Modulation of Hippocampus-Dependent Learning and Synaptic Plasticity by Nicotine

A long-standing relationship between nicotinic acetylcholine receptors (nAChRs) and cognition exists. Drugs that act at nAChRs can have cognitive-enhancing effects and diseases that disrupt cognition such as Alzheimer's disease and schizophrenia are associated with altered nAChR function. Specifically, hippocampus-dependent learning is particularly sensitive to the effects of nicotine. However, the effects of nicotine on hippocampus-dependent learning vary not only with the doses of nicotine used and whether nicotine is administered acutely, chronically, or withdrawn after chronic nicotine treatment but also vary across different hippocampus-dependent tasks such as the Morris water maze, the radial arm maze, and contextual fear conditioning. In addition, nicotine has variable effects across different types of hippocampal long-term potentiation (LTP). Because different types of hippocampus-dependent learning and LTP involve different neural and molecular substrates, comparing the effects of nicotine across these paradigms can yield insights into the mechanisms that may underlie the effects of nicotine on learning and memory and aid in understanding the variable effects of nicotine on cognitive processes. This review compares and contrasts the effects of nicotine on hippocampus-dependent learning and LTP and briefly discusses how the effects of nicotine on learning could contribute to nicotine addiction.     

High-Frequency rTMS Improves Cognitive Function by Regulating Synaptic Plasticity in Cerebral Ischemic Rats

Neurochemical Research - Poststroke cognitive impairment (PSCI) is one of the most severe sequelae of stroke and lacks effective treatment. Previous studies have shown that high-frequency...     

Molecular Basis of Impaired Glycogen Metabolism during Ischemic Stroke and Hypoxia

Background

Ischemic stroke is the combinatorial effect of many pathological processes including the loss of energy supplies, excessive intracellular calcium accumulation, oxidative stress, and inflammatory responses. The brain''s ability to maintain energy demand through this process involves metabolism of glycogen, which is critical for release of stored glucose. However, regulation of glycogen metabolism in ischemic stroke remains unknown. In the present study, we investigate the role and regulation of glycogen metabolizing enzymes and their effects on the fate of glycogen during ischemic stroke.

Results

Ischemic stroke was induced in rats by peri-vascular application of the vasoconstrictor endothelin-1 and forebrains were collected at 1, 3, 6 and 24 hours post-stroke. Glycogen levels and the expression and activity of enzymes involved in glycogen metabolism were analyzed. We found elevated glycogen levels in the ipsilateral hemispheres compared with contralateral hemispheres at 6 and 24 hours (25% and 39% increase respectively; P<0.05). Glycogen synthase activity and glycogen branching enzyme expression were found to be similar between the ipsilateral, contralateral, and sham control hemispheres. In contrast, the rate-limiting enzyme for glycogen breakdown, glycogen phosphorylase, had 58% lower activity (P<0.01) in the ipsilateral hemisphere (24 hours post-stroke), which corresponded with a 48% reduction in cAMP-dependent protein kinase A (PKA) activity (P<0.01). In addition, glycogen debranching enzyme expression 24 hours post-stroke was 77% (P<0.01) and 72% lower (P<0.01) at the protein and mRNA level, respectively. In cultured rat primary cerebellar astrocytes, hypoxia and inhibition of PKA activity significantly reduced glycogen phosphorylase activity and increased glycogen accumulation but did not alter glycogen synthase activity. Furthermore, elevated glycogen levels provided metabolic support to astrocytes during hypoxia.

Conclusion

Our study has identified that glycogen breakdown is impaired during ischemic stroke, the molecular basis of which includes reduced glycogen debranching enzyme expression level together with reduced glycogen phosphorylase and PKA activity.     

Stroke Prevention Rehabilitation Intervention Trial of Exercise (SPRITE) - a randomised feasibility study

Background

The value of cardiac rehabilitation (CR) after a transient ischaemic attack (TIA) or minor stroke is untested despite these conditions sharing similar pathology and risk factors to coronary heart disease. We aimed to evaluate the feasibility of conducting a trial of an adapted home-based CR programme, ‘The Healthy Brain Rehabilitation Manual’, for patients following a TIA/minor stroke, participants’ views on the intervention and, to identify the behaviour change techniques (BCTs) used.

