Inhibitory corticotropin-releasing factor neurons in the dorsomedial prefrontal cortex promote stress-resilient behavior in male rodents.

Adaptive behavior in response to adverse experiences facilitates faster recovery and less time spent engaging in maladaptive behaviors that contribute to psychopathology, including anxiety, depression, and posttraumatic stress disorder. Dysregulation of activity in the prefrontal cortex (PFC) has been implicated in these disorders, with stress further exacerbating these negative effects. Corticotropin-releasing factor is an important regulator of the stress-response system and may have a differential involvement in individuals who are especially susceptible to negative stress-related outcomes. A recent study by Chen et al. (Chen P, Lou S, Huang ZH, Wang Z, Shan QH, Wang Y, Yang Y, Li X, Gong H, Jin Y, Zhang Z, Zhou Z. Neuron 106: 301-315, 2020) has identified a novel subtype of GABAergic CRF interneurons in the dorsomedial PFC that, upon activation, can promote active responses and resilient behavior in response to stress.

Effects of early- and mid-life stress on DNA methylation of genes associated with subclinical cardiovascular disease and cognitive impairment: a systematic review.

BACKGROUND: Traditional and novel risk factors cannot sufficiently explain the differential susceptibility to cardiovascular disease (CVD). Epigenetics may serve to partially explain this residual disparity, with life course stressors shown to modify methylation of genes implicated in various diseases. Subclinical CVD is often comorbid with cognitive impairment (CI), which warrants research into the identification of common genes for both conditions. METHODS: We conducted a systematic review of the existing literature to identify studies depicting the relationship between life course stressors, DNA methylation, subclinical CVD, and cognition. RESULTS: A total of 16 articles (8 human and 8 animal) were identified, with the earliest published in 2008. Four genes (COMT, NOS3, Igfl1, and Sod2) were analyzed by more than one study, but not in association with both CVD and CI. One gene (NR3C1) was associated with both outcomes, albeit not within the same study. There was some consistency among studies with markers used for subclinical CVD and cognition, but considerable variability in stress exposure (especially in human studies), cell type/tissue of interest, method for detection of DNA methylation, and risk factors. Racial and ethnic differences were not considered, but analysis of sex in one human study found statistically significant differentially methylated X-linked loci associated with attention and intelligence. CONCLUSIONS: This review suggests the need for additional studies to implement more comprehensive and methodologically rigorous study designs that can better identify epigenetic biomarkers to differentiate individuals vulnerable to both subclinical CVD and associated CI.

From learned value to sustained bias: how reward conditioning changes attentional priority.

Introduction: Attentional bias to reward-associated stimuli can occur even when it interferes with goal-driven behavior. One theory posits that dopaminergic signaling in the striatum during reward conditioning leads to changes in visual cortical and parietal representations of the stimulus used, and this, in turn, sustains attentional bias even when reward is discontinued. However, only a few studies have examined neural activity during both rewarded and unrewarded task phases. Methods: In the current study, participants first completed a reward-conditioning phase, during which responses to certain stimuli were associated with monetary reward. These stimuli were then included as non-predictive cues in a spatial cueing task. Participants underwent functional brain imaging during both task phases. Results: The results show that striatal activity during the learning phase predicted increased visual cortical and parietal activity and decreased ventro-medial prefrontal cortex activity in response to conditioned stimuli during the test. Striatal activity was also associated with anterior cingulate cortex activation when the reward-conditioned stimulus directed attention away from the target. Discussion: Our findings suggest that striatal activity during reward conditioning predicts the degree to which reward history biases attention through learning-induced changes in visual and parietal activities.

Effects of adolescent intermittent ethanol exposure on cortical perineuronal net and parvalbumin expression in adulthood mediate behavioral inflexibility.

