Anterior thalamic lesions reduce spine density in both hippocampal CA1 and retrosplenial cortex,but enrichment rescues CA1 spines only

Injury to the anterior thalamic nuclei (ATN) may affect both hippocampus and retrosplenial cortex thus explaining some parallels between diencephalic and medial temporal lobe amnesias. We found that standard‐housed rats with ATN lesions, compared with standard‐housed controls, showed reduced spine density in hippocampal CA1 neurons (basal dendrites, ?11.2%; apical dendrites, ?9.6%) and in retrospenial granular b cortex (Rgb) neurons (apical dendrites, ?20.1%) together with spatial memory deficits on cross maze and radial‐arm maze tasks. Additional rats with ATN lesions were also shown to display a severe deficit on spatial working memory in the cross‐maze, but subsequent enriched housing ameliorated their performance on both this task and the radial‐arm maze. These enriched rats with ATN lesions also showed recovery of both basal and apical CA1 spine density to levels comparable to that of the standard‐housed controls, but no recovery of Rgb spine density. Inspection of spine types in the CA1 neurons showed that ATN lesions reduced the density of thin spines and mushroom spines, but not stubby spines; while enrichment promoted recovery of thin spines. Comparison with enriched rats that received pseudo‐training, which provided comparable task‐related experience, but no explicit spatial memory training, suggested that basal CA1 spine density in particular was associated with spatial learning and memory performance. Distal pathology in terms of reduced integrity of hippocampal and retrosplenial microstructure provides clear support for the influence of the ATN lesions on the extended hippocampal system. The reversal by postoperative enrichment of this deficit in the hippocampus but not the retrosplenial cortex may indicate region‐specific mechanisms of recovery after ATN injury. © 2014 Wiley Periodicals, Inc.     

Environmental enrichment upregulates micro‐RNA‐183 and alters acetylcholinesterase splice variants to reduce anxiety‐like behavior in the little Indian field mouse (Mus booduga)

Environmental enrichment (EE) has an influential role in reducing behavioral reactivity to stress. We previously observed that EE reduces the anxiety‐like behavior in the field mouse Mus booduga accompanied by a reduction in the expression of molecules involved in the stress pathway. In this study, we demonstrate the effect of different housing condition on regulation of micro‐RNA‐183‐SC35‐mediated splicing of acetylcholinesterase (AChE). Adult male M. booduga were captured from an agricultural field and housed under nonenriched standard conditions (SC) for 7 days and considered as directly from the wild (DW). On day 8, individuals were randomly assigned to three groups; DW, SC, and EE. The DW group's anxiety‐like behavior was assessed in the elevated plus maze (EPM) and open field test (OFT). The SC and EE groups were transferred to their respective conditions and housed for another 30 days. The mice housed in EE showed less anxiety‐like behavior on EPM and in OFT compared with DW and SC mice. Interestingly, miR‐183 expression was increased following exposure to EPM in EE mice but not in SC mice. Subsequently, the upregulated miR‐183 expression suppresses the SC35 expression and shifting of splicing from AChE‐S (synaptic) to AChE‐R (read‐through) form, whereas standard housing condition downregulate miR‐183 and induces the splicing of AChE. The upregulated AChE‐R form possibly terminates ACh transmission, which is reflected in the level of anxiety‐like behavior. Overall, the present study suggests that EE effectively regulates the miR‐183 pathway to reduce anxiety‐like behavior. © 2012 Wiley Periodicals, Inc.     

基于网络药理学探讨小青龙汤治疗慢性阻塞性肺疾病的作用机制

目的：利用网络药理学分析小青龙汤治疗慢性阻塞性肺疾病（COPD）的作用机制。方法：在中药系统药理学数据库与分析平台（TCMSP）检索小青龙汤药物活性成分和靶点,绘制中药-化合物-靶基因网络,筛选关键化合物;利用GeneCards和人类孟德尔遗传数据库（OMIM）搜索COPD疾病基因;绘制韦恩图并获取药物-疾病共同基因;利用小青龙汤-慢阻肺药物疾病共同基因绘制蛋白质-蛋白质相互作用（PPI）网络,根据网络关系选择核心基因;对核心基因分别进行基因本体（GO）功能注释和富集分析和京都基因和基因组百科全书（KEGG）通路富集分析。结果：挖掘得到小青龙汤中药活性成分137个,潜在作用靶点188个,慢性阻塞性肺疾病相关靶点6 949个,小青龙汤-COPD共同靶点160个,主要富集于92个生物过程和49条信号通路上。结论：小青龙汤中多个药物含有山柰酚、槲皮素、（+）-儿茶素、豆甾醇、β-谷固醇等成分,可作用于AKT1、IL6、MAPK1、PTGS2、TP53等核心基因,调控氧化应激反应、血小板α-颗粒等生物过程,参与HIF-1、PI3K-AKT信号通路的调节,干预氧化应激反应和炎症反应等过程,产生抑制炎症反应、抗氧化应激的作用,进而通过上述过程参与COPD的炎症反应与氧化应激过程。     

