Leptin acts in the hippocampus to enhance cognition and reduce depression and anxiety. Cognitive and emotional disorders are associated with abnormal hippocampal dendritic spine formation and synaptogenesis. Although leptin has been shown to induce synaptogenesis in the hypothalamus, its effects on hippocampal synaptogenesis and the mechanism(s) involved are not well understood. Here we show that leptin receptors (LepRs) are critical for hippocampal dendritic spine formation in vivo because db/db mice lacking the long form of the leptin receptor (LepRb) have reduced spine density on CA1 and CA3 neurons. Leptin promotes the formation of mature spines and functional glutamate synapses on hippocampal pyramidal neurons in both dissociated and slice cultures. These effects are blocked by short hairpin RNAs specifically targeting the LepRb and are absent in cultures from db/db mice. Activation of the LepR leads to cAMP response element–binding protein (CREB) phosphorylation and initiation of CREB-dependent transcription via the MAPK kinase/Erk pathway. Furthermore, both Mek/Erk and CREB activation are required for leptin-induced synaptogenesis. Leptin also increases expression of microRNA-132 (miR132), a well-known CREB target, which is also required for leptin-induced synaptogenesis. Last, leptin suppresses the expression of p250GAP, a miR132 target, and this suppression is obligatory for leptin's effects as is the downstream target of p250GAP, Rac1. LepRs appear to be critical in vivo as db/db mice have lowered hippocampal miR132 levels and elevated p250GAP expression. In conclusion, we identify a novel signaling pathway by which leptin increases synaptogenesis through inducing CREB transcription and increasing microRNA-mediated suppression of p250GAP activity, thus removing a known inhibitor of Rac1-stimulated synaptogenesis.

Neuroendocrine prostate cancer (NEPC) is a lethal prostate cancer subtype arising as a consequence of more potent androgen receptor (AR) targeting in castration-resistant prostate cancer (CRPC). Its molecular pathogenesis remains elusive. Here, we report that the Wnt secretion mediator Wntless (WLS) is a major driver of NEPC and aggressive tumor growth in vitro and in vivo. Mechanistic studies showed that WLS is a transcriptional target suppressed by AR that activates the ROR2/PKCδ/ERK signaling pathway to support the neuroendocrine (NE) traits and proliferative capacity of NEPC cells. Analysis of clinical samples and datasets revealed that WLS was highly expressed in CRPC and NEPC tumors. Finally, treatment with the Wnt secretion inhibitor LGK974 restricted NE prostate tumor xenograft growth in mice. These findings collectively characterize the contribution of WLS to NEPC pathogenesis and suggest that WLS is a potential therapeutic target in NEPC.

Background: Medical students often struggle to engage with and retain complex pharmacology topics during their preclinical education. Traditional teaching methods can lead to passive learning and poor long-term retention of critical concepts. Objective: This study aims to enhance the teaching of clinical pharmacology in medical school by using a multimodal generative artificial intelligence (genAI) approach to create compelling, cinematic clinical narratives (CCNs). Methods: We transformed a standard clinical case into an engaging, interactive multimedia experience called “Shattered Slippers.” This CCN used various genAI tools for content creation: GPT-4 for developing the storyline, Leonardo.ai and Stable Diffusion for generating images, Eleven Labs for creating audio narrations, and Suno for composing a theme song. The CCN integrated narrative styles and pop culture references to enhance student engagement. It was applied in teaching first-year medical students about immune system pharmacology. Student responses were assessed through the Situational Interest Survey for Multimedia and examination performance. The target audience comprised first-year medical students (n=40), with 18 responding to the Situational Interest Survey for Multimedia survey (n=18). Results: The study revealed a marked preference for the genAI-enhanced CCNs over traditional teaching methods. Key findings include the majority of surveyed students preferring the CCN over traditional clinical cases (14/18), as well as high average scores for triggered situational interest (mean 4.58, SD 0.53), maintained interest (mean 4.40, SD 0.53), maintained-feeling interest (mean 4.38, SD 0.51), and maintained-value interest (mean 4.42, SD 0.54). Students achieved an average score of 88% on examination questions related to the CCN material, indicating successful learning and retention. Qualitative feedback highlighted increased engagement, improved recall, and appreciation for the narrative style and pop culture references. Conclusions: This study demonstrates the potential of using a multimodal genAI-driven approach to create CCNs in medical education. The “Shattered Slippers” case effectively enhanced student engagement and promoted knowledge retention in complex pharmacological topics. This innovative method suggests a novel direction for curriculum development that could improve learning outcomes and student satisfaction in medical education. Future research should explore the long-term retention of knowledge and the applicability of learned material in clinical settings, as well as the potential for broader implementation of this approach across various medical education contexts.

