A [2.2]Isoindolinophanyl-Based Carbene (iPC) Ligand: Synthesis, Electronic and Photophysical Properties, and Application in Photocatalysis*.

Cyclic amino(alkyl) and cyclic amino(aryl) carbenes (cAACs/cAArCs) have been established as very useful ligands for catalytic and photonic applications of transition metal complexes. Herein, we describe the synthesis of a structurally related sterically demanding, electrophilic [2.2]isoindolinophanyl-based carbene (iPC) with a [2.2]paracyclophane moiety. The latter leads to more delocalized frontier orbitals and intense green fluorescence of (HiPC)OTf (2) from an intra-ligand charge transfer (1ILCT) state in the solid state. Base-promoted synthesis of the free carbene led to an unusual ring expansion and subsequent dimerization reaction, but the beneficial ligand properties can be exploited by trapping in situ at a metal center. The iPC ligand is a very potent π-chromophore, which participates in low energy metal-to-ligand (ML)CT transitions in [RhCl(CO)2(iPC)] (4) and IL-"through-space"-CT transitions in [Au(iPC)2]OTf (5). The steric demand of the iPC leads to high stability of 5 against air, moisture, or solvent attack, and ultralong-lived green phosphorescence with a lifetime of 185 µs is observed in solution. The beneficial photophysical and electronic properties of the iPC ligand, including a large accessible π surface area, were exploited by employing highly efficient energy transfer (EnT) photocatalysis in a [2+2] styrene cycloaddition reaction using 5, which outperformed other established photocatalysts in comparison.

The psychosomatic impact of Yoga in medical education: a systematic review and meta-analysis.

Non-clinical approaches such as meditation, yoga, and mindfulness are popular traditional therapeutical interventions adopted by many educational institutions to improve the physical and mental well-being of learners. This study aimed to evaluate the effectiveness of yoga intervention in improving cardiopulmonary parameters such as blood pressure, heart rate, pulmonary function tests and psychosomatic symptoms such as depression, anxiety and stress in medical and dental students. Using the PRISMA protocol, a search from databases such as PubMed, Scopus, and Embase resulted in 304 relevant articles. After screening the title and abstracts, 47 papers were analyzed thoroughly and included in the qualitative analysis. 18 articles with homogenous statistical data on physiology and psychological parameters were included for meta-analysis. In comparison to the control group, the study showed a significant reduction of systolic blood pressure (SBP: 6.82 mmHg, z = -3.06, p = 0.002), diastolic blood pressure (DBP: 2.92 mmHg, z = -2.22, p = 0.03), and heart rate (HR: 2.55 beats/min, z = -2.77, p = 0.006). Additionally, data from 4 studies yielded a significant overall effect of a stress reduction of 0.77 on standardized assessments due to the yoga intervention (z = 5.29, p < 0.0001). Lastly, the results also showed a significant (z = -2.52, p = 0.01) reduction of 1.2 in standardized anxiety tests in intervention group compared to the control. The findings offer promising prospects for medical educators globally, encouraging them to consider reformation and policymaking in medical curricula to enhance academic success and improve the overall quality of life for medical students worldwide.

Enhanced Intersystem Crossing, Yet Still Fluorescence Upon Introduction of Intermediate Charge-Transfer States in Hemicaged [Zn(bpy)3]2.

Photoactive zinc(II) complexes typically undergo fluorescence from the singlet excited state as the dominant radiative pathway, as the operative spin-orbit coupling is usually very small and phosphorescence from the triplet state is strongly forbidden. Although dicationic zinc(II) tris(bipyridine) strictly follows this scheme with fluorescence at λem = 326 nm, constructing the ligand sphere as a hemicage was reported to lead to quantitative intersystem crossing (ISC) and subsequent fast phosphorescence with λem = 485 and a short radiative lifetime of ca. 1 µs. Surprised by this finding, we reinvestigated [Zn(bpy)3]2+ and its hemicage derivative in great detail, including variable temperature and time-resolved photophysical measurements in solution and solid state as well as high-level theoretical calculations to resolve their excited state behavior. Our investigations suggest that both compounds undergo fluorescence at room temperature with significantly different radiative rate constants of kr = 2 × 108 and 1.2 × 106 s-1, respectively, and only weak phosphorescence on the millisecond time scale at low temperatures. The major difference is the occurrence of additional charge-transfer states within the ligand scaffold of the hemicage, which accelerate the ISC to the 3LC(bpy) state from 350 s down to 82 ns and reduce the fluorescence rate constant.

