Biology subjects

Shallcross, J.

Publications and source records attributed to Shallcross, J..

3 recordsLinked to original sources

bioRxiv2023

Circuit and cell-specific contributions to decision making involving risk of explicit punishment in male and female rats.

Decision making is a complex cognitive process that recruits a distributed network of brain regions, including the basolateral amygdala (BLA) and nucleus accumbens shell (NAcSh). Recent work suggests that communication between these structures, as well as activity of cells expressing dopamine D2 receptors (D2R) in the NAcSh, are necessary for some forms of decision making; however, the contributions of this circuit and cell population during decision making under risk of punishment are unknown. The current experiments addressed this question using circuit- and cell type-specific optogenetic approaches in rats during a decision-making task involving risk of punishment. In Experiment 1, Long-Evans rats received intra-BLA injections of halorhodopsin or mCherry (control) and in Experiment 2, D2-Cre transgenic rats received intra-NAcSh injections of Cre-dependent halorhodopsin or mCherry. Optic fibers were implanted in the NAcSh in both experiments. Following training in the decision-making task, BLA[->]NAcSh or D2R-expressing neurons were optogenetically inhibited during different phases of the decision process. Inhibition of the BLA[->]NAcSh during deliberation (the time between trial initiation and choice) increased choice of the large, risky reward (increased risk taking). Similarly, inhibition during delivery of the large, punished reward increased risk taking, but only in males. Inhibition of D2R-expressing neurons in the NAcSh during deliberation increased risk taking. In contrast, inhibition of these neurons during delivery of the small, safe reward decreased risk taking. These findings extend our knowledge of the neural dynamics of risk taking, revealing sex-dependent circuit recruitment and dissociable activity of selective cell populations during decision making.

neuroscience↗

bioRxiv2020

Increased mGlu5 mRNA expression in BLA glutamate neurons facilitates resilience to the long- term effects of a single predator scent stress exposure.

Post-traumatic stress disorder (PTSD) develops in a subset of individuals exposed to a trauma with core features being increased anxiety, and impaired fear extinction. To model the heterogeneity of PSTD behavioral responses, we exposed Sprague-Dawley rats to predator scent stress (TMT) once for 10 minutes and then tested for anxiety-like behavior 7 days later using the elevated plus-maze and acoustic startle response. Rats displaying anxiety-like behavior in both tasks were classified as stress-Susceptible, and rats exhibiting behavior no different from unstressed Controls were classified as stress-Resilient. Our previous findings revealed increased mRNA expression of mGlu5 in the amygdala and PFC and CB1R mRNA in the amygdala of Resilient rats. Here, we performed fluorescent in situ hybridization (FISH) to determine the subregion and cell-type-specific expression of these genes in Resilient rats. We found higher mRNA expression of mGlu5 in the BLA, IL, and PL, and CB1R in the BLA of Resilient rats relative to Controls. Using dual-labeled FISH we determined that mGlu5 and CB1R mRNA increases were limited to vGlut+ cells. To test the necessity of mGlu5 receptor activity for attenuating contextual fear, intra-BLA infusions of the mGlu5 negative allosteric modulator MTEP were administered prior to context re-exposure. MTEP increased contextual fear on the day of administration, which extinguished over the course of two additional un-drugged sessions. These results suggest that an enhanced mGlu5 expression within BLA glutamate neurons contributes to the behavioral flexibility observed in stress-Resilient animals by facilitating a capacity for extinguishing contextual fear associations.

neuroscience↗

bioRxiv2019

The divergent effects of CDPPB and cannabidiol on fear extinction and anxiety in a predator scent stress model of PTSD in rats.

Post-traumatic stress disorder (PTSD) is a disorder with no clear FDA-approved treatments that reduce symptoms in the majority of patients. PTSD individuals possess an impaired capacity for extinguishing fear memory associations. As such, considerable focus has been given to the development of extinction-enhancing pharmacological agents to be used in combination with PTSD treatments. Here we use a predator-threat animal model of PTSD to test the ability of two compounds to enhance contextual fear extinction and reduce anxiety. Mirroring the heterogeneity observed in human response to trauma, an exposure to predator threat, including the fox odor TMT, have been shown to induce long-term changes in anxiety behavior in only subsets of susceptible rats. Here, two weeks following a ten-minute exposure to a predator odor, rats were classified into stress-Susceptible (Sus) and stress-Resilient (Res) phenotypes using cut-off behavioral criteria for elevated plus maze and acoustic startle response performance. One week following classification, Sus rats underwent three days of context fear extinction. We found that Sus rats increased freezing from day one to day two. Treatment with the mGlu5 positive allosteric modulator CDPPB, but not the phytocannabinoid cannabidiol (CBD), prior to sessions resulted in reduced freezing. CDPPB administration resulted in an increase of Fos immunoreactive cells in the medial prefrontal cortex, indicative of increased neuronal activity. Finally, we used the light-dark box test to measure phenotypic differences and the effects of CDPPB and CBD on unconditioned anxiety two weeks after classification. We found that Res rats showed less anxiety compared to Sus rats, and that CBD, but not CDPPB, administered prior to testing was anxiolytic in Sus rats. Taken together, the present data indicate that mGlu5 PAMs such as CDPPB hold promise for treating human PTSD patients as they enhance extinction of fear without increasing general anxiety. Polytherapy with medications such as CBD may be necessary in order to attenuate general anxiety and future directions will explore this hypothesis.

neuroscience↗