BACKGROUND: Alcohol is commonly consumed by adolescents in a binge-like pattern, which can lead to long-lasting cognitive deficits, including reduced behavioral flexibility. We and others have determined that adolescent intermittent ethanol (AIE) exposure leads to increased number of perineuronal net (PNN) numbers in brain regions that are important for behavioral flexibility. However, whether altered neurochemistry stemming from AIE exposure plays a significant role in reduced behavioral flexibility is unknown. METHODS: We measured the number and size of parvalbumin expressing (PV+) interneurons and associated PNNs within the orbitofrontal cortex (OFC), prelimbic cortex (PrL), infralimbic cortex (IL), and anterior insular cortex (AIC) of female and male rats following AIE or control exposure and subsequent training on an attentional set-shift task (ASST). We then ran analyses to determine whether AIE-induced changes in PV and PNN measures statistically mediated the AIE-induced behavioral deficit in reversal learning. RESULTS: We demonstrate that AIE exposure impaired behavioral flexibility on reversal two of the ASST (i.e., recalling the initial learned associations), and led to smaller PV+ cells and increased PNN numbers in the AIC. Interestingly, PNN size and number were not altered in the PrL or IL following AIE exposure, in contrast to prior reports. Mediation analyses suggest that AIE alters behavioral flexibility, at least in part through changes in PV and PNN fluorescent measures in the AIC. CONCLUSIONS: This study reveals a significant link between AIE exposure, neural alterations, and diminished behavioral flexibility in rats, and highlights a potential novel mechanism comprising changes in PV and PNN measures within the AIC. Future studies should explore the impact of PNN degradation within the AIC on behavioral flexibility.

Pathways to opioid use and implications for prevention: voices of young adults in recovery.

BACKGROUND: Opioid use remains a major public health issue, especially among young adults. Despite investment in harm reduction and supply-side strategies such as reducing overprescribing and safe medication disposal, little is known about demand-side issues, such as reasons for use and pathways to opioid use. Adolescents and young adults who struggle with opioid use disorder (OUD) are multifaceted individuals with varied individual histories, experiences, challenges, skills, relationships, and lives. METHODS: To inform the development of prevention strategies that hold promise for addressing opioid use, this study employs brief structured surveys and semi-structured in-depth interviews with 30 young adults (ages 18-29; 19 female, 23 White, 16 from Suburban areas) in recovery from OUD. For survey data, we used descriptive statistics to summarize the means and variance of retrospectively reported risk and protective factors associated with opioid use. For in-depth interview data, we used a combination of thematic analysis and codebook approaches to generate common themes and experiences shared by participants. RESULTS: Surveys revealed that the most endorsed risk factors pertained to emotions (emotional neglect and emotional abuse) followed by sexual abuse, physical abuse, and physical neglect. Themes generated from qualitative analyses reveal challenging experiences during adolescence, such as unaddressed mental health, social, and emotional needs, which were often reported as reasons for opioid initiation and use. Through surveys and interviews, we also identified positive assets, such as skills and social relationships that were present for many participants during adolescence. CONCLUSION: Implications include the need for universal prevention strategies that include emotion-focused interventions and supports alongside current harm reduction and environmental strategies to regulate prescriptions; the potential utility of more emotion-focused items being included on screening tools; and more voices of young people in recovery.

Engaging Youth in Substance Misuse Prevention within State Prevention Systems: Provider Perspectives.

Objective: Engaging youth in planning, developing, and implementing substance misuse prevention efforts can improve those efforts. However, specific local policies and systems constrain youth engagement practice. This study examines how to engage youth in substance misuse prevention within state prevention systems. Methods: In the qualitative study, semi-structured interviews with 13 prevention providers in the North Carolina prevention system were conducted via video call and transcribed and analyzed via thematic and codebook approaches. Procedures are reported according to the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist. Results: Providers viewed youth engagement favorably yet mostly did not differentiate between youth-targeted prevention initiatives and youth-engaged initiatives. Findings reveal how state-level decisions, such as definitions and funding policies, support and challenge how providers implement youth engagement. Conclusions: To encourage youth engagement, state prevention systems should clarify for providers the distinction between prevention efforts targeted to youth and those that engage youth in planning and implementing and define which activities are desirable and what the role of youth should be in the activities. Finally, prevention providers need support for youth-engaged approaches to prevention, specifically training for youth and adult allies and opportunities for knowledge-sharing.