How Student and Faculty Perceptions Differ on the Stressors that Medical Students Face.

OBJECTIVES: Medical education is notorious for the stress that students face as they strive to succeed both academically and clinically. This stress has been linked to declining academic performance and worsening mental health. To combat these negative outcomes, it is essential for medical school faculty and administration to address common stressors among medical students. No studies have addressed whether medical school faculty and students perceive stressors similarly, however. METHODS: In this two-part study, data collected from medical students in 2021 to 2022 to identify their most significant sources of stress were used to create a survey that queries the frequency and intensity of these stressors. This survey was distributed to medical students and faculty at the same institution. The responses between students and faculty were compared and student data also were analyzed by academic year to observe changes in perception that accompany progression through the medical curriculum. RESULTS: The results showed that faculty overestimated the impact of certain stressors on medical students (eg, in-house examinations, US Medical Licensing Examination Steps 1 and 2 examinations, and patient interactions). In addition, preclinical students were more concerned with finding extracurricular activities, missing opportunities, and performing research compared with clinical students. CONCLUSIONS: This study demonstrated that although faculty anticipated most medical student stressors, there are significant gaps that still need to be addressed to better reduce and respond to the stress experienced by medical students.

Matching Against Men: 5 Years of Residency Match Data Show Disparities Still Exist.

OBJECTIVES: Despite progress toward equal representation by sex in medical practice, women remain underrepresented in many specialties. This study sought to examine the current state of gender equality among recently graduated doctors in multiple specialties. METHODS: Deidentified demographics, standardized examination scores, and Match results were gathered for 829 graduates. Participants were selected from an allopathic medical school between 2016 and 2020. Nineteen students (2.29%) were excluded from the study. Descriptive statistics were calculated, and χ2 tests for independence were used to compare proportions between reported sex and specialty and program Match results. One-way analysis of variance was then performed to test for differences in US Medical Licensing Examination Step 1 and Step 2 scores between sexes. P < 0.05 was considered statistically significant. RESULTS: Of the 829 individuals studied, 44.6% were women. A significantly smaller proportion of women matched into the most competitive specialties, despite no significant difference in US Medical Licensing Examination Step 1 scores between sexes. Furthermore, there was an overall significant trend of women matching into more competitive programs for any given specialty. CONCLUSIONS: In this study, we found that men matched into more highly competitive specialties, whereas women matched into more competitive residency program locations. Further research is needed to determine why women matched into specific specialties at lower rates than their male peers and seek to understand how sex affects the narrative of specialty choice.

Student-Produced Guides alongside First-Year Medical Curriculum: How Peer-Produced Textbooks Change Student Success within Neurology, Cardiopulmonary, and Mixed Systems Courses.

OBJECTIVES: In the United States, medical schools do not have a unified curricular plan that integrates basic sciences and organ-based systems in undergraduate medical education. Instead, institutions rely on independently created lecture material during the first-year medical school curriculum. The drawback to this approach is that no commercial or organizational resources cater to this individualized study plan. This study explored whether students who use student-produced "course guides" experience increased first-year success and improved skills. METHODS: First-year students at an allopathic medical school completed anonymous surveys about their reference guide usage, time management, organization, stress level, and examination scores. Statistical analysis was performed using Spearman's coefficient of correlation and χ2 tests. All of the tests were performed with a significance level of α = 0.05 and a 95% confidence interval. RESULTS: In total, 186 total students received the survey three times immediately after completing each organ system-based course. A total of n = 49 viable responses were received. One-fourth of the respondents used the guides for ≥3 hours/week. Respondents who used the reference guides reported improved time management, organization, self-confidence, and reduced student stress levels during the first year of medical school, but examination scores were unaffected. CONCLUSIONS: Access to student-produced guides increased confidence in self-rated measures of time management skills, organizational ability, and ability to balance medical course expectations. Because of the small sample size, future work will expand the survey population to increase the power to detect differences in these factors.

