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Background: Medical students are at risk of poor mental health and burnout compared to general population age- and education-matched peers, which has future implications for patient care. Research has suggested that demographic factors can predict mental illness and burnout among medical students. However, less is known about predictors of mental health and how they compare to predictors of burnout, and few studies have examined multiple demographics simultaneously. Objectives: This study examined and compared demographic predictors (gender, ethnicity, age, level of education, year of study and proposed specialty) of mental health and burnout in first to fourth year Canadian medical students. Method: Medical students (n = 129) completed online surveys comprised of validated questionnaires. Results: Multiple regression indicated that third year [Beta] = -0.243, p = 0.013) negatively predicted mental health (R[superscript 2] = 15.0%). Female gender ([Beta] = 0.242, p = 0.005), 'other' ethnicities ([Beta] = 0.189, p = 0.028), third year ([Beta] = 0.391, p < 0.001) and fourth year ([Beta] = 0.212, p = 0.023) positively predicted burnout (R[superscript 2] = 32.7%). Female gender and fourth year predicted mental health and burnout differently. 'Other' ethnicity, second year and third year predicted mental health and burnout similarly. Conclusion: Findings fill gaps in the literature and may inform medical stakeholders in developing targeted programmes for improving medical students' mental health and burnout. Medical students with greater well-being can progress into physicians who will be more likely to promote well-being in their patients.

Background The Coronavirus Disease 2019 (COVID-19) pandemic has exacerbated mental health challenges among physicians and non-physicians. However, it is unclear if the worsening mental health among physicians is due to specific occupational stressors, reflective of general societal stressors during the pandemic, or a combination. We evaluated the difference in mental health and addictions health service use between physicians and non-physicians, before and during the COVID-19 pandemic. Methods and findings We conducted a population-based cohort study in Ontario, Canada between March 11, 2017 and August 11, 2021 using data collected from Ontario's universal health system. Physicians were identified using registrations with the College of Physicians and Surgeons of Ontario between 1990 and 2020. Participants included 41,814 physicians and 12,054,070 non-physicians. We compared the first 18 months of the COVID-19 pandemic (March 11, 2020 to August 11, 2021) to the period before COVID-19 pandemic (March 11, 2017 to February 11, 2020). The primary outcome was mental health and addiction outpatient visits overall and subdivided into virtual versus in-person, psychiatrists versus family medicine and general practice clinicians. We used generalized estimating equations for the analyses. Pre-pandemic, after adjustment for age and sex, physicians had higher rates of psychiatry visits (aIRR 3.91 95% CI 3.55 to 4.30) and lower rates of family medicine visits (aIRR 0.62 95% CI 0.58 to 0.66) compared to non-physicians. During the first 18 months of the COVID-19 pandemic, the rate of outpatient mental health and addiction (MHA) visits increased by 23.2% in physicians (888.4 pre versus 1,094.7 during per 1,000 person-years, aIRR 1.39 95% CI 1.28 to 1.51) and 9.8% in non-physicians (615.5 pre versus 675.9 during per 1,000 person-years, aIRR 1.12 95% CI 1.09 to 1.14). Outpatient MHA and virtual care visits increased more among physicians than non-physicians during the first 18 months of the pandemic. Limitations include residual confounding between physician and non-physicians and challenges differentiating whether observed increases in MHA visits during the pandemic are due to stressors or changes in health care access. Conclusions The first 18 months of the COVID-19 pandemic was associated with a larger increase in outpatient MHA visits in physicians than non-physicians. These findings suggest physicians may have had larger negative mental health during COVID-19 than the general population and highlight the need for increased access to mental health services and system level changes to promote physician wellness., Author(s): Daniel T. Myran 1,2,3,*, Rhiannon Roberts 1, Eric McArthur 4, Nivethika Jeyakumar 4, Jennifer M. Hensel 5, Claire Kendall 1,2,3,6, Caroline Gerin-Lajoie 7,8, Taylor McFadden 7, Christopher Simon 7, [...]

