain damage. Whether these impairments result from neuronal dysfunction/altered plasticity is an area that has received limited attention. In this study, we recorded activity of neurons in the cornu Ammonis (CA)1 subfield of the hippocampus in sham and mild lateral fluid percussion injured (mFPI) rats while these animals were performing an object location task. Electrophysiology results showed that the number of excitatory neurons encoding spatial information (i.e., place cells) was reduced in mFPI rats, and that these cells had broader and less stable place fields. Additionally, the in-field firing rate of place cells in sham operated, but not in mFPI, animals increased when objects within the testing arena were moved. Immunostaining indicated no visible damage or overall neuronal loss in mFPI brain sections. However, a reduction in the number of parvalbumin-positive inhibitory neurons in the CA1 subfield of mFPI animals was observed, suggesting that this reduction could have influenced place cell physiology. Alterations in spatial information content, place cell stability, and activity in mFPI rats coincided with poor performance in the object location task. These results indicate that altered place cell physiology may underlie the hippocampus-dependent cognitive impairments that result from mTBI.