Circadian rhythm shifts and alcohol access in adolescence synergistically increase alcohol preference and intake in adulthood in male C57BL/6 mice.

BACKGROUND: Adolescents have a natural tendency to be night owls, maintaining delayed circadian rhythms, and this rhythm is in direct conflict with the early wake times required during the school year. This leads to 'social jetlag', chronic circadian stress or desynchrony (CD) in which the rhythm of the intrinsic body clock is out of sync with behavior. CD increases alcohol intake in adolescents and adults, yet it is unknown whether adolescent CD also increases long-term addiction risk. The goal of this study was to determine whether adolescent alcohol intake in CD would increase adult alcohol preference and intake in male C57BL/6 J mice. METHODS: We measured free access alcohol intake, water intake, and wheel-running activity during a normal 12 h (h) baseline photoperiod and then during shifting lighting schedules (Experiment 1) or a shortened circadian day (Experiment 2). RESULTS: In Experiment 1, altered lighting produced a persistent increase in adolescent alcohol intake and in binge-like drinking (drinking at least 5 licks per minute, with no more than a 1 min break in drinking) in adulthood, but only a transient increase in total alcohol intake for the first week after alcohol was reintroduced in adulthood. In Experiment 2, the circadian shift produced a significant increase in alcohol intake in both adolescence and adulthood. Molecular analysis demonstrated changes in plasma corticosterone and neuronal markers of stress and addiction at the conclusion of these experiments in the CD and alcohol-exposed groups. CONCLUSIONS: Thus, we conclude that circadian stress during adolescence is sufficient to produce a long-lasting susceptibility to alcohol use.

DISC1 and reelin interact to alter cognition, inhibition, and neurogenesis in a novel mouse model of schizophrenia.

The etiology of schizophrenia (SCZ) is multifactorial, and depending on a host of genetic and environmental factors. Two putative SCZ susceptibility genes, Disrupted-in-Schizophrenia-1 (DISC1) and reelin (RELN), interact at a molecular level, suggesting that combined disruption of both may lead to an intensified SCZ phenotype. To examine this gene-gene interaction, we produced a double mutant mouse line. Mice with heterozygous RELN haploinsufficiency were crossed with mice expressing dominant-negative c-terminal truncated human DISC1 to produce offspring with both mutations (HRM/DISC1 mice). We used an array of behavioral tests to generate a behavioral phenotype for these mice, then examined the prefrontal cortex and hippocampus using western blotting and immunohistochemistry to probe for SCZ-relevant molecular and cellular alterations. Compared to wild-type controls, HRM/DISC1 mice demonstrated impaired pre-pulse inhibition, altered cognition, and decreased activity. Diazepam failed to rescue anxiety-like behaviors, paradoxically increasing activity in HRM/DISC1 mice. At a cellular level, we found increased α1-subunit containing GABA receptors in the prefrontal cortex, and a reduction in fast-spiking parvalbumin positive neurons. Maturation of adult-born neurons in the hippocampus was also altered in HRM/DISC1 mice. While there was no difference in the total number proliferating cells, more of these cells were in immature stages of development. Homozygous DISC1 mutation combined with RELN haploinsufficiency produces a complex phenotype with neuropsychiatric characteristics relevant to SCZ and related disorders, expanding our understanding of how multiple genetic susceptibility factors might interact to influence the variable presentation of these disorders.

Association of an Early Interest in Orthopedic Surgery with Match Rate into Orthopedic Surgery.