Polymelia (thoracomelia), an extremely rare appearance of congenital anomalic limb in a Nepalese child and its embryological basis.

Polymelia is an extremely rare congenital anomaly where an individual is born with an abnormally developed extra or supernumerary limb which is generally shrunken and functionless. A case of thoracomelia (a type of polymelia) was observed macroscopically and confirmed radiologically in 1.5 years old boy born in Nepal with an abnormal supernumerary upper limb attached to his back in the thoracic region. The limb was successfully amputated, and the boy had a favorable outcome after surgical treatment, without any adverse effects or impairment. Understanding the embryogenesis of thoracomelia is essential for unraveling the complex mechanisms underlying this condition and potentially aiding in early diagnosis and intervention. This case report and review aims to shed light on the intricate processes governing forelimb formation and their perturbations leading to thoracomelia.

A Review and Meta-Analysis of the Prevalence and Health Impact of Polycystic Ovary Syndrome Among Medical and Dental Students.

Women currently comprise the majority of students graduating from medical school and face unique stressors not seen with their male counterparts. In particular, during their medical education, women with polycystic ovary syndrome (PCOS) experience symptoms of the disorder, which strongly impact both their academic and social lives. This in turn influences their academic and professional future. Although women as medical professionals, in general, are happy with their careers, awareness, and understanding on the part of medical educators will definitely be helpful to women medical students in their path to being successful medical professionals. The first objective of our current study is to find the prevalence of PCOS in medical and dental students. The second objective is to find the academic and health impacts of PCOS and what type of interventions are being adopted to relieve the symptoms. Using the keywords such as "PCOS," "medical students," and "dental students", the search engines PubMed, Embase, and Scopus were used to retrieve relevant articles published from 2020 to 2022. After removing the duplicates, 11 prospective cross-sectional studies were utilized for qualitative and quantitative analysis. The pooled prevalence of 2,206 female medical students diagnosed with PCOS was 24.7%. The students in the various studies were aware of their PCOS diagnosis and were taking therapeutic medications. The most common associated complications reported were BMI abnormalities, abnormal hair growth, and acne, along with other complications such as stress and poor academic and social life. The majority also had significant family histories of concurrent clinical conditions such as diabetes, hypertension, and other menstrual abnormalities. Considering the huge impact of PCOS, medical educators, policymakers, and all stakeholders should take proactive measures to accommodate students' needs and bridge the social gap. Special awareness of needed lifestyle changes should be a part of the medical education curriculum for an inclusive educational environment, as it will minimize the gender discrepancy in academic satisfaction and professional life.

Efficacy of Lanthanum Carbonate and Sevelamer Carbonate as Phosphate Binders in Chronic Kidney Disease-A Comparative Clinical Study.

(1) Background: Hyperphosphatemia is correlated with an increased rate of mortality and morbidity due to cardiovascular diseases in chronic kidney disease (CKD) patients. It can be improved by restricting dietary intake of phosphate and oral phosphate binders, such as lanthanum carbonate and sevelamer carbonate. (2) Objective: To evaluate the clinical efficacy of sevelamer carbonate in comparison to lanthanum carbonate as phosphate binders for the treatment of hyperphosphatemia in CKD patients. (3) Methods: A randomized control comparative clinical study was conducted for one year on 150 CKD patients associated with hyperphosphatemia, divided into two groups, i.e., Group 1 (n = 75) treated with sevelamer carbonate 800 mg thrice daily and Group 2 (n = 75) treated with lanthanum carbonate 500 mg thrice daily. The patients were assessed at the time of enrollment in the study, after three months and after six months from baseline for different parameters, i.e., complete blood count, liver function tests, renal function tests, electrolytes, and serum phosphate level. (4) Results: 150 CKD patients aged 51-60 participated in the study. The mean age of patients was 54 ± 4.6 years, and males (55.71%) were more common than females (44.29%). Hypertension was the common comorbidity in both groups with chronic kidney disease. After six months of treatment, the mean serum phosphate level was significantly decreased from 8.31 ± 0.09 mg/dL to 5.11 ± 0.18 (38%) in Group 1 and from 8.79 ± 0.28 mg/dl to 4.02 ± 0.12 (54%; p < 0.05) in Group 2, respectively. In both groups, no significant difference was found in other parameters such as parathyroid hormone, calcium, uric acid, LFT, RFT, CBC, etc. (5) Conclusion: Lanthanum carbonate is more efficacious in lowering serum phosphate concentrations and effectively managing hyperphosphatemia as compared to sevelamer carbonate.