Background: Health care providers have reported low knowledge, skill, and confidence for discussing movement behaviours (i.e., physical activity, sedentary behaviour, and sleep), which may be improved with the use of tools to guide movement behaviour discussions in their practice. Past reviews have examined the psychometric properties, scoring, and behavioural outcomes of physical activity discussion tools. However, the features, perceptions, and effectiveness of discussion tools for physical activity, sedentary behaviour, and/or sleep have not yet been synthesized. The aim of this review was to report and appraise tools for movement behaviour discussions between health care providers and adults 18 + years in a primary care context within Canada or analogous countries. Methods: An integrated knowledge translation approach guided this review, whereby a working group of experts in medicine, knowledge translation, communications, kinesiology, and health promotion was engaged from research question formation to interpretation of findings. Three search approaches were used (i.e., peer-reviewed, grey literature, and forward searches) to identify studies reporting on perceptions and/or effectiveness of tools for physical activity, sedentary behaviour, and/or sleep. The quality of included studies was assessed using the Mixed Methods Appraisal Tool. Results: In total, 135 studies reporting on 61 tools (i.e., 51 on physical activity, one on sleep, and nine combining two movement behaviours) met inclusion criteria. Included tools served the purposes of assessment (n = 57), counselling (n = 50), prescription (n = 18), and/or referral (n = 12) of one or more movement behaviour. Most tools were used or intended for use by physicians, followed by nurses/nurse practitioners (n = 11), and adults accessing care (n = 10). Most tools were also used or intended to be used with adults without chronic conditions aged 18–64 years (n = 34), followed by adults with chronic conditions (n = 18). The quality of the 116 studies that evaluated tool effectiveness varied. Conclusions: Many tools were positively perceived and were deemed effective at enhancing knowledge of, confidence for, ability in, and frequency of movement behaviour discussions. Future tools should guide discussions of all movement behaviours in an integrated manner in line with the 24-Hour Movement Guidelines. Practically, this review offers seven evidence-based recommendations that may guide future tool development and implementation. [ABSTRACT FROM AUTHOR]

Physical Activity Counselling (PAC) is a Motivational Interviewing (MI)-based counselling intervention that has been shown to promote motivation for physical activity (PA), PA behaviour, and reduce depressive symptoms. However, no studies have looked at positive psychological variables, such as self-compassion (SC) within PAC. Moreover, no research has examined SC's association with PA in the PAC context. Thus, the purpose of this study was to examine the impact of PAC over time on SC (total and subcomponents), and PA (total, moderate and strenuous), and to see if any improvements in SC and PA variables were sustained at 1-month follow-up. Lastly, this study examined the relationship between SC at endpoint and PA at follow-up. Insufficiently active individuals participating in the PAC program (N = 31) completed validated online questionnaires before, immediately after, and 1-month following PAC. Paired samples t-tests and repeated measures multivariate analysis of variance tests revealed that there were significant increases in total SC, self-kindness, and total, moderate, and strenuous PA from baseline to endpoint, as well as decreases in self-judgement, and isolation. These improvements were all sustained at 1-month follow-up. Finally, no significant relationship was found between SC and PA, likely due to the fact that self-compassionate individuals might prioritize other health behaviors such as sleep or healthy eating over PA. This provides preliminary experimental evidence to support MI-based PAC as an effective means to increase not only PA behaviour, but also SC, an important psychological resource that has been linked to a myriad of positive health benefits. [ABSTRACT FROM AUTHOR]

Obesity is a complex medical condition that is linked to various health complications such as infertility, stroke, and osteoarthritis. Understanding the neurobiology of obesity is crucial for responding to the etiology of this disease. The hypothalamus coordinates many integral activities such as hormone regulation and feed intake and numerous studies have observed altered hypothalamic gene regulation in obesity models. Previously, it was reported that the promoter region of the satiety gene, Pomc, has increased DNA methylation in the hypothalamus following short-term exposure to a high fat diet, suggesting that epigenetic-mediated repression of hypothalamic Pomc might contribute to the development of obesity. However, due to technical limitations, this has never been directly tested. Here, we used the CRISPR-dCas9-TET1 and dCas9-DNMT3a systems to test the role of Pomc DNA methylation in the hypothalamus in abnormal weight gain following acute exposure to a high fat diet in male rats. We found that exposure to a high fat diet increases Pomc DNA methylation and reduces gene expression in the hypothalamus. Despite this, we found that CRISPR-dCas9-TET1-mediated demethylation of Pomc was not sufficient to prevent abnormal weight gain following exposure to a high fat diet. Furthermore, CRISPR-dCas9-DNMT3a-mediated methylation of Pomc did not alter weight gain following exposure to standard or high fat diets. Collectively, these results suggest that high fat diet induced changes in Pomc DNA methylation are a consequence of, but do not directly contribute to, abnormal weight gain during the development of obesity. [ABSTRACT FROM AUTHOR]