OBJECTIVES: Orthopedic surgery residency is considered one of the most competitive specialties in which to match. Studies examining the factors associated with a successful match have neglected whether participation in an orthopedic interest group (OIG) improves the chances of orthopedic residency match. The goal of this study was to test the hypothesis that participation in the OIG would improve matching into an orthopedic surgery residency. METHODS: We performed a retrospective cohort study between May 2017 and 2019 at one state-funded medical school. All of the applicants in orthopedic surgery from 2004 to 2019 were identified and contacted for OIG membership status. The Office of Student Affairs provided academic performance data (US Medical Licensing Examination scores and third-year clinical clerkship grades), Alpha Omega Alpha and Gold Humanism Honor Society status, and demographics (race and sex) of applicants. RESULTS: Between 2004 and 2019, 67 students (56 OIG and 11 non-OIG) applied for orthopedic surgery residency match. The match rate for the OIG was 86% compared with 64% for the non-OIG group, resulting in an adjusted odds ratio (adjusted for academic performance) of 10.23 (95% confidence interval 1.14-92.3, P = 0.038). CONCLUSIONS: OIG membership was associated with a significantly higher rate of orthopedic surgery residency matches. The higher rate of match associated with OIG membership may be the result of opportunities to diversify a residency application. Future studies are needed to further evaluate the potential association between OIG involvement and orthopedic surgery match.

Improving Gene Therapy for Angelman Syndrome with Secreted Human UBE3A.

The rare genetic neurodevelopmental disease Angelman syndrome (AS) is caused by the loss of function of UBE3A, a ubiquitin ligase. The disease results in a lifetime of severe symptoms, including intellectual disability and motor impairments for which there are no effective treatments. One avenue of treatment for AS is the use of gene therapy to reintroduce a functional copy of the UBE3A gene. Our group had previously shown that recombinant adeno-associated virus (rAAV) expressing mouse Ube3a could rescue deficits in a mouse model of AS. Here, we expand on this work and show that this approach could be successfully replicated in a second AS model using the human UBE3A gene. Furthermore, we address the challenge of limited vector distribution in the brain by developing a novel modified form of UBE3A. This modified protein, termed STUB, was designed with a secretion signal and a cell-penetrating peptide. This allowed transduced cells to act as factories for the production of UBE3A protein that could be taken up by neighboring non-transduced cells, thus increasing the number of neurons receiving the therapeutic protein. Combining this construct with intracerebroventricular injections to maximize rAAV distribution within the brain, we demonstrate that this novel approach improves the recovery of behavioral and electrophysiological deficits in the AS rat model. More importantly, a comparison of rAAV-STUB to a rAAV expressing the normal human UBE3A gene showed that STUB was a more effective therapeutic. These data suggest that rAAV-STUB is a new potential approach for the treatment of AS.

Prevalence of, Qualities, and Barriers Associated with Mentoring Relationships from Medical Students' Perspective: A Multi-Institutional Cross-Sectional Study.

OBJECTIVES: Reports of medical student mentorship prevalence range between 26% and 77%. This broad range likely reflects the tendencies of studies to focus on specific populations of medical students. There is little consensus about the characteristics of mentoring relationships among medical students. The primary goal of this study was to determine the reported prevalence of mentorship among medical students in the United States. The secondary goals were to assess the desired qualities of and barriers to successful mentoring from a medical student perspective. METHODS: A cross-sectional online survey was administered via Qualtrics to all medical students at participating accredited medical schools from July 2018 to March 2019. The questionnaire contained a subsection of questions that assessed the existence of mentoring, facilitators, and barriers in finding a mentor, and the desired qualities of a successful mentor. RESULTS: With a 94% completion rate, 369 (69%) of 532 medical students reported having a mentor. Adjusted analysis showed that fourth-year medical students were significantly more likely to have a mentor compared with first-year (odds ratio [OR] 2.65, 95% confidence interval [CI] 1.49-4.73, P = 0.001), second-year (OR 2.07, 95% CI 1.14-3.76, P = 0.016), and third-year medical students (OR 2.16, 95% CI 1.2-3.90, P = 0.011). Compassion (64%) was the most commonly reported quality in a successful mentoring relationship. Lack of time from mentor (75%) was the most commonly reported barrier. CONCLUSIONS: This study may serve as a guide to fostering more supportive mentoring relationships. Each mentoring relationship should be tailored to the needs of the mentee, however.

Impact of Alcohol Abuse on Susceptibility to Rare Neurodegenerative Diseases.