BDNF contributes to the facilitation of hippocampal synaptic plasticity and learning enabled by environmental enrichment

Sensory, motor, and cognitive stimuli, resulting from interactions with the environment, play a key role in optimizing and modifying the neuronal circuitry required for normal brain function. An experimental animal model for this phenomenon comprises environmental enrichment (EE) in rodents. EE causes profound changes in neuronal and signaling levels of excitation and plasticity throughout the entire central nervous system and the hippocampus is particularly affected. The mechanisms underlying these changes are not yet fully understood. As brain‐derived neurotrophic factor (BDNF) supports hippocampal long‐term potentiation (LTP), we explored whether it participates in the facilitation of synaptic plasticity and hippocampus‐dependent learning that occurs following EE. In the absence of EE, LTP elicited by high‐frequency stimulation was equivalent in wildtype mice and heterozygous BDNF^+/? siblings. LTP elicited by theta‐burst stimulation in BDNF^+/? mice was less than in wildtypes. Long‐term depression (LTD) was also impaired. EE for three weeks, beginning after weaning, improved hippocampal LTP in both wildtype and transgenic animals, with LTP in transgenics achieving levels seen in wildtypes in the absence of EE. Object recognition memory was evident in wildtypes 24 h and 7 days after initial object exposure. EE improved memory performance in wildtypes 24 h but not 7 days after initial exposure. BDNF^+/? mice in the absence of EE showed impaired memory 7 days after initial object exposure that was restored by EE. Western blotting revealed increased levels of BDNF, but not proBDNF, among both EE cohorts. These data support that BDNF plays an intrinsic role in improvements of synaptic plasticity and cognition that occur in EE. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

Neurobehavioral effects of environmental enrichment and drug abuse vulnerability

Environmental enrichment during development produces a host of neurobehavioral effects in preclinical models. Early work demonstrated that enrichment enhances learning of a variety of behavioral tasks in rats and these changes are associated with neural changes in various cortical regions. In addition to promoting superior learning, more recent evidence suggests that environmental enrichment also has a protective effect in reducing drug abuse vulnerability. The current review describes some of the most important environment-dependent neural changes in reward-relevant brain structures and summarizes some of the key findings from the extensive literature showing how enrichment decreases the impact of drugs of abuse. Some critical neural mechanisms that may mediate the behavioral changes are postulated, along with some notes of caution about the limitations of the work cited.     

Environmental enrichment improves cognitive deficits in Spontaneously Hypertensive Rats (SHR): Relevance for Attention Deficit/Hyperactivity Disorder (ADHD)

The interaction between genes and environment seems to be relevant for the development of Attention Deficit/Hyperactivity Disorder (ADHD), one of the most prevalent childhood psychiatric diseases. The occurrence of ADHD is typically associated with poor academic performance, probably reflecting learning difficulties and/or cognitive impulsiveness. The inbred Spontaneously Hypertensive Rats (SHR) strain has often been considered as an animal model of ADHD, since they ‘naturally’ display the main ADHD symptomatology. Although pharmacological agents improve SHR's cognitive deficits, little is known about the involvement of environmental factors in SHR disabilities and to what extent ‘protective’ non-pharmacological factors may be considered as strategy for ADHD prevention. Here we investigated whether the rearing environment during neurodevelopment may counteract later cognitive deficits presented by adult SHR. Wistar (WIS) rats were also used to investigate whether the putative effects of environmental enrichment depend on a specific genetic background. The animals were reared in enriched environment (EE) or standard environment (SE) from the post-natal day 21 until 3 months of age (adulthood) and tested for cognitive and non-cognitive phenotypes. EE improved SHR's performance in open field habituation, water maze spatial reference, social and object recognition tasks, while non-cognitive traits, such as nociception and hypertension, were not affected by EE. Response of WIS rats was generally not affected by the present EE. These results show that the general low cognitive performance presented by SHR rats strongly depends on the rearing environment and they may suggest modifications of the familial environment as a putative preventive strategy to cope with ADHD.     