Virtual Versus Light Microscopy Usage among Students: A Systematic Review and Meta-Analytic Evidence in Medical Education.

BACKGROUND: The usage of whole-slide images has recently been gaining a foothold in medical education, training, and diagnosis. OBJECTIVES: The first objective of the current study was to compare academic performance on virtual microscopy (VM) and light microscopy (LM) for learning pathology, anatomy, and histology in medical and dental students during the COVID-19 period. The second objective was to gather insight into various applications and usage of such technology for medical education. MATERIALS AND METHODS: Using the keywords "virtual microscopy" or "light microscopy" or "digital microscopy" and "medical" and "dental" students, databases (PubMed, Embase, Scopus, Cochrane, CINAHL, and Google Scholar) were searched. Hand searching and snowballing were also employed for article searching. After extracting the relevant data based on inclusion and execution criteria, the qualitative data were used for the systematic review and quantitative data were used for meta-analysis. The Newcastle Ottawa Scale (NOS) scale was used to assess the quality of the included studies. Additionally, we registered our systematic review protocol in the prospective register of systematic reviews (PROSPERO) with registration number CRD42020205583. RESULTS: A total of 39 studies met the criteria to be included in the systematic review. Overall, results indicated a preference for this technology and better academic scores. Qualitative analyses reported improved academic scores, ease of use, and enhanced collaboration amongst students as the top advantages, whereas technical issues were a disadvantage. The performance comparison of virtual versus light microscopy meta-analysis included 19 studies. Most (10/39) studies were from medical universities in the USA. VM was mainly used for teaching pathology courses (25/39) at medical schools (30/39). Dental schools (10/39) have also reported using VM for teaching microscopy. The COVID-19 pandemic was responsible for the transition to VM use in 17/39 studies. The pooled effect size of 19 studies significantly demonstrated higher exam performance (SMD: 1.36 [95% CI: 0.75, 1.96], p < 0.001) among the students who used VM for their learning. Students in the VM group demonstrated significantly higher exam performance than LM in pathology (SMD: 0.85 [95% CI: 0.26, 1.44], p < 0.01) and histopathology (SMD: 1.25 [95% CI: 0.71, 1.78], p < 0.001). For histology (SMD: 1.67 [95% CI: -0.05, 3.40], p = 0.06), the result was insignificant. The overall analysis of 15 studies assessing exam performance showed significantly higher performance for both medical (SMD: 1.42 [95% CI: 0.59, 2.25], p < 0.001) and dental students (SMD: 0.58 [95% CI: 0.58, 0.79], p < 0.001). CONCLUSIONS: The results of qualitative and quantitative analyses show that VM technology and digitization of glass slides enhance the teaching and learning of microscopic aspects of disease. Additionally, the COVID-19 global health crisis has produced many challenges to overcome from a macroscopic to microscopic scale, for which modern virtual technology is the solution. Therefore, medical educators worldwide should incorporate newer teaching technologies in the curriculum for the success of the coming generation of health-care professionals.

Norepinephrine, beyond the Synapse: Coordinating Epigenetic Codes for Memory.

The noradrenergic system is implicated in neuropathologies contributing to major disorders of the memory, including post-traumatic stress disorder and Alzheimer's disease. Determining the impact of norepinephrine on cellular function and plasticity is thus essential for making inroads into our understanding of these brain conditions, while expanding our capacity for treating them. Norepinephrine is a neuromodulator within the mammalian central nervous system which plays important roles in cognition and associated synaptic plasticity. Specifically, norepinephrine regulates the formation of memory through the stimulation of ß-ARs, increasing the dynamic range of synaptic modifiability. The mechanisms through which NE influences neural circuit function have been extended to the level of the epigenome. This review focuses on recent insights into how the noradrenergic recruitment of epigenetic modifications, including DNA methylation and post-translational modification of histones, contribute to homo- and heterosynaptic plasticity. These advances will be placed in the context of synaptic changes associated with memory formation and linked to brain disorders and neurotherapeutic applications.

