Brain plasticity (Amsterdam, Netherlands)最新文献

Many advancements have been made over the years looking at the individual and combined effects of drugs of abuse on the brain, with one key area of research focusing on the effects on neurogenesis. An integral part of fetal brain development and, later, maintenance in the adult brain, neurogenesis occurs in three main regions: subventricularzone of the lateral ventricles (SVZ), subgranularzone of the dentate gyrus (SGZ), and the tanycyte layer in the hypothalamus (TL). We will review current literature on combined drugs of abuse and their effect on adult neurogenesis. More specifically, this review will focus on the effect of combining cocaine and alcohol. Additionally, the tanycyte layer will be explored in more depth and probed to look at the neurogenic properties of tanycytes and their role in neurogenesis.

Background: Fetal alcohol spectrum disorders (FASDs) are associated with a wide range of cognitive deficiencies.

Objective: We previously found that gestational exposure to moderate levels of alcohol in mice throughout the 1st-2nd human trimester-equivalents for brain development results in profound impairment of the hippocampal neurogenic response to enriched environment (EE) in adulthood, without altering baseline neurogenesis rate under standard housing (SH). However, the functional and structural consequences of impaired EE-mediated neurogenesis in the context of prenatal alcohol exposure (PAE) have not been determined.

Results: Here, we demonstrate that PAE-EE mice display impaired performance on a neurogenesis-dependent pattern discrimination task, broadened behavioral activation of the dentate gyrus, as assessed by expression of the immediate early gene, c-Fos, and impaired dendritic branching of adult-generated dentate granule cells (aDGCs).

Conclusions: These studies further underscore the impact of moderate gestational alcohol exposure on adult hippocampal plasticity and support adult hippocampal neurogenesis as a potential therapeutic target to remediate certain neurological outcomes in FASD.

Alcohol is one of the oldest pharmacological agents used for its sedative/hypnotic effects, and alcohol abuse and alcohol use disorder (AUD) continues to be major public health issue. AUD is strongly indicated to be a brain disorder, and the molecular and cellular mechanism/s by which alcohol produces its effects in the brain are only now beginning to be understood. In the brain, synaptic plasticity or strengthening or weakening of synapses, can be enhanced or reduced by a variety of stimulation paradigms. Synaptic plasticity is thought to be responsible for important processes involved in the cellular mechanisms of learning and memory. Long-term potentiation (LTP) is a form of synaptic plasticity, and occurs via N-methyl-D-aspartate type glutamate receptor (NMDAR or GluN) dependent and independent mechanisms. In particular, NMDARs are a major target of alcohol, and are implicated in different types of learning and memory. Therefore, understanding the effect of alcohol on synaptic plasticity and transmission mediated by glutamatergic signaling is becoming important, and this will help us understand the significant contribution of the glutamatergic system in AUD. In the first part of this review, we will briefly discuss the mechanisms underlying long term synaptic plasticity in the dorsal striatum, neocortex and the hippocampus. In the second part we will discuss how alcohol (ethanol, EtOH) can modulate long term synaptic plasticity in these three brain regions, mainly from neurophysiological and electrophysiological studies. Taken together, understanding the mechanism(s) underlying alcohol induced changes in brain function may lead to the development of more effective therapeutic agents to reduce AUDs.

Background: Despite considerable research on exercise-induced neuroplasticity in the brain, a major ongoing challenge in translating findings from animal studies to humans is that clinical and preclinical settings employ very different techniques.

Objective: Here we aim to bridge this divide by using diffusion tensor imaging MRI (DTI), an advanced imaging technique commonly applied in human studies, in a longitudinal exercise study with mice.

Methods: Wild-type mice were exercised using voluntary free-wheel running, and MRI scans were at baseline and after four weeks and nine weeks of running.

Results: Both hippocampal volume and fractional anisotropy, a surrogate for microstructural directionality, significantly increased with exercise. In addition, exercise levels correlated with effect size. Histological analysis showed more PDGFRα+ oligodendrocyte precursor cells in the corpus callosum of running mice.

Conclusions: These results provide compelling in vivo support for the concept that similar adaptive changes occur in the brains of mice and humans in response to exercise.

Background: Microglia are the resident macrophages of the central nervous system (CNS). In multiple sclerosis (MS) and related experimental models, microglia have either a pro-inflammatory or a pro-regenerative/pro-remyelinating function. Inhibition of Bruton's tyrosine kinase (BTK), a member of the Tec family of kinases, has been shown to block differentiation of pro-inflammatory macrophages in response to granulocyte-macrophage colony-stimulating factor in vitro. However, the role of BTK in the CNS is unknown.

Methods: Our aim was to investigate the effect of BTK inhibition on myelin repair in ex vivo and in vivo experimental models of demyelination and remyelination. The remyelination effect of a BTK inhibitor (BTKi; BTKi-1) was then investigated in LPC-induced demyelinated cerebellar organotypic slice cultures and metronidazole-induced demyelinated Xenopus MBP-GFP-NTR transgenic tadpoles.