Despite the prevalence and well-recognized adverse effects of prenatal alcohol exposure and alcohol use disorder in the causation of numerous diseases, their potential roles in the etiology of neurodegenerative diseases remain poorly characterized. This is especially true of the rare neurodegenerative diseases, for which small population sizes make it difficult to conduct broad studies of specific etiological factors. Nonetheless, alcohol has potent and long-lasting effects on neurodegenerative substrates, at both the cellular and systems levels. This review highlights the general effects of alcohol in the brain that contribute to neurodegeneration across diseases, and then focuses on specific diseases in which alcohol exposure is likely to play a major role. These specific diseases include dementias (alcohol-induced, frontotemporal, and Korsakoff syndrome), ataxias (cerebellar and frontal), and Niemann-Pick disease (primarily a Type B variant and Type C). We conclude that there is ample evidence to support a role of alcohol abuse in the etiology of these diseases, but more work is needed to identify the primary mechanisms of alcohol's effects.

The Molecular Clock and Neurodegenerative Disease: A Stressful Time.

Circadian rhythm dysfunction occurs in both common and rare neurodegenerative diseases. This dysfunction manifests as sleep cycle mistiming, alterations in body temperature rhythms, and an increase in symptomatology during the early evening hours known as Sundown Syndrome. Disruption of circadian rhythm homeostasis has also been implicated in the etiology of neurodegenerative disease. Indeed, individuals exposed to a shifting schedule of sleep and activity, such as health care workers, are at a higher risk. Thus, a bidirectional relationship exists between the circadian system and neurodegeneration. At the heart of this crosstalk is the molecular circadian clock, which functions to regulate circadian rhythm homeostasis. Over the past decade, this connection has become a focal point of investigation as the molecular clock offers an attractive target to combat both neurodegenerative disease pathogenesis and circadian rhythm dysfunction, and a pivotal role for neuroinflammation and stress has been established. This review summarizes the contributions of molecular clock dysfunction to neurodegenerative disease etiology, as well as the mechanisms by which neurodegenerative diseases affect the molecular clock.

Inhibition of casein kinase 1 δ/ε improves cognitive performance in adult C57BL/6J mice.

Time-of-day effects have been noted in a wide variety of cognitive behavioral tests, and perturbation of the circadian system, either at the level of the master clock in the SCN or downstream, impairs hippocampus-dependent learning and memory. A number of kinases, including the serine-threonine casein kinase 1 (CK1) isoforms CK1δ/ε, regulate the timing of the circadian period through post-translational modification of clock proteins. Modulation of these circadian kinases presents a novel treatment direction for cognitive deficits through circadian modulation. Here, we tested the potential for PF-670462, a small molecule inhibitor of CK1δ/ε, to improve cognitive performance in C57BL/6J mice in an array of behavioral tests. Compared to vehicle-treated mice tested at the same time of the circadian day, mice treated with PF-670462 displayed better recall of contextual fear conditioning, made fewer working memory errors in the radial arm water maze, and trained more efficiently in the Morris Water Maze. These benefits were accompanied by increased expression of activity-regulated cytoskeleton-associated protein (Arc) in the amygdala in response to an acute learning paradigm. Our results suggest the potential utility of CK1δ/ε inhibition in improving time-of-day cognitive performance.

Inter-relationships of Metacarpals 1 to 5, Regarding Their Length, Metaphyseal Midshaft Width, Articular Surface Area of Head and Base, Age, and Sex: A Cadaveric Study.