Previous work has shown that exposure to a high fat diet dysregulates the protein degradation process in the hypothalamus of male rodents. However, whether this occurs in a sex-independent manner is unknown. The objective of this study was to determine the effects of a short-term obesogenic diet on the ubiquitin-proteasome mediated protein degradation process in the hypothalamus of female rats. We fed young adult female rats a high fat diet or standard rat chow for 7 weeks. At the end of the 7th week, animals were euthanized and hypothalamus nuclear and cytoplasmic fractions were collected. Proteasome activity and degradation-specific (K48) ubiquitin signaling were assessed. Additionally, we transfected female rats with CRISPR-dCas9-VP64 plasmids in the hypothalamus prior to exposure to the high fat diet in order to increase proteasome activity and determine the role of reduced proteasome function on weight gain from the obesogenic diet. We found that across the diet period, females gained weight significantly faster on the high fat diet than controls and showed dynamic downregulation of proteasome activity, decreases in proteasome subunit expression and an accumulation of degradation-specific K48 polyubiquitinated proteins in the hypothalamus. Notably, while our CRISPR-dCas9 manipulation was able to selectively increase some forms of proteasome activity, it was unable to prevent diet-induced proteasome downregulation or abnormal weight gain. Collectively, these results reveal that acute exposure to an obesogenic diet causes reductions in the protein degradation process in the hypothalamus of females. [ABSTRACT FROM AUTHOR]

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Rates of mental illness among Canadian medical students are higher than age-, gender-, and education-matched peers. One predictor of mental health is physical activity; though the relationship between different intensities of physical activity and mental health has not been investigated in medical students. The purpose of this study was to examine relationships between physical activity and mental health profiles in a sample of Canadian medical students. A total of N = 125 students completed an online survey. Latent profile analysis was performed to identify distinct profiles using four continuous latent profile indicators (emotional well-being, social well-being, psychological well-being,resilience). Three mental health profiles emerged, showing low (n = 18), moderate (n = 72) and high (n = 36) self-reported ratings of mental health. The classification quality was good (entropy = 0.81). Individuals in the high mental health profile engaged in more mild physical activity (M = 144.28 mins/week; SD = 22.12) and less moderate-to-vigorous physical activity (M = 195.86 mins/week; SD = 25.67) compared to students in the moderate and low profiles, though not significantly. This suggests that mild physical activity might be the most effective intensity in supporting mental health among medical students, though further research is recommended. [ABSTRACT FROM AUTHOR]

Youth sport programme structures and processes can directly influence participation outcomes, including mental health and well-being. Researchers have found that programme quality and basic needs satisfaction foster psychosocial outcomes; however, limited research has examined the mechanisms that facilitate mental health. The purpose of this study was to examine relationships between programme quality, basic needs satisfaction, and mental well-being in competitive youth sport. Youth (N = 160, 89 males, 71 females; Mage = 15.36, SD = 2.50) completed questionnaires at mid-season, with questions related to quality of their sport programming, and at programme end, with questions pertaining to basic needs satisfaction and mental well-being. Structural equation modelling was used to test the direct relationships between programme quality and mental well-being (r =.46, p <.001; model 1) and between basic needs satisfaction and mental well-being (r =.63, p <.001; model 2). Using several fit indices, results showed an adequate fit of both models to the data, suggesting that programme quality significantly predicted basic needs satisfaction and basic needs satisfaction significantly predicted mental well-being. Bootstrapping analysis was used to test if basic needs satisfaction mediated the relationship between programme quality and mental well-being. Results supported mediation, with a large effect (k2 = 0.28). The study findings help to emphasise the value of structuring youth sport programmes to satisfy basic needs, which may have positive implications on youth mental health. This is important because supporting mental well-being at an earlier age may facilitate mental health and well-being in adulthood. [ABSTRACT FROM AUTHOR]