Background: Medical education increasingly relies on digital learning materials. Despite recognition by the Association of American Medical Colleges Institute for Improving Medical Education, medical education design often fails to consider quality multimedia design principles. Further, the AAMC-IIME issued a call to study the role of design principles in medical education. Thus, the current study investigated the cognitive and affective effects of redesigningPowerPointslides used to support pharmacology content during the preclinical years of medical school training.Methods: Researchers implemented a quasi-experimental design, using traditionally-designed (original) slides with a Traditional group (n = 100) and slides redesigned to follow principles from the Cognitive Theory of Multimedia Learning with an Experimental group (n = 40). Participants in the Experimental group completed a post-survey incorporating the Situational Interest Survey for Multimedia to indicate motivational engagement with the media. Students in the Experimental group also responded to additional preference questions. Researchers analyzed survey responses and students’ scores in pharmacology-related coursework across the preclinical Foundations Phase of training to determine the impact on achievement and motivation.Results: Findings related to learner achievement showed a modest but significant increase in the Experimental group compared to the Traditional group in the Cardiac, Pulmonary, and Renal (CPR) educational block (105%, normalized to Traditional group,p = 0.013) and cumulative pharmacology grades (101%, normalized to Traditional group,p = 0.043). Additionally, participants in the Experimental group indicated a significantly higher average triggered situational interest in redesigned slides (M = 4.85, SD = 0.25) than the original slides (M = 3.23, SD = 1.40, t=-6.33,p < 0.001). Similarly, the interest rating of the redesigned slides (M = 4.87, SD = 0.24) was significantly greater than that of the original slides (M = 3.89, SD = 0.86, t=-6.824,p < 0.001). Moreover, results further indicated significant differences in the maintained-feeling and maintained-value constructs, and all participants in the Experimental group indicated a preference for the redesigned slides.Conclusions: The findings provide strong evidence in support of using the Cognitive Theory of Multimedia Learning design principles to intentionally design media in medical education. In addition to increased achievement scores, students in the Experimental group demonstrated significantly higher levels of situational interest in the redesigned slides, especially triggered interest and maintained-feeling interest. Medical education learning designers should seriously consider redesigning media to achieve similar results.

Leptin has neurotrophic actions in the hippocampus to increase synapse formation and stimulate neuronal plasticity. Leptin also enhances cognition and has anti-depressive and anxiolytic-like effects, two hippocampal dependent behaviors. In contrast, mice lacking leptin or the long-form of the leptin receptor (LepRb) have lower cortical volume, decreased memory, and exhibit depressive-like behaviors. A number of the signaling pathways regulated by LepRb are known, but how membrane LepRb levels are regulated in the central nervous system is not well understood. Here we show that the lysosomal inhibitor, chloroquine, increases LepRb expression in hippocampal cultures, suggesting that LepRb is degraded in the lysosome. Furthermore, we show that leptin increases surface expression of its own receptor by decreasing the level of ubiquitinated LepRbs. This decrease is mediated by the deubiquitinase USP8, which we show is in complex with LepRb. Acute leptin stimulation increases USP8 activity. Moreover, leptin stimulates USP8 gene expression through CREB dependent transcription, an effect blocked by expression of a dominant negative CREB or with shRNA knockdown of CREB. Increased expression of USP8 causes increased surface localization of LepRb, which in turn enhances leptin-mediated activation of the Mek/Erk pathway and CREB activation. Lastly, increased USP8 expression increases glutamatergic synapse formation in hippocampal cultures, an effect dependent on expression of LepRbs. Leptin stimulated synapse formation also requires USP8. In conclusion, we show that USP8 deubiquitinates LepRb, thus inhibiting lysosomal degradation and enhancing surface localization of LepRb, which is essential for leptin stimulated synaptogenesis in the hippocampus.