Background: Metacarpal factures are common, comprising up to 50% of hand fractures. More work is needed to further our understanding of metacarpal anatomy to improve fixation techniques and reduce postoperative complications following surgical implants. The purpose of this anatomic study was to evaluate the length, midshaft metaphyseal width, and area of the articular surface of the head (AH) and base (AB) of metacarpals 1 to 5. Methods: This prospective study assessed measures from 17 cadavers at 1 institution's anatomy lab. The anatomic dimensions of the metacarpals in both the right and left hands were measured. Epidemiological data including sex and age at death were also collected. Results: In all, 29 hands were dissected for metacarpal anatomic measurements, for a total of 145 metacarpals. The second metacarpal was longest, at 69.58 mm. Multivariate analysis of variance revealed a significant effect of sex overall, with greater metacarpal dimensions in men. Increasing age was associated with decreasing dimensions, except for AH of metacarpal 1 (F = 3.43, P = .02) and AB of metacarpal 1 (F = 11.54, P < .001) and 4 (F = 4.21, P = .01). Multiple metacarpal dimensions were also significantly correlated with each other. Conclusion: Our data reveal further information regarding metacarpal dimensions of length, midshaft width, and AH and AB. The results allow for potential to improve surgical management through improving metacarpal implants, developing an optimal plate and screw design, techniques to better accommodate anatomical differences based on age and sex, reducing postoperative complications and improving the standard of care.

Treatment with shCCL20-CCR6 nanodendriplexes and human mesenchymal stem cell therapy improves pathology in mice with repeated traumatic brain injury.

Traumatic brain injury (TBI) is a devastating neurological disorder, although the underlying pathophysiology is poorly understood. TBI causes blood-brain barrier (BBB) disruption, immune cell trafficking, neuroinflammation and neurodegeneration. CCL20 is an important chemokine mediating neuroinflammation. Human mesenchymal stem cell (hMSC) therapy is a promising regenerative approach but the inflammatory microenvironment in the brain tends to decrease the efficacy of the hMSC transplantation. Reducing the inflammation prior to hMSC therapy improves the outcome. We developed a combined nano-cell therapy by using dendrimers complexed with plasmids (dendriplexes) targeting CCL20 and its sole receptor CCR6 to reduce inflammation followed by hMSC transplantation. Treatment of TBI mice with shRNA conjugated dendriplexes followed by hMSC administration downregulated the inflammatory markers and significantly increased brain-derived neurotrophic factor (BDNF) expression in the cerebral cortex indicating future possible neurogenesis and improved behavioral deficits. Taken together, this nano-cell therapy ameliorates neuroinflammation and promotes brain tissue repair after TBI.

FKBP5 and early life stress affect the hippocampus by an age-dependent mechanism.

Early life stress (ELS) adversely affects the brain and is commonly associated with the etiology of mental health disorders, like depression. In addition to the mood-related symptoms, patients with depression show dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, increased peripheral inflammation, and structural brain alterations. Although the underlying causes are unknown, polymorphisms in the FK506-binding protein 5 (FKBP5) gene, a regulator of glucocorticoid receptor (GR) activity, interact with childhood adversities to increase vulnerability to depressive disorders. We hypothesized that high FKBP5 protein levels combined with early life stress (ELS) would alter the HPA axis and brain, promoting depressive-like behaviors. To test this, we exposed males and females of a mouse model overexpressing FKBP5 in the brain (rTgFKBP5 mice), or littermate controls, to maternal separation for 14 days after birth. Then, we evaluated neuroendocrine, behavioral, and brain changes in young adult and aged mice. We observed lower basal corticosterone (CORT) levels in rTgFKBP5 mice, which was exacerbated in females. Aged, but not young, rTgFKBP5 mice showed increased depressive-like behaviors. Moreover, FKBP5 overexpression reduced hippocampal neuron density in aged mice, while promoting markers of microglia expression, but these effects were reversed by ELS. Together, these results demonstrate that high FKBP5 affects basal CORT levels, depressive-like symptoms, and numbers of neurons and microglia in the hippocampus in an age-dependent manner.

Morphometric analysis of the second through fifth metacarpal through posteroanterior X-Rays.