Depression is the most common and prevalent mental disorder today, affecting an estimated 1 in 4 Canadians at some point in their lifetime. Physical activity is recommended as a primary treatment for mild to moderate depression and a secondary treatment for moderate to severe depression. Despite this, specific guidelines are still lacking on how to best promote physical activity in this population. Accordingly, this policy brief provides evidence-based recommendations for primary care providers and allied health professionals to promote lifelong physical activity in individuals with depression. Recommendations include asking for permission to discuss physical activity with the individual; framing physical activity as something that they have control over in order to feel better; clarifying that incorporating even a few more minutes of weekly physical activity is better than nothing and that mild forms are enough to achieve mental health benefits; and providing choices of activities to try and accompanying them on their first few sessions. Moreover, this article highlights the importance of promoting physical activity enjoyment for this population, which can be done by guiding the individual to slowly build up the frequency, duration and intensity of activity; encouraging them to be self-compassionate toward physical activity; suggesting they engage in outdoor activity, listen to music, and/or participate with a buddy or group; and incorporate self-monitoring or journalling to solidify the link between physical activity and improved mood. Practitioners are encouraged to use these evidence-informed recommendations--especially maximizing choices, enhancing physical activity enjoyment and emphasizing personal preferences--to help individuals with depression move, recover and flourish. These recommendations may also be used to tailor future interventions and inform policy guidelines to reduce depression rates in Canada. [ABSTRACT FROM AUTHOR]

Background: Physical activity (PA) remains under prescribed by physicians. Motivation and confidence are clear drivers of frequency of promoting PA. Research shows demographic differences in physicians' preventive practices, yet none have included medical students who form habits during training.Objectives: Study objectives were to (i) examine how Canadian medical students' motivation to recommend PA to future patients differs according to six demographic variables (i.e. gender, ethnicity, year of study, university, proposed specialty and academic background) and (ii) examine how Canadian medical students' confidence to recommend PA to future patients differs according to these same demographic variables.Methods: A cross-sectional design was used. First to fourth year medical students from three medical schools responded to an online survey (N = 221).Results: Female participants were more motivated to counsel patients on PA and refer to an exercise specialist compared to males (P < 0.01). Second year students were more motivated to assess a patients' level of PA compared to third and fourth year students (P < 0.01). Students pursuing family medicine were more confident to assess and counsel compared to students pursuing paediatrics (P < 0.01).Conclusion: Given that motivation and confidence have a positive influence on frequency-promoting PA, these results suggest where future efforts should focus, to improve PA promotion in medical practice. Physical inactivity continues to be a major issue worldwide, and medical students as future physicians have a unique opportunity to enhance PA amongst the population. [ABSTRACT FROM AUTHOR]

Background: This article presents secondary outcome variables from a randomized controlled trial evaluating the efficacy of two guided self-help interventions for the treatment of depression: behavioral activation (BA) and physical activity (PA). Both interventions resulted in significant reductions in depressive symptoms compared to the wait-list control group, however the mechanisms by which these interventions influenced depression were not presented. Purpose: The purpose of this paper was to compare changes in secondary outcome variables to gain insight into the mechanisms by which reactivation interventions reduce depressive symptoms. Results: Mixed-model analysis of variances (ANOVAs) revealed significant increases in life satisfaction (Main effect: F(3, 91.71) = 4.63, p < 0.01) and self-efficacy (Main effect: F(3, 91.32) = 4.05, p < 0.01) as well as significant decreases in negative affect (Main effect: F(2, 75.88) = 5.24, p < 0.01) and loneliness (Main effect: F(2, 71.78) = 7.49, p < 0.01) in both interventions at pre-, mid-, post-intervention and follow-up. The group x time interactions were not significant, suggesting that the PA and BA interventions had comparable effects over time. Conclusion: These findings provide insight into the potential mechanisms underlying the effectiveness of guided self-help PA and BA interventions on depressive symptoms. [ABSTRACT FROM AUTHOR]