Human Epidermal Growth Factor Receptor 2 (HER2) Expression in Colorectal Carcinoma: A Potential Area of Focus for Future Diagnostics.

Objective In this study, we aimed to explore the potential diagnostic utility of human epidermal growth factor receptor 2 (HER2) expression in colorectal carcinoma. We investigated the association of HER2 expression with the type and grade of the tumor along with the pattern, staining intensity, and the percentage of cells stained. Methods This was an observational study involving 50 cases of colorectal carcinoma that underwent immunohistochemistry to analyze the HER2 expression. Results The positive expression of HER2 was seen in 16 (32%) cases. The majority of the study population was between the fifth-seventh decades of life. The most commonly diagnosed tumor was conventional adenocarcinoma with grade II, cytoplasmic pattern, +2 positivity, and moderate intensity. The maximum positivity for HER2 was seen in tumors of the rectum in eight (16%) cases. Conclusion A substantial rate of HER2 overexpression paves the way for it to become a potential future target in cancer therapeutics.

Academic and Social Impact of Menstrual Disturbances in Female Medical Students: A Systematic Review and Meta-Analysis.

BACKGROUND: The stressful academic schedule of medical students poses an obvious challenge to their daily lifestyle. Psychosomatic discomfort poses a significant risk for inaccurate self-medication for ameliorating menstrual complications and feeling better, thus directly impacting personal and academic wellbeing. OBJECTIVE: The impact of menstrual disturbances on academic life is not extensively explored. Therefore, the primary objective of this research was to probe the prevalence of menstrual disturbances and assess the academic and social impact. Finally, the authors provide an overview of pharmacological and other interventions students adopt to reduce clinical symptoms. METHODS: A database search was conducted from the year 2016 till September 2021 for the studies reporting the prevalence of menstrual disorders in all geographic locations of the world. Keywords used for searching databases included "menstrual disturbances" and "medical students," "prevalence" OR "symptoms" of "Premenstrual syndrome" OR "Premenstrual dysphoric disorder" OR "Dysmenorrhea" in medical students. Prospero Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) protocols were followed. The protocol was registered in the International prospective register of systematic reviews (PROSPERO), the Center for Reviews and Dissemination, University of York (CRD42021277962). The quality of the methodologies used in selected studies was evaluated by a modified version of Newcastle Ottawa Scale (NOS). RESULTS: Initially, 1527 articles were available. After a review, 26 papers were selected for analysis. A total of 25 citations were identified for quantitative analyses, out of which 16 studies reported Pre-menstrual syndrome, 7 reported Pre-menstrual dysphoric disorder, and 13 articles reported dysmenorrhea. The pooled prevalence of Pre-menstrual syndrome was 51.30%, Pre-menstrual dysphoric disorder was 17.7%, and dysmenorrhea was 72.70%. Most common associated lifestyle factors were stress, excessive caffeine intake and lack of exercise. Painkillers, hot packs and hot beverages were amongst the common measures taken by the students to relieve their symptoms. CONCLUSIONS: The current situation calls for action to accommodate students' needs and bridge the social gap regarding menstrual health. Proactive measures by medical educators and stakeholders are required for an inclusive, accommodating educational environment which will minimize the gender discrepancy in academic satisfaction and professional life.

Epigenetic Mechanisms in Memory and Cognitive Decline Associated with Aging and Alzheimer's Disease.