Methods

Clinicians were asked to identify patients attending the Ulster Hospital, Belfast within 4 weeks of a first TIA or minor stroke. Those who agreed to participate underwent assessments of physical fitness, cardiovascular risk, quality of life and mental health, before random allocation to: Group (1) standard/usual care; (2) rehabilitation manual or (3) manual plus pedometer. All participants received telephone support at 1 and 4 weeks, reassessment at 6 weeks and an invitation to a focus group exploring views regarding the study. Two trained review authors independently assessed the manual to identify the BCTs used.

Results

Twenty-eight patients were invited to participate, with 15 (10 men, 5 women; 9 TIA, 6 minor stroke; mean age 69 years) consenting and completing the study. Mean time to enrolment from the TIA/stroke was 20.5 days. Participants completed all assessment measures except VO_2max testing, which all declined. The manual and telephone contact were viewed positively, as credible sources of advice. Pedometers were valued highly, particularly for goal-setting. Overall, 36 individual BCTs were used, the commonest being centred around setting goals and planning as well as social support.

Conclusion

Recruitment and retention rates suggest that a trial to evaluate the effectiveness of a novel home-based CR programme, implemented within 4 weeks of a first TIA/minor stroke is feasible. The commonest BCTs used within the manual revolve around goals, planning and social support, in keeping with UK national guidelines. The findings from this feasibility work have been used to further refine the next stage of the intervention’s development, a pilot study.

Trial registration

ClinicalTrials.gov Identifier: NCT02712385. This study was registered prospectively on 18/03/2016.

     

Age and the Metabolic Syndrome as Risk Factors for Ischemic Stroke: Improving Preclinical Models of Ischemic Stroke

Ischemic stroke represents a leading cause of morbidity and mortality in thedeveloped world. This disabling and sometimes fatal event puts an everincreasing burden on the family members and medical professionals who care forstroke victims. Preclinical ischemic stroke research has predominantly utilizedyoung adult, healthy animals, a clear discrepancy when considering the clinicalpopulation affected by stroke. A broad spectrum of risk factors such as age,obesity, diabetes, and hypertension has been associated with an increased strokerisk. The effect of these comorbidities on both stroke pathophysiology andoutcome has not been emphasized and has been recognized as a shortcoming ofpreclinical studies. By addressing these conditions in experimental models ofischemic stroke, it may be possible to more accurately represent the clinicalscenario and improve therapeutic translation from bench-to-bedside. In thiswork, we review many of the risk factors associated with increased stroke risk,particularly as each risk factor relates to inflammation. Additionally, weexplore potential animal models that could be utilized in identifying thecontribution of these risk factors to stroke outcome. By investigating the riskfactors for stroke and how these may alter stroke pathophysiology, the presentdiscrepancies between preclinical studies and the clinical reality can bereconciled in an effort to improve therapeutic development and translation frombench-to-bedside.     

Proteolytic Remodeling of the Synaptic Cell Adhesion Molecules (CAMs) by Metzincins in Synaptic Plasticity

Cell adhesion molecules participate in the formation, maturation, function and plasticity of synaptic connections. The growing body of evidence indicates that in the regulation of the synaptic plasticity, in which these molecules play pivotal role, also the proteolytic processes are involved. This review focuses on extracellular proteolysis of the cell adhesion molecules by specific subgroup of the matrix metalloproteinases, a disintegrin and metalloproteases and a disintegrin and metalloproteinase with thrombospondin motifs, jointly referred to as metzincins, in driving coordinated synaptic structural and functional modifications underlying synaptic plasticity in the adult brain.     

Synaptic Vesicular Glutamate Uptake: Modulation by a Synaptosomal Cytosolic Factor

We have demonstrated previously that L-glutamate is taken up into isolated synaptic vesicles in an ATP-dependent manner, supporting the neurotransmitter role of this acidic amino acid. We now report that a nerve terminal cytosolic factor inhibits the ATP-dependent vesicular uptake of glutamate in a dose-dependent manner. This factor appears to be a protein with a molecular weight greater than 100,000, as estimated by size exclusion chromatography, and is precipitated by ammonium sulfate (40% saturation). The inhibitory factor is inactivated by heating to 100 degrees C. Proteolytic digestion of the ammonium sulfate fraction by trypsin or chymotrypsin did not reduce, but rather increased slightly, the inhibition of glutamate uptake. Unlike the native factor, the digest retained inhibitory activity after heating, suggesting that proteolytic digestion may generate active fragments. The inhibition of ATP-dependent vesicular glutamate uptake is not species-specific, as the factor obtained from both rat and bovine brains produced an equal degree of inhibition of glutamate uptake into vesicles of each species. These observations raise the possibility that vesicular uptake of glutamate may be regulated by an endogenous factor in vivo.     