Behavioural activation and physical activity have received empirical support that highlight their efficacy in reducing depression. Even though both behavioural activation and physical activity share the common goal of reactivating the individual, limited research has directly compared these interventions, and more research is required to evaluate their efficacy when offered in low-intensity formats. The present study involves a randomized controlled clinical trial comparing the efficacy of two guided self-help interventions for the treatment of depression: behavioural activation and physical activity. Fifty-nine participants presenting mild-to-moderate symptoms of depression were randomized either to a behavioural activation intervention (n = 20), a physical activity intervention (n = 19) or a wait-list control group (n = 20). All participants completed symptom measure pre-, mid- and post-intervention, as well as at a two-month follow-up. Mixed-model analyses of variance revealed that both interventions were significantly more efficacious in reducing depressive symptoms in comparison with the control group. Physical activity involved significantly less time-investment compared to the behavioural activation condition (less than half the amount of time). These results indicate that physical activity and behavioural activation both effectively reduce depressive symptoms and are favourably applicable in low-intensity formats. Implications of these results and avenues for future research are discussed. [ABSTRACT FROM PUBLISHER]

• Acute exposure to high fat diet impairs memory for an object location task in rats. • These memory impairments are associated with altered hippocampus protein degradation. • Changes in trypsin activity is most strongly correlated with behavioral performance. • Dysregulation of protein degradation extends into the retrosplenial cortex. Studies have shown that long-term exposure to high fat and other obesogenic diets results in insulin resistance and altered blood brain barrier permeability, dysregulation of intracellular signaling mechanisms, changes in DNA methylation levels and gene expression, and increased oxidative stress and neuroinflammation in the hippocampus, all of which are associated with impaired spatial memory. The ubiquitin-proteasome system controls the majority of protein degradation in cells and is a critical regulator of synaptic plasticity and memory formation. Yet, whether protein degradation in the hippocampus becomes dysregulated following weight gain and is associated with obesity-induced memory impairments is unknown. Here, we used a high fat diet procedure in combination with behavioral and subcellular fractionation protocols and a variety of biochemical assays to determine if ubiquitin-proteasome activity becomes altered in the hippocampus during obesity development and whether this is associated with impaired spatial memory. We found that only 6 weeks of exposure to a high fat diet was sufficient to impair performance on an object location task in rats and resulted in dynamic dysregulation of ubiquitin-proteasome activity in the nucleus and cytoplasm of cells in the hippocampus. Furthermore, these changes in the protein degradation process extended into cortical regions also involved in spatial memory formation. Collectively, these results indicate that weight gain-induced memory impairments may be due to altered ubiquitin-proteasome signaling that occurs during the early stages of obesity development. [ABSTRACT FROM AUTHOR]

The Developmental Model of Sport Participation describes three pathways that youth can follow: recreational participation, late specialization and early specialization. Many competitive sport programmes are promoting early specialization in hopes that their athletes will gain an advantage over others; however, research indicates that youth who wait until adolescence to specialize in a given sport may achieve physical and psychological benefits. The purpose of this study was to investigate the psychological effects of sport specialization by examining relationships between youth hockey players’ level of specialization, psychological needs satisfaction (PNS), psychological needs dissatisfaction (PND), mental health and mental illness. Sixty-one youth male hockey players (Mage = 14.90) responded to an online survey. Results indicated that PND according to specialization was significant with early specializers reporting the highest PND and recreational athletes reporting the lowest PND (p = .029), indicating a large effect size (η2 = .157). No other significant differences were found. Bivariate correlations revealed significant relationships between all variables. Moreover, regression analyses showed that PNS positively predicted mental health (β = .47) and negatively predicted mental illness (β = −.51), while PND positively predicted mental illness (β = .71) and negatively predicted mental health (β = −.44). Results suggest that PNS is important to promote mental health and avoid mental illness. Future research is needed to fully understand the psychological consequences of early sport specialization. [ABSTRACT FROM PUBLISHER]