Epigenetic mechanisms, which include DNA methylation, a variety of post-translational modifications of histone proteins (acetylation, phosphorylation, methylation, ubiquitination, sumoylation, serotonylation, dopaminylation), chromatin remodeling enzymes, and long non-coding RNAs, are robust regulators of activity-dependent changes in gene transcription. In the brain, many of these epigenetic modifications have been widely implicated in synaptic plasticity and memory formation. Dysregulation of epigenetic mechanisms has been reported in the aged brain and is associated with or contributes to memory decline across the lifespan. Furthermore, alterations in the epigenome have been reported in neurodegenerative disorders, including Alzheimer's disease. Here, we review the diverse types of epigenetic modifications and their role in activity- and learning-dependent synaptic plasticity. We then discuss how these mechanisms become dysregulated across the lifespan and contribute to memory loss with age and in Alzheimer's disease. Collectively, the evidence reviewed here strongly supports a role for diverse epigenetic mechanisms in memory formation, aging, and neurodegeneration in the brain.

Effectiveness of Empagliflozin With Vitamin D Supplementation in Peripheral Neuropathy in Type 2 Diabetic Patients.

BACKGROUND: Neuropathy is the most prevalent broad-spectrum microvascular complication of diabetes. The present study aims to evaluate the effect of empagliflozin with vitamin D supplementation on diabetic peripheral neuropathy. METHODS: A prospective, randomized, controlled study was conducted for six months including 150 type 2 diabetic patients, divided into three groups (n=50/group): Group 1, patients on oral hypoglycemic agents; Group 2, patients on empagliflozin and Group 3, patients on empagliflozin with vitamin D. Biochemical parameters were estimated for outcome measurements and patients' neuropathic pain was analysed using Douleur Neuropathique 4 Questions, Neuropathic Pain Symptom Inventory and Ipswich Touch the toes test questionnaire. Data were analysed using a one-way analysis of variance. RESULTS: Diabetic neuropathy in males was more prevalent (more than 50%) as compared to females in all three groups, with an average age of 50±6 years, along with a diabetic history of 15±4.5 years and a glycated hemoglobin A1C (HbA1C) level of >10%. The mean value of serum vitamin D level significantly increased by 64.7% (19±5 to 54±8 ng/mL; p<0.05). A remarkable decrease (by 17.4%) from baseline in the HbA1C level was observed after six months of treatment only in Group 3, whereas in other groups (1 and 2), there was a non-significant decrease in HbA1C levels when compared to baseline. Moreover, a significant improvement in neuropathic condition was seen only in Group 3. CONCLUSION: The results indicated that empagliflozin with vitamin D supplementation significantly controlled or reduced HbA1C and improved diabetic neuropathic symptoms in patients. It is suggested that this combination can be considered as the primary therapeutic approach for neuropathic complications in diabetic patients.

Norepinephrine stabilizes translation-dependent, homosynaptic long-term potentiation through mechanisms requiring the cAMP sensor Epac, mTOR and MAPK.

Neuromodulators regulate higher-order cognitive processes including learning and memory through modulation of synaptic transmission and plasticity. Norepinephrine is a neuromodulator that is secreted throughout the brain in response to novelty or increased arousal, which alters neural circuits by increasing the modifiability of CNS synapses. Norepinephrine activates metabotropic receptors, initiating complex intracellular signalling cascades that can promote enduring changes in synaptic strength including long-term potentiation (LTP). In particular, activation of beta-adrenergic receptors (ß-ARs) by norepinephrine enhances LTP through downstream engagement of signalling cascades which upregulate protein synthesis at synapses. Here, we sought to determine the select signalling pathways recruited by norepinephrine to promote homosynaptic LTP at hippocampal synapses in mice. Application of norepinephrine initiated a long-lasting form of homosynaptic LTP that requires protein synthesis. Norepinephrine-mediated enhancement of LTP was reduced by inhibition of mammalian target of rapamycin and exchange protein directly activated by cAMP (Epac) but not cAMP-dependent protein kinase A, suggesting that the endogenous ß-AR ligand norepinephrine may preferentially recruit Epac signalling to promote enduring changes in synaptic strength. These findings advance our understanding of the mechanisms through which norepinephrine regulates synaptic plasticity associated with formation of new memories.

Associations of Alpha and Beta Interhemispheric EEG Coherences with Indices of Attentional Control and Academic Performance.