Bioinformatic Analysis of Exosomal MicroRNAs of Cerebrospinal Fluid in Ischemic Stroke Rats After Physical Exercise

Neurochemical Research - Physical exercise is beneficial to the structural and functional recovery of post-ischemic stroke, but its molecular mechanism remains obscure. Herein, we aimed to explore...     

Nucleolar Integrity Is Required for the Maintenance of Long-Term Synaptic Plasticity

Long-term memory (LTM) formation requires new protein synthesis and new gene expression. Based on our work in Aplysia, we hypothesized that the rRNA genes, stimulation-dependent targets of the enzyme Poly(ADP-ribose) polymerase-1 (PARP-1), are primary effectors of the activity-dependent changes in synaptic function that maintain synaptic plasticity and memory. Using electrophysiology, immunohistochemistry, pharmacology and molecular biology techniques, we show here, for the first time, that the maintenance of forskolin-induced late-phase long-term potentiation (L-LTP) in mouse hippocampal slices requires nucleolar integrity and the expression of new rRNAs. The activity-dependent upregulation of rRNA, as well as L-LTP expression, are poly(ADP-ribosyl)ation (PAR) dependent and accompanied by an increase in nuclear PARP-1 and Poly(ADP) ribose molecules (pADPr) after forskolin stimulation. The upregulation of PARP-1 and pADPr is regulated by Protein kinase A (PKA) and extracellular signal-regulated kinase (ERK)—two kinases strongly associated with long-term plasticity and learning and memory. Selective inhibition of RNA Polymerase I (Pol I), responsible for the synthesis of precursor rRNA, results in the segmentation of nucleoli, the exclusion of PARP-1 from functional nucleolar compartments and disrupted L-LTP maintenance. Taken as a whole, these results suggest that new rRNAs (28S, 18S, and 5.8S ribosomal components)—hence, new ribosomes and nucleoli integrity—are required for the maintenance of long-term synaptic plasticity. This provides a mechanistic link between stimulation-dependent gene expression and the new protein synthesis known to be required for memory consolidation.     

Regulation of Calpain-2 in Neurons: Implications for Synaptic Plasticity

The family of calcium-dependent neutral proteases, calpains, was discovered more than 30 years ago, but their functional roles in the nervous system under physiological or pathological conditions still remain unclear. Although calpain was proposed to participate in synaptic plasticity and in learning and memory in the early 1980s, the precise mechanism regarding its activation, its target(s) and the functional consequences of its activation have remained controversial. A major issue has been the identification of roles of the two major calpain isoforms present in the brain, calpain-1 and calpain-2, and the calcium requirement for their activation, which exceeds levels that could be reached intracellularly under conditions leading to changes in synaptic efficacy. In this review, we discussed the features of calpains that make them ideally suited to link certain patterns of presynaptic activity to the structural modifications of dendritic spines that could underlie synaptic plasticity and learning and memory. We then summarize recent findings that provide critical answers to the various questions raised by the initial hypothesis, and that further support the idea that, in brain, calpain-2 plays critical roles in developmental and adult synaptic plasticity.     

Identification of Isoxsuprine Hydrochloride as a Neuroprotectant in Ischemic Stroke through Cell-Based High-Throughput Screening

Stroke is a leading cause of death and disability and treatment options are limited. A promising approach to accelerate the development of new therapeutics is the use of high-throughput screening of chemical libraries. Using a cell-based high-throughput oxygen-glucose deprivation (OGD) model, we evaluated 1,200 small molecules for repurposed application in stroke therapy. Isoxsuprine hydrochloride was identified as a potent neuroprotective compound in primary neurons exposed to OGD. Isoxsuprine, a β₂-adrenergic agonist and NR2B subtype-selective N-methyl-D-aspartate (NMDA) receptor antagonist, demonstrated no loss of efficacy when administered up to an hour after reoxygenation in an in vitro stroke model. In an animal model of transient focal ischemia, isoxsuprine significantly reduced infarct volume compared to vehicle (137±18 mm³ versus 279±25 mm³, p<0.001). Isoxsuprine, a peripheral vasodilator, was FDA approved for the treatment of cerebrovascular insufficiency and peripheral vascular disease. Our demonstration of the significant and novel neuroprotective action of isoxsuprine hydrochloride in an in vivo stroke model and its history of human use suggest that isoxsuprine may be an ideal candidate for further investigation as a potential stroke therapeutic.     