17β-estradiol and enriched environment accelerate cognitive recovery after focal brain ischemia

Cognitive impairments, including spatial memory and learning deficiencies, are common after ischemic stroke. Estrogen substitution improves cognitive functions in post-menopausal women and ovariectomized rodents, partially through induction of neuroplasticity in the hippocampal formation. Post-ischemic housing of male rats in an enriched environment (EE) improves functional outcome, without changing infarct volume. We hypothesized that 17β-estradiol combined with an EE would accelerate cognitive recovery after focal brain ischemia in ovariectomized rats and that recovery would be related to altered expression of nerve growth factor-induced gene (NGFI)-A in the hippocampus. 17β-estradiol or placebo pellets were implanted 6 h after transient middle cerebral artery occlusion. Two days later, rats were placed in an EE or a deprived environment (DE) for 6 weeks. At 5 weeks after middle cerebral artery occlusion, 17β-estradiol-treated rats housed in an EE showed improvements in cognitive function (i.e. shorter latency and path in the Morris water maze task) compared with placebo-treated animals housed in an EE. Furthermore, beneficial effects on latency and path were observed when comparing EE-housed vs. DE-housed 17β-estradiol-treated rats. When comparing 17β-estradiol-treated EE-housed rats vs. placebo-treated DE-housed rats, pronounced effects on latency and path were observed. Infarct volumes did not differ between groups. 17β-estradiol-treated EE-housed rats had significantly higher NGFI-A mRNA expression bilaterally in the cornu ammonis 1 region and in the ipsilateral dentate gyrus of the hippocampus, compared with placebo-treated EE-housed rats. In conclusion, 17β-estradiol treatment combined with an EE improved recovery of cognitive function after experimental brain ischemia, putatively through the upregulation of NGFI-A in hippocampal subregions.     

Environmental conditions influence hippocampus-dependent behaviours and brain levels of amyloid precursor protein in rats

Sprague-Dawley rats were reared in enriched (EC; group housing, exposure to stimulating objects, frequent handling) or restricted (RC; individual housing, no exposure to stimulating objects, minimal handling) environments starting on day 23 of life. At six months of age, they underwent behavioural tests to assess 'cognitive' and 'stimulus-response' memory, selective attention, and inflammatory pain processing. Alterations in synapses and cell survival may occur as a result of environment differences; therefore we assessed the brain levels of several proteins implicated in neurite outgrowth, synaptogenesis, and cell survival. Brains were dissected and analysed for amyloid precursor protein (APP) and other synaptic and cytoskeletal proteins using Western blotting. The performance of EC animals in a hidden platform water maze task, and in a test of selective attention (both of which are thought to involve the hippocampus) was superior to that of RC animals. In contrast, performance of RC animals on two stimulus-response tasks, the visible platform water maze test and simple visual discrimination (both of which are thought to be hippocampal independent) was indistinguishable from that of EC animals. Male EC rats displayed a different behavioural response to formalin during the inflammatory phase of nociception--the phase affected by hippocampal processing; a similar trend was observed in females. Female but not male RC rats exhibited elevated plasma corticosterone levels; adrenal weights were unaffected by environmental conditions. Region-specific increases in brain levels of APP, neurofilament-70 (NF-70), and platelet-activating factor receptor (PAF-R) were found in EC rats. These data suggest that enriched animals manifest enhanced functioning of certain hippocampus-mediated behaviours when compared with that of their restricted counterparts; and that brain levels of various synaptic and structural proteins involved in neurite outgrowth, cell survival, and synaptogenesis, are affected by environmental factors.     

Attendance at cultural events and physical exercise and health: a randomized controlled study

The aim of this study was to assess the specific biomedico-social effects of participating in cultural events and gentle physical exercise effects apart from the general effect of participating in group activities. This was a randomized controlled investigation using a factorial design, where attending cultural events and taking easy physical exercise were tested simultaneously. The 21 participants, aged between 18 and 74 y were from a simple random sample of people registered as residents in Ume?, a town in northern Sweden. Among the 1000 in the sample, 21 individuals (11 men, 10 women) were recruited into the experiment. Two out of the 21 subjects dropped out and were discounted from our analysis. Nine people were encouraged to engage in cultural activity for a two-month period. Diastolic blood pressure in eight of these nine was significantly reduced following the experiment. There were no marked changes observed in either systolic or diastolic blood pressure in those not required to engage in any form of extra-cultural activity. A decrease in the levels of both adrenocorticotropical hormone (ACTH) and s-prolactin was observed in culturally stimulated subjects, whereas the average baseline s-prolactin level of 7 ng/l for the non-culturally stimulated group was unchanged after the experiment. Physical exercise produced an increase in the high density lipoprotein (HDL) cholesterol level and in the ratio of HDL to LDL (low density lipoprotein). It was concluded that cultural stimulation may have specific effects on health related determinants.