Posttranslational histone modifications play a critical role in the regulation of gene transcription underlying synaptic plasticity and memory formation. One such epigenetic change is histone ubiquitination, a process that is mediated by the ubiquitin–proteasome system in a manner similar to that by which proteins are normally targeted for degradation. However, histone ubiquitination mechanisms are poorly understood in the brain and in learning. In this article, we describe a new role for the ubiquitin–proteasome system in histone crosstalk, showing that learning-induced monoubiquitination of histone H2B (H2Bubi) is required for increases in the transcriptionally active H3 lysine 4 trimethylation (H3K4me3) mark at learning-related genes in the hippocampus. Using a series of molecular, biochemical, electrophysiological, and behavioral experiments, we interrogated the effects of short interfering RNA–mediated knockdown and CRISPR (clustered regularly interspaced short palindromic repeats)-mediated upregulation of ubiquitin ligases, deubiquitinating enzymes and histone methyltransferases in the rat dorsal hippocampus during memory consolidation. We show that H2Bubi recruits H3K4me3 through a process that is dependent on the 19S proteasome subunit RPT6 and that a loss of H2Bubi in the hippocampus prevents learning-induced increases in H3K4me3, gene transcription, synaptic plasticity, and memory formation. Furthermore, we show that CRISPR–dCas9-mediated increases in H2Bubi promote H3K4me3 and memory formation under weak training conditions and that promoting histone methylation does not rescue memory impairments resulting from loss of H2Bubi. These results suggest that H2B ubiquitination regulates histone crosstalk in learning by way of nonproteolytic proteasome function, demonstrating a novel mechanism by which histone modifications are coordinated in response to learning. [ABSTRACT FROM AUTHOR]

The ubiquitin-proteasome system (UPS) controls the degradation of ~ 90% of short-lived proteins in cells and is involved in activity- and learning-dependent synaptic plasticity in the brain. Calcium/calmodulin dependent protein kinase II (CaMKII) and Protein Kinase A (PKA) can regulate activity of the proteasome. However, there have been a number of conflicting reports regarding under what conditions CaMKII and PKA regulate proteasome activity in the brain. Furthermore, this work has been done exclusively in males, leaving questions about whether these kinases also regulate the proteasome in females. Here, using subcellular fractionation protocols in combination with in vitro pharmacology and proteasome activity assays, we investigated the conditions under which CaMKII and PKA regulate proteasome activity in the brains of male and female rats. In males, nuclear proteasome chymotrypsin activity was regulated by PKA in the amygdala but CaMKII in the hippocampus. Conversely, in females CaMKII regulated nuclear chymotrypsin activity in the amygdala, but not hippocampus. Additionally, in males CaMKII and PKA regulated proteasome trypsin activity in the cytoplasm of hippocampal, but not amygdala cells, while in females both CaMKII and PKA could regulate this activity in the nucleus of cells in both regions. Proteasome peptidylglutamyl activity was regulated by CaMKII and PKA activity in the nuclei of amygdala and hippocampus cells in males. However, in females PKA regulated nuclear peptidylglutamyl activity in the amygdala, but not hippocampus. Collectively, these results suggest that CaMKII- and PKA-dependent regulation of proteasome activity in the brain varies significantly across subcellular compartments and between males and females. • CaMKII and PKA regulate proteasome activity in the brain of both males and females. • The regulation of the proteasome by CaMKII and PKA varies by sex, subcellular compartment and brain region. • CaMKII and PKA can regulate the proteasome in all subcellular compartments but exert largest effects in the nucleus. • PKA was a better regulator of proteasome activity than CaMKII in both males and females. [ABSTRACT FROM AUTHOR]

Strong evidence has implicated proteasome-mediated protein degradation in the memory consolidation process. However, due to the use of pharmacological approaches, the cell type specificity of this remains unknown. Here, we used neuron-specific and novel astrocyte-specific CRISPR-dCas9-KRAB-MECP2 plasmids to inhibit protein degradation in a cell type-specific manner in the amygdala of male rats. We found that while inhibition of neuronal, but not astrocytic, protein degradation impaired performance during the training session, both resulted in impaired contextual fear memory retention. Together, these data provide the first evidence of a cell type-specific role for protein degradation in the memory consolidation process., (© 2023 Farrell et al.; Published by Cold Spring Harbor Laboratory Press.)