脑卒中偏瘫患者临床康复的护理效应

目的:通过脑卒中偏瘫患者4期的康复护理训练的疗效观察,探讨康复训练护理对脑卒中偏瘫患者的功能恢复的临床效果。方法:本资料收集2004年1月至2004年12月共75例脑卒中偏瘫患者,随机分为两组,对照组和康复组,均采用内科常规护理,康复组接受康复护理训练;而对照组不进行康复护理训练。采用Barther指数评分法予以评定。结果:康复组功能改善程度明显高于对照组(P<0.05)。结论:脑卒中偏瘫患者日常生活活动能力改善在很大程度上取决于早期运动功能的恢复。对脑卒中偏瘫的早期功能恢复是必要的、有益的。     

Anticoagulation for the Acute Management of Ischemic Stroke

Few prospective studies support the use of anticoagulation during the acute phase of ischemic stroke, though observational data suggest a role in certain populations. Depending on the mechanism of stroke, systemic anticoagulation may prevent recurrent cerebral infarction, but concomitantly carries a risk of hemorrhagic transformation. In this article, we describe a case where anticoagulation shows promise for ischemic stroke and review the evidence that has discredited its use in some circumstances while showing its potential in others.     

Local Plasticity of Dendritic Excitability Can Be Autonomous of Synaptic Plasticity and Regulated by Activity-Based Phosphorylation of Kv4.2

While plasticity is typically associated with persistent modifications of synaptic strengths, recent studies indicated that modulations of dendritic excitability may form the other part of the engram and dynamically affect computational processing and output of neuronal circuits. However it remains unknown whether modulation of dendritic excitability is controlled by synaptic changes or whether it can be distinct from them. Here we report the first observation of the induction of a persistent plastic decrease in dendritic excitability decoupled from synaptic stimulation, which is localized and purely activity-based. In rats this local plasticity decrease is conferred by CamKII mediated phosphorylation of A-type potassium channels upon interaction of a back propagating action potential (bAP) with dendritic depolarization.     

Modulation of Calmodulin Plasticity by the Effect of Macromolecular Crowding

In vitro biochemical reactions are most often studied in dilute solution, a poor mimic of the intracellular space of eukaryotic cells, which are crowded with mobile and immobile macromolecules. Such crowded conditions exert volume exclusion and other entropic forces that have the potential to impact chemical equilibria and reaction rates. In this article, we used the well-characterized and ubiquitous molecule calmodulin (CaM) and a combination of theoretical and experimental approaches to address how crowding impacts CaM's conformational plasticity. CaM is a dumbbell-shaped molecule that contains four EF hands (two in the N-lobe and two in the C-lobe) that each could bind Ca²⁺, leading to stabilization of certain substates that favor interactions with other target proteins. Using coarse-grained molecular simulations, we explored the distribution of CaM conformations in the presence of crowding agents. These predictions, in which crowding effects enhance the population of compact structures, were then confirmed in experimental measurements using fluorescence resonance energy transfer techniques of donor- and acceptor-labeled CaM under normal and crowded conditions. Using protein reconstruction methods, we further explored the folding-energy landscape and examined the structural characteristics of CaM at free-energy basins. We discovered that crowding stabilizes several different compact conformations, which reflects the inherent plasticity in CaM's structure. From these results, we suggest that the EF hands in the C-lobe are flexible and can be thought of as a switch, while those in the N-lobe are stiff, analogous to a rheostat. New combinatorial signaling properties may arise from the product of the differential plasticity of the two distinct lobes of CaM in the presence of crowding. We discuss the implications of these results for modulating CaM's ability to bind Ca²⁺ and target proteins.