Introduction. Heretofore, research on optimizing academic performance has suffered from an inability to translate what is known about an individual's learning behaviors to how effectively they are able to use the critical nodes and hubs in their cerebral cortex for learning. A previous study from our laboratory suggests that lower theta-beta ratios (TBRs) measured by EEG may be associated with higher academic performance in a medical school curriculum. METHODS: In this study, we tested the hypothesis that TBR and academic performance may be correlated with EEG coherence, a measure of brain connectivity. We analyzed the interhemispheric coherences of the subjects involved in our prior study. TBR and coherence measurements were made at 19 scalp electrode recording sites and 171 electrode combinations with eyes open and closed (EO, EC). Control data were acquired during a session of acclimation to the research protocol 3 d before an initial examination in anatomy-physiology (control exam) and were repeated five weeks later, 3 d before a second exam covering different anatomy-physiology topics (comparison exam). RESULTS: Between the control and comparison exams, beta coherences increased significantly at the frontal pole, frontal, parietal, midtemporal, posterior temporal, and occipital recording sites under the EO condition and at the inferior frontal, central, midtemporal, and posterior temporal sites under the EC condition. Alpha coherences increased significantly at the same sites and under the same EO/EC conditions as found for the beta coherences. The beta coherences were negatively correlated with the TBR and were positively correlated with the comparison exam score at the midfrontal electrode site (F3-F4) but only under the EO condition. Beta and alpha coherences at the midfrontal, inferior frontal midtemporal, posterior temporal, and occipital sites were also negatively correlated with the average TBR under the EO condition. CONCLUSIONS: Lower TBR, an indicator of attentional control, was associated with higher alpha and beta interhemispheric coherences measured with eyes open at sites overlying the frontal, temporal, and occipital cortices. Changes in EEG coherences and TBRs might be useful as neurophysiological measures of neuroplasticity and the efficacy of strategies for preventing academic underachievement and treatments for improving academic performance.

Palladium-Catalyzed Directed meta-Selective C-H Allylation of Arenes: Unactivated Internal Olefins as Allyl Surrogates.

Palladium(II)-catalyzed meta-selective C-H allylation of arenes has been developed utilizing synthetically inert unactivated acyclic internal olefins as allylic surrogates. The strong σ-donating and π-accepting ability of pyrimidine-based directing group facilitates the olefin insertion by overcoming inertness of the typical unactivated internal olefins. Exclusive allyl over styrenyl product selectivity as well as E stereoselectivity were achieved with broad substrate scope, wide functional-group tolerance, and good to excellent yields. Late-stage functionalisations of pharmaceuticals were demonstrated. Experimental and computational studies shed light on the mechanism and point to key steric control in the palladacycle, thus determining product selectivities.

SYNGAP1 heterozygosity disrupts sensory processing by reducing touch-related activity within somatosensory cortex circuits.

In addition to cognitive impairments, neurodevelopmental disorders often result in sensory processing deficits. However, the biological mechanisms that underlie impaired sensory processing associated with neurodevelopmental disorders are generally understudied and poorly understood. We found that SYNGAP1 haploinsufficiency in humans, which causes a sporadic neurodevelopmental disorder defined by cognitive impairment, autistic features, and epilepsy, also leads to deficits in tactile-related sensory processing. In vivo neurophysiological analysis in Syngap1 mouse models revealed that upper-lamina neurons in somatosensory cortex weakly encode information related to touch. This was caused by reduced synaptic connectivity and impaired intrinsic excitability within upper-lamina somatosensory cortex neurons. These results were unexpected, given that Syngap1 heterozygosity is known to cause circuit hyperexcitability in brain areas more directly linked to cognitive functions. Thus, Syngap1 heterozygosity causes a range of circuit-specific pathologies, including reduced activity within cortical neurons required for touch processing, which may contribute to sensory phenotypes observed in patients.

Noradrenaline goes nuclear: epigenetic modifications during long-lasting synaptic potentiation triggered by activation of ß-adrenergic receptors.