There is substantial evidence showing that medical student wellness is a worsening problem in Canada. It is apparent that medical students' wellness deteriorates throughout their training. Medical schools and their governing bodies are responding by integrating wellness into competency frameworks and accreditation standards through a combination of system- and individual-level approaches. System-level strategies that consider how policies, medical culture, and the "hidden curriculum" impact student wellness, are essential for reducing burnout prevalence and achieving optimal wellness outcomes. Individual-level initiatives such as wellness programming are widespread and more commonly used. These are often didactic, placing the onus on the student without addressing the learning environment. Despite significant progress, there is little programming consistency across schools or training levels. There is no wellness curriculum framework for Canadian undergraduate medical education that aligns with residency competencies. Creating such a framework would help align individual- and system-level initiatives and smooth the transition from medical school to residency. The framework would organize goals within relevant wellness domains, allow for local adaptability, consider basic learner needs, and be learner-informed. Physicians whose wellness has been supported throughout their training will positively contribute to the quality of patient care, work environments, and in sustaining a healthy Canadian population., Competing Interests: No potential competing interest was reported by the authors. The opinions and conclusions expressed are the writers’ own and are not those of the Canadian Medical Association, nor those of any of the medical schools associated with the authors., (© 2021 Bourcier, Far, King, Cai, Mader, Xiao, Simon, McFadden, Flynn; licensee Synergies Partners.)

Numerous studies have shown that following retrieval, a previously consolidated memory requires increased transcriptional regulation in order to be reconsolidated. Previously, it was reported that histone H3 lysine-4 trimethylation (H3K4me3), a marker of active transcription, is increased in the hippocampus after the retrieval of contextual fear memory. However, it is currently unknown how this epigenetic mark is regulated during the reconsolidation process. Furthermore, though recent evidence suggests that neuronal activity triggers DNA double-strand breaks (DSBs) in some early-response genes, it is currently unknown if DSBs contribute to the reconsolidation of a memory following retrieval. Here, using chromatin immunoprecipitation (ChIP) analyses, we report a significant overlap between DSBs and H3K4me3 in area CA1 of the hippocampus during the reconsolidation process. We found an increase in phosphorylation of histone H2A.X at serine 139 (H2A.XpS139), a marker of DSB, in the Npas4 , but not c-fos , promoter region 5 min after retrieval, which correlated with increased H3K4me3 levels, suggesting that the two epigenetic marks may work in concert during the reconsolidation process. Consistent with this, in vivo siRNA-mediated knockdown of topoisomerase II β, the enzyme responsible for DSB, prior to retrieval, reduced Npas4 promoter-specific H2A.XpS139 and H3K4me3 levels and impaired long-term memory, indicating an indispensable role of DSBs in the memory reconsolidation process. Collectively, our data propose a novel mechanism for memory reconsolidation through increases in epigenetic-mediated transcriptional control via DNA double-strand breaks.

The ubiquitin-proteasome system is a key regulator of protein degradation and a variety of other cellular processes in eukaryotes. In the brain, increases in ubiquitin-proteasome activity are critical for synaptic plasticity and memory formation and aberrant changes in this system are associated with a variety of neurological, neurodegenerative and psychiatric disorders. One of the issues in studying ubiquitin-proteasome functioning in the brain is that it is present in all cellular compartments, in which the protein targets, functional role and mechanisms of regulation can vary widely. As a result, the ability to directly compare brain ubiquitin protein targeting and proteasome catalytic activity in different subcellular compartments within the same animal is critical for fully understanding how the UPS contributes to synaptic plasticity, memory and disease. The method described here allows collection of nuclear, cytoplasmic and crude synaptic fractions from the same rodent (rat) brain, followed by simultaneous quantification of proteasome catalytic activity (indirectly, providing activity of the proteasome core only) and linkage-specific ubiquitin protein tagging. Thus, the method can be used to directly compare subcellular changes in ubiquitin-proteasome activity in different brain regions in the same animal during synaptic plasticity, memory formation and different disease states. This method can also be used to assess the subcellular distribution and function of other proteins within the same animal.