Over the past 10 years, metacarpal fractures have had an annual incidence of 13.6 per 10,000 individuals. Literature has not reviewed anatomical variations through radiographic imaging, which may play a role in reducing postoperative complications. The purpose of this study was to use radiographic imaging to provide a detailed anatomy of the second through fifth metacarpals. This retrospective study measured length, neck width, narrowest body width, and narrowest medullary canal width of the second through fifth metacarpals through the use of posteroanterior X-rays. Patients who were ≥18 years and received hand radiographs from January 2015 to July 2019 were included in this study. Those with acute injury or fracture of the metacarpal were excluded. Five hundred and seventy-two metacarpals were included in this study, with 143 metacarpals measured each for the second through fifth metacarpal. The second metacarpal had the largest measured length, neck width, and narrowest body width at 68.72, 12.34, and 8.74 mm, respectively. The fifth metacarpal had the greatest average medullary canal width at 4.15 mm. This is the largest study in literature to comprehensively examine the anatomical variation of the second through fifth metacarpals. The second metacarpal had greatest dimensions except for canal width, which was the fifth metacarpal. Men almost consistently had greater metacarpal size when compared to women, and age was associated with second and third metacarpal canal width. The increased knowledge of metacarpal anatomy may potentially lay the foundation of further improvement of metacarpal implants and potentially reduce postoperative complications. Clin. Anat., 33:1014-1018, 2020. © 2019 Wiley Periodicals, Inc.

Hsp90 Heterocomplexes Regulate Steroid Hormone Receptors: From Stress Response to Psychiatric Disease.

The hypothalamus-pituitary-adrenal (HPA) axis directly controls the stress response. Dysregulation of this neuroendocrine system is a common feature among psychiatric disorders. Steroid hormone receptors, like glucocorticoid receptor (GR), function as transcription factors of a diverse set of genes upon activation. This activity is regulated by molecular chaperone heterocomplexes. Much is known about the structure and function of these GR/heterocomplexes. There is strong evidence suggesting altered regulation of steroid receptor hormones by chaperones, particularly the 51 kDa FK506-binding protein (FKBP51), may work with environmental factors to increase susceptibility to various psychiatric illnesses including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), and anxiety. This review highlights the regulation of steroid receptor dynamics by the 90kDa heat shock protein (Hsp90)/cochaperone heterocomplexes with an in depth look at how the structural regulation and imbalances in cochaperones can cause functional effects on GR activity. Links between the stress response and circadian systems and the development of novel chaperone-targeting therapeutics are also discussed.

Racing the clock: The role of circadian rhythmicity in addiction across the lifespan.

Although potent effects of psychoactive drugs on circadian rhythms were first described over 30 years ago, research into the reciprocal relationship between the reward system and the circadian system - and the impact of this relationship on addiction - has only become a focus in the last decade. Nonetheless, great progress has been made in that short time toward understanding how drugs of abuse impact the molecular and physiological circadian clocks, as well as how disruption of normal circadian rhythm biology may contribute to addiction and ameliorate the efficacy of treatments for addiction. In particular, data have emerged demonstrating that disrupted circadian rhythms, such as those observed in shift workers and adolescents, increase susceptibility to addiction. Furthermore, circadian rhythms and addiction impact one another longitudinally - specifically from adolescence to the elderly. In this review, the current understanding of how the circadian clock interacts with substances of abuse within the context of age-dependent changes in rhythmicity, including the potential existence of a drug-sensitive clock, the correlation between chronotype and addiction vulnerability, and the importance of rhythmicity in the mesocorticolimbic dopamine system, is discussed. The primary focus is on alcohol addiction, as the preponderance of research is in this area, with references to other addictions as warranted. The implications of clock-drug interactions for the treatment of addiction will also be reviewed, and the potential of therapeutics that reset the circadian rhythm will be highlighted.

Alcohol Intake Increases in Adolescent C57BL/6J Mice during Intermittent Cycles of Phase-Delayed, Long-Light Conditions.

