Development of a curricular thread to foster medical students' critical reflection and promote action on climate change, health, and equity.

INTRODUCTION: Due to the health consequences arising from climate change, medical students will inevitably interact with affected patients during their training and careers. Accordingly, medical schools must incorporate education on the impacts of climate change on health and equity into their curricula. We created a curricular thread called "Climate Change, Health, and Equity" in the first-year preclinical medical program to teach foundational concepts and foster self-reflection and critical consciousness. METHODS: The authors developed a continuum of practice including administrators, educators and faculty members, students, and community partners to plan and design curricular activities. First-year medical students at Duke University School of Medicine participated in seven mandatory foundational lectures and two experiential learning opportunities in the local community. Following completion of activities, students wrote a critical reflection essay and completed a self-directed learning exercise. Essays were evaluated using the REFLECT rubric to assess if students achieved critical reflection and for thematic analysis by Bloom's Taxonomy. RESULTS: All students (118) submitted essays. A random sample of 30 (25%) essays underwent analysis. Evaluation by the REFLECT rubric underscored that all students were reflecting or critically reflecting on thread content. Thematic analysis highlighted that all students (30/30, 100%) were adept at identifying new areas of medical knowledge and connecting concepts to individual experiences, institutional practices, and public health and policy. Most students (27/30; 90%) used emotionally laden words, expressing negative feelings like frustration and fear but also positive sentiments of solidarity and hope regarding climate change and effects on health. Many students (24/30; 80%) expressed actionable items at every level including continuing self-directed learning and conversing with patients, minimizing healthcare waste, and advocating for climate-friendly policies. CONCLUSION: After participating in the curricular thread, most medical students reflected on cognitive, affective, and actionable aspects relating to climate change, health, and equity.

Inflamed brain: Targeting immune changes and inflammation for treatment of depression.

Although there are a number of clinically effective treatments for depression, many patients exhibit treatment resistance. Recent clinical and preclinical studies reveal that peripheral and brain immune changes and inflammation are involved in the pathophysiology of depression. This 'Inflamed Brain' research provides critical clues for understanding of disease pathophysiology and many candidate molecules that are potentially useful for identifying novel drug targets for the treatment of depression. In this review, we will present clinical evidence on the role of inflammation in the pathophysiology of depression. We will also summarize current clinical trials which test drugs targeting inflammation for the treatment of patients with depression. Furthermore, we will briefly provide preclinical evidence demonstrating altered immune system function and inflammation in stress-induced animal models and will discuss the future potential of inflammation-related drug targets. Collectively, inflammatory signatures identified in clinical and preclinical studies may allow us to stratify depressive patients based on biotypes, contributing to the development of novel mechanism-based interventions that target specific patient populations.

In vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene.

Many neuropsychiatric risk genes contribute to epigenetic regulation but little is known about specific chromatin-associated mechanisms governing the formation of neuronal connectivity. Here we show that transcallosal connectivity is critically dependent on C11orf46, a nuclear protein encoded in the chromosome 11p13 WAGR risk locus. C11orf46 haploinsufficiency was associated with hypoplasia of the corpus callosum. C11orf46 knockdown disrupted transcallosal projections and was rescued by wild type C11orf46 but not the C11orf46R236H mutant associated with intellectual disability. Multiple genes encoding key regulators of axonal development, including Sema6a, were hyperexpressed in C11orf46-knockdown neurons. RNA-guided epigenetic editing of Sema6a gene promoters via a dCas9-SunTag system with C11orf46 binding normalized SEMA6A expression and rescued transcallosal dysconnectivity via repressive chromatin remodeling by the SETDB1 repressor complex. Our study demonstrates that interhemispheric communication is sensitive to locus-specific remodeling of neuronal chromatin, revealing the therapeutic potential for shaping the brain's connectome via gene-targeted designer activators and repressor proteins.

Hippocampal-Prefrontal Theta Transmission Regulates Avoidance Behavior.

Long-range synchronization of neural oscillations correlates with distinct behaviors, yet its causal role remains unproven. In mice, tests of avoidance behavior evoke increases in theta-frequency (∼8 Hz) oscillatory synchrony between the ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC). To test the causal role of this synchrony, we dynamically modulated vHPC-mPFC terminal activity using optogenetic stimulation. Oscillatory stimulation at 8 Hz maximally increased avoidance behavior compared to 2, 4, and 20 Hz. Moreover, avoidance behavior was selectively increased when 8-Hz stimulation was delivered in an oscillatory, but not pulsatile, manner. Furthermore, 8-Hz oscillatory stimulation enhanced vHPC-mPFC neurotransmission and entrained neural activity in the vHPC-mPFC network, resulting in increased synchrony between vHPC theta activity and mPFC spiking. These data suggest a privileged role for vHPC-mPFC theta-frequency communication in generating avoidance behavior and provide direct evidence that synchronized oscillations play a role in facilitating neural transmission and behavior.