In addition to cognitive impairments, neurodevelopmental disorders (NDDs) often result in sensory processing deficits. However, the biological mechanisms that underlie impaired sensory processing associated with NDDs 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 (SSC) weakly encode information related to touch. This was caused by reduced synaptic connectivity and impaired intrinsic excitability within upper-lamina SSC 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.
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 (b)-adrenergic receptors (b-ARs). Previous studies demonstrated that a b-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 mM), 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 b1-AR activation, as coapplication of the b1-receptor antagonist CGP-20712A (1 mM) attenuated maintenance of LTP. We also found that NE-mediated metaplasticity was translationand transcription-dependent. Polysomal profiles of CA1 revealed increased translation rates for specific mRNAs during NEinduced metaplasticity. Thus, activation of b-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.
Key pointsr Transcription is recruited by noradrenaline in the hippocampus. r Epigenetic mechanisms are recruited by hippocampal noradrenergic receptor activation. r 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 β-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 β-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.
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.
BackgroundThe 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.ObjectiveThe 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.MethodsA 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).ResultsInitially, 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.ConclusionsThe 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.
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 badrenergic 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 b-adrenergic agonist, isoproterenol (ISO), and the cholinergic agonist, carbachol (CCh), induces translationdependent LTP in mouse CA1. This form of LTP requires both b1-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 b-adrenergic and muscarinic receptors facilitates the conversion of STP to LTP through a mechanism requiring translation initiation.Memory formation is believed to rely on an activity-dependent, enduring modification of synaptic strength known as long-term potentiation (LTP) (Bliss and Lomo 1973;Bliss and Collingridge 1993;Kandel 2001). LTP has been demonstrated in the hippocampus following events which induce behavioral changes indicative of learning and memory (Whitlock et al. 2006). The hippocampus plays a time-limited role in the establishment of new memories (Scoville and Milner 1957;Zola-Morgan et al. 1986;Neves et al. 2008), a process subject to modification through the release of neuromodulatory transmitters.Cholinergic and noradrenergic neuromodulatory systems can enhance synaptic plasticity (Hu et al. 2007;Dringenberg et al. 2008;Fernández de Sevilla et al. 2008) and long-term memory formation (Cahill et al. 1994 Although the individual contributions of b-and muscarinic receptors to synaptic function have been investigated, the effects of simultaneous activation of these receptors have yet to be fully elucidated. Previous research has demonstrated that coactivation of a-adrenergic and muscarinic receptors facilitates the induction of long-term depression (LTD) (Scheiderer et al. 2008). LTD induced by a-adrenergic and M1 receptors is facilitated through a synergistic elevation of extracellular signal-regulated kinase (ERK) phosphorylation. A similar effect on ERK stimulation was observed when the b-adrenergic receptor agonist, isoproterenol (ISO), was paired with carbachol (CCh), a broad-spectrum mu...
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.
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 (β-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 β-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.
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