KEY POINTS: Transcription is recruited by noradrenaline in the hippocampus. Epigenetic mechanisms are recruited by hippocampal noradrenergic receptor activation. Epigenetic regulation by noradrenaline offers a novel mechanism for long-term potentiation ABSTRACT: Noradrenaline (NA) is a neuromodulator that can effect long-lasting changes in synaptic strength such as long-term potentiation (LTP), a putative cellular mechanism for memory formation in the mammalian brain. Persistent LTP requires alterations in gene expression that may involve epigenetic mechanisms such as DNA methylation, histone acetylation and histone phosphorylation. It is known that ß-adrenergic receptors and NA can boost LTP maintenance by regulating translation. However, it is unclear whether NA can additionally engage epigenetic mechanisms to regulate transcription and boost LTP endurance. To address this issue, we probed NA-treated mouse hippocampal slices with pharmacological inhibitors targeting epigenetic regulatory pathways and discovered that NA activates ß-adrenergic receptors to boost LTP maintenance in area CA1 through DNA methylation and post-translational histone modifications. Specifically, NA paired with 100 Hz stimulation enhanced histone H3 acetylation and phosphorylation, both of which were required for NA-induced boosting of LTP maintenance. Together, our findings identify NA as a neuromodulatory transmitter capable of triggering epigenetic, transcriptional control of genes required for establishing persistent LTP in the mouse hippocampus. These modifications may contribute to the stabilization of memory.

Norepinephrine triggers metaplasticity of LTP by increasing translation of specific mRNAs.

Norepinephrine (NE) is a key modulator of synaptic plasticity in the hippocampus, a brain structure crucially involved in memory formation. NE boosts synaptic plasticity mostly through initiation of signaling cascades downstream from beta (ß)-adrenergic receptors (ß-ARs). Previous studies demonstrated that a ß-adrenergic receptor agonist, isoproterenol, can modify the threshold for long-term potentiation (LTP), a putative cellular mechanism for learning and memory, in a process known as "metaplasticity." Metaplasticity is the ability of synaptic plasticity to be modified by prior experience. We asked whether NE itself could engage metaplastic mechanisms in area CA1 of mouse hippocampal slices. Using extracellular field potential recording and stimulation, we show that application of NE (10 µM), which did not alter basal synaptic strength, enhances the future maintenance of LTP elicited by subthreshold, high-frequency stimulation (HFS: 1 × 100 Hz, 1 sec). HFS applied 30 min after NE washout induced long-lasting (>4 h) LTP, which was significantly extended in duration relative to HFS alone. This NE-induced metaplasticity required ß1-AR activation, as coapplication of the ß1-receptor antagonist CGP-20712A (1 µM) attenuated maintenance of LTP. We also found that NE-mediated metaplasticity was translation- and transcription-dependent. Polysomal profiles of CA1 revealed increased translation rates for specific mRNAs during NE-induced metaplasticity. Thus, activation of ß-ARs by NE primes synapses for future long-lasting plasticity on time scales extending beyond fast synaptic transmission; this may facilitate neural information processing and the subsequent formation of lasting memories.

Conversion of short-term potentiation to long-term potentiation in mouse CA1 by coactivation of ß-adrenergic and muscarinic receptors.

Encoding new information requires dynamic changes in synaptic strength. The brain can boost synaptic plasticity through the secretion of neuromodulatory substances, including acetylcholine and noradrenaline. Considerable effort has focused on elucidating how neuromodulatory substances alter synaptic properties. However, determination of the potential synergistic interactions between different neuromodulatory systems remains incomplete. Previous results indicate that coactivation of ß-adrenergic and cholinergic receptors facilitated the conversion of STP to LTP through an extracellular signal-regulated kinase (ERK)-dependent mechanism. ERK signaling has been linked to synaptically localized translation regulation. Thus, we hypothesized that costimulation of noradrenergic and cholinergic receptors could initiate the transformation of STP to LTP through up-regulation of protein synthesis. Our results indicate that a protocol which yields STP (5 Hz, 5 sec) when paired with coapplication of the ß-adrenergic agonist, isoproterenol (ISO), and the cholinergic agonist, carbachol (CCh), induces translation-dependent LTP in mouse CA1. This form of LTP requires both ß1-adrenergic and M1 muscarinic receptor activation, as blocking either receptor subtype prevented LTP induction. Blocking ERK, mTOR, or translation reduced the expression of LTP induced with ISO + CCh. Taken together, our data demonstrate that coactivation of ß-adrenergic and muscarinic receptors facilitates the conversion of STP to LTP through a mechanism requiring translation initiation.