Results: Cellular detection of BTK and its activated form BTK-phospho-Y223 (p-BTK) was determined by immunohistochemistry in organotypic cerebellar slice cultures, before and after lysophosphatidylcholine (LPC)-induced demyelination. A low BTK signal detected by immunolabeling under normal conditions in cerebellar slices was in sharp contrast to an 8.5-fold increase in the number of BTK-positive cells observed in LPC-demyelinated slice cultures. Under both conditions, approximately 75% of cells expressing BTK and p-BTK were microglia and 25% were astrocytes. Compared with spontaneous recovery, treatment of demyelinated slice cultures and MTZ-demyelinated transgenic tadpoles with BTKi resulted in at least a 1.7-fold improvement of remyelination.

Conclusion: Our data demonstrate that BTK inhibition is a promising therapeutic strategy for myelin repair.

Background: Schizophrenia (SCZ) is a severe, chronic illness characterized by psychotic symptoms and impairments in many cognitive domains. Dysregulation of brain derived neurotrophic factor (BDNF) is associated with the cognitive impairments seen in patients with SCZ. Given the growing literature supporting a positive effect of aerobic exercise on cognition in other populations, we hypothesized that a structured aerobic exercise program would improve cognitive and functional outcomes in subjects with SCZ, potentially mediated by increases in BDNF.

Methods: The study was a small randomized parallel group clinical trial of subjects with SCZ comparing 12 weeks of aerobic exercise (AE) against control (CON) stretching and balance training. At Baseline, Week 12, and Week 20 we collected serum samples for analysis of brain derived neurotrophic factor (BDNF), and assessed functional, physical, and cognitive outcomes. Linear regression models were used to compare change scores between timepoints.

Results: We randomized 21 subjects to AE and 17 to CON; however, only 9 AE and 6 CON completed their programs. Subjects in both groups were slower at the 400 m walk in Week 12 compared to Baseline, but the AE group had significantly less slowing than the CON group (B = -28.32, p = 0.011). Between Week 12 and Week 20, the AE group had a significantly greater change score on the Composite and Visual Learning Domain of the MATRICS Consensus Cognitive Battery (B = 5.11, p = 0.03; B = 13.96, p = 0.006).

Conclusion: These results indicate that participation in a structured aerobic exercise paradigm may modestly blunt physical function decline and enhance cognitive function in individuals with SCZ.

Objective: The purpose of this study was to examine the effect of exposure of a low-intensity blast wave on androgen receptor (AR) density in the hippocampus and the potential influence on behavioral and cognitive responses.

Methods: Sprague-Dawley rats were randomly assigned to either a blast exposed group (n = 27) or an unexposed (control) group (n = 10). Animals were treated identically, except that rats within the control group were not exposed to any of the characteristics of the blast wave. Behavior measures were conducted on day seven post-exposure. The rats were initially assessed in the elevated plus maze followed by the acoustic startle response paradigm. Spatial memory performance using the Morris water-maze test was assessed at 8-days post-exposure, for seven consecutive days. Following all behavioral tests AR immunofluorescence staining was performed in different hippocampal subregions.

Results: A significant elevation in anxiety index (p < 0.001) and impaired learning (p < 0.015) and spatial memory (p < 0.0015) were noted in exposed rats. In addition, a significant attenuation of the AR was noted in the CA1 (p = 0.006) and dentate gyrus (p = 0.031) subregions of the hippocampus in blast exposed animals. Correlational analyses revealed significant associations between AR and both anxiety index (r = -.36, p = 0.031) and memory (r = -0.38, p = 0.019).

Conclusions: The results of this study demonstrate that exposure to a low-pressure blast wave resulted in a decrease in AR density, which was associated with significant behavioral and cognitive changes.

Aerobic exercise has been associated with reduced burden of brain and cognitive changes related to Alzheimer's disease (AD). However, it is unknown whether exercise training in asymptomatic individuals harboring risk for AD improves outcomes associated with AD. We investigated the effect of 26 weeks of supervised aerobic treadmill exercise training on brain glucose metabolism and cognition among 23 late-middle-aged adults from a cohort enriched with familial and genetic risk of AD. They were randomized to Usual Physical Activity (PA) or Enhanced PA conditions. Usual PA received instruction about maintaining an active lifestyle. Enhanced PA completed a progressive exercise training program consisting of 3 sessions of treadmill walking per week for 26 weeks. By week seven, participants exercised at 70- 80% heart rate reserve for 50 minutes per session to achieve 150 minutes of moderate intensity activity per week in accordance with public health guidelines. Before and after the intervention, participants completed a graded treadmill test to assess VO₂peak as a measure of cardiorespiratory fitness (CRF), wore an accelerometer to measure free-living PA, underwent ¹⁸F-fluorodeoxyglucose positron emission tomography imaging to assess brain glucose metabolism, and a neuropsychological battery to assess episodic memory and executive function. VO₂peak increased, sedentary behavior decreased, and moderate-to-vigorous PA increased significantly in the Enhanced PA group as compared to Usual PA. Glucose metabolism in the posterior cingulate cortex (PCC) did not change significantly in Enhanced PA relative to Usual PA. However, change in PCC glucose metabolism correlated positively with change in VO₂peak. Executive function, but not episodic memory, was significantly improved after Enhanced PA relative to Usual PA. Improvement in executive function correlated with increased VO₂peak. Favorable CRF adaptation after 26 weeks of aerobic exercise training was associated with improvements in PCC glucose metabolism and executive function, important markers of AD.