Adolescents naturally go to bed and awaken late, but are forced to awaken early for school and work. This leads to "social jetlag", a state of circadian desynchrony (CD), in which internal biological rhythms are out of sync with behavioral rhythms. CD is associated with increased alcohol intake in adults, but has been less well-studied in adolescents. The goal of this study was to model adolescent alcohol intake during similar CD conditions in male C57BL/6J mice. Free access alcohol intake, water intake and wheel-running activity were measured during a normal 12HR photoperiod or during alternating photoperiod (Experiment 1: 12 h light for 4 days followed by 18 h light for 3 days, with dark (activity onset) delayed 9 h during the 18HR photoperiod; Experiment 2: 12 h light for 4 days followed by 6 h light for 3 days, with dark onset delayed 3 h during the 6HR photoperiod). In Experiment 1, CD produced a small but significant increase in the total alcohol intake per day as well as in intake in bouts, with the greatest increase over controls in the hours following the 6HR dark period. Additionally, the pattern of alcohol intake in bouts shifted to increase alcohol intake during the shorter dark period. In Experiment 2, the opposite effect occurred-the longer dark cycle led to lower alcohol drinking in the second half of the dark period. However, in Experiment 2, CD produced no significant changes in either total alcohol intake or alcohol intake in bouts. CONCLUSION: shifts in the light cycle that disrupt the regular pattern of day and night, and increase the length of the night phase, are sufficient to increase both drinking in bouts and restricted drinking in adolescent mice, modeling increased alcohol intake in adolescents during CD.

Disruption of normal circadian clock function in a mouse model of tauopathy.

Disruption of normal circadian rhythm physiology is associated with neurodegenerative disease, which can lead to symptoms such as altered sleep cycles. In Alzheimer's disease (AD), circadian dysfunction has been attributed to ß-amyloidosis. However, it is unclear whether tauopathy, another AD-associated neuropathology, can disrupt the circadian clock. We have evaluated the status of the circadian clock in a mouse model of tauopathy (Tg4510). Tg4510 mice display a long free-running period at an age when tauopathy is present, and show evidence of tauopathy in the suprachiasmatic nucleus (SCN) of the hypothalamus - the site of the master circadian clock. Additionally, cyclic expression of the core clock protein PER2 is disrupted in the hypothalamus of Tg4510 mice. Finally, disruption of the cyclic expression of PER2 and BMAL1, another core circadian clock protein, is evident in the Tg4510 hippocampus. These results demonstrate that tauopathy disrupts normal circadian clock function both at the behavioral and molecular levels, which may be attributed to the tauopathy-induced neuropathology in the SCN. Furthermore, these results establish the Tg4510 mouse line as a model to study how tauopathy disrupts normal circadian rhythm biology.

Desipramine enhances the ability of paliperidone to decrease alcohol drinking.

Alcohol use disorder commonly occurs in patients with schizophrenia and dramatically worsens their course. The atypical antipsychotic clozapine has been associated with reduced drinking in these patients, but its toxicity reduces its use. We have attempted to create a clozapine-like drug by combining agents that capture components of clozapine's pharmacologic action, including its weak dopamine D2 blockade and noradrenergic modulation. The current study assessed whether paliperidone, a dopamine D2 receptor and adrenergic alpha-2 receptor antagonist like clozapine, would attenuate alcohol drinking in the alcohol-preferring P rat and the Syrian golden hamster, and whether desipramine, a norepinephrine reuptake inhibitor, would potentiate the ability of paliperidone to attenuate alcohol drinking in the P rat and the Syrian golden hamster. Daily subcutaneous injections of paliperidone (5 mg/kg for the rat; 1 mg/kg for the hamster) over 20 days slightly and transiently attenuated initiation of alcohol consumption in both animals. Desipramine (3 mg/kg) or lower doses of paliperidone alone did not affect alcohol drinking. However, the combination of desipramine (3 mg/kg) and paliperidone essentially prevented initiation of alcohol drinking and acquisition of alcohol preference in the P rat (2.5 or 5 mg/kg), and almost as dramatically suppressed chronic alcohol intake and alcohol preference in the hamster (2.5 mg/kg). Taken together, the current data suggest that (1) the desipramine and paliperidone combination attenuates alcohol drinking in a synergistic manner, and (2) desipramine and paliperidone may serve as an effective new treatment for alcohol use disorder in patients with schizophrenia.