Environmental enrichment improves learning and memory and long-term potentiation in young adult rats through a mechanism requiring mGluR5 signaling and sustained activation of p70s6k

Hullinger, Rikki; O’Riordan, Kenneth J.; Bürger, Corinna

doi:10.1016/j.nlm.2015.08.006

Cited by 74 publications

(68 citation statements)

References 36 publications

(49 reference statements)

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“…Memory formation with mTOR also may require metabotropic glutamate receptor (mGluR) signalling . Environmental enrichment for improvements in learning and memory relies upon long term potentiation with mGluR5 activation and sustained phosphorylation of the mTOR pathway p70S6K . Loss of mTOR signalling can impair long term potentiation and synaptic plasticity in animal models of AD that can be restored by mTOR activation .…”

Section: Mtor and Neurodegenerative Disordersmentioning

confidence: 99%

Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders

Maiese¹

2015

Brit J Clinical Pharma

161

122

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Neurodegenerative disorders are significantly increasing in incidence as the age of the global population continues to climb with improved life expectancy. At present, more than 30 million individuals throughout the world are impacted by acute and chronic neurodegenerative disorders with limited treatment strategies. The mechanistic target of rapamycin (mTOR), also known as the mammalian target of rapamycin, is a 289 kDa serine/threonine protein kinase that offers exciting possibilities for novel treatment strategies for a host of neurodegenerative diseases that include Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, stroke and trauma. mTOR governs the programmed cell death pathways of apoptosis and autophagy that can determine neuronal stem cell development, precursor cell differentiation, cell senescence, cell survival and ultimate cell fate. Coupled to the cellular biology of mTOR are a number of considerations for the development of novel treatments involving the fine control of mTOR signalling, tumourigenesis, complexity of the apoptosis and autophagy relationship, functional outcome in the nervous system, and the intimately linked pathways of growth factors, phosphoinositide 3‐kinase (PI 3‐K), protein kinase B (Akt), AMP activated protein kinase (AMPK), silent mating type information regulation two homologue one (Saccharomyces cerevisiae) (SIRT1) and others. Effective clinical translation of the cellular signalling mechanisms of mTOR offers provocative avenues for new drug development in the nervous system tempered only by the need to elucidate further the intricacies of the mTOR pathway.

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Section: Mtor and Neurodegenerative Disordersmentioning

confidence: 99%

Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders

Maiese¹

2015

Brit J Clinical Pharma

161

122

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“…Indeed, mTOR can increase dendritic arborization in the hippocampus via calmodulin-dependent protein kinase IIα (CaMKIIα) [27] and downstream activation of RS6K1 has been reported to enhance dendritic arborization in the PFC [36]. Interestingly, Rapamycin has been recently reported to block the facilitation of hippocampal long-term potentiation provided by an enriched environment [37], suggesting that mTOR signaling could be critical for beneficial effects of environmental manipulations on cognitive function.…”

Section: Introductionmentioning

confidence: 99%

Exercise increases mTOR signaling in brain regions involved in cognition and emotional behavior

Lloyd

Hake

Ishiwata

et al. 2017

Behavioural Brain Research

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Exercise can enhance learning and memory and produce resistance against stress-related psychiatric disorders such as depression and anxiety. In rats, these beneficial effects of exercise occur regardless of exercise controllability: both voluntary and forced wheel running produce stress-protective effects. The mechanisms underlying these beneficial effects of exercise remain unknown. The mammalian target of rapamycin (mTOR) is a translation regulator important for cell growth, proliferation, and survival. mTOR has been implicated in enhancing learning and memory as well as antidepressant effects. Moreover, mTOR is sensitive to exercise signals such as metabolic factors. The effects of exercise on mTOR signaling, however, remain unknown. The goal of the present study was to test the hypothesis that exercise, regardless of controllability, increases levels of phosphorylated mTOR (p-mTOR) in brain regions important for learning and emotional behavior. Rats were exposed to 6 weeks of either sedentary (locked wheel), voluntary, or forced wheel running conditions. At 6 weeks, rats were sacrificed during peak running and levels of p-mTOR were measured using immunohistochemistry. Overall, both voluntary and forced exercise increased p-mTOR-positive neurons in the medial prefrontal cortex, striatum, hippocampus, hypothalamus, and amygdala compared to locked wheel controls. Exercise, regardless of controllability, also increased numbers of p-mTOR-positive glia in the striatum, hippocampus, and amygdala. For both neurons and glia, the largest increase in p-mTOR positive cells was observed after voluntary running, with forced exercise causing a more modest increase. Interestingly, voluntary exercise preferentially increased p-mTOR in astrocytes (GFAP+), while forced running increased p-mTOR in microglia (CD11+) in the inferior dentate gyrus. Results suggest that mTOR signaling is sensitive to exercise, but subtle differences exist depending on exercise controllability. Increases in mTOR signaling could contribute to the beneficial effects of exercise on cognitive function and mental health.

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“…Behavioral strategies and approaches, such as exercise and environmental enrichment can have preventative and therapeutic benefits on cognitive behaviors. Environmental enrichment, which includes physical exercise, has the capacity to increase cognitive functions of the hippocampus [239,240], increase levels of BDNF [241,242], suppress neuroinflammation [240], and protect against neurodegeneration associated with AD [243]. Moreover, environmental enrichment has been shown to enhance learning and memory behavior as well as increase BDNF-dependent signaling pathways, including TrkB phosphorylation and extracellular signal-regulated kinases (ERK) activation [244].…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammatory challenges compromise neuronal function in the aging brain: Postoperative cognitive delirium and Alzheimer’s disease

Cortese

Bürger

2017

Behavioural Brain Research

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Alzheimer's disease (AD) is a progressive neurodegenerative disease that targets memory and cognition, and is the most common form of dementia among the elderly. Although AD itself has been extensively studied, very little is known about early-stage preclinical events and/or mechanisms that may underlie AD pathogenesis. Since the majority of AD cases are sporadic in nature, advancing age remains the greatest known risk factor for AD. However, additional environmental and epigenetic factors are thought to accompany increasing age to play a significant role in the pathogenesis of AD. Postoperative cognitive delirium (POD) is a behavioral syndrome that primarily occurs in elderly patients following a surgical procedure or injury and is characterized by disruptions in cognition. Individuals that experience POD are at an increased risk for developing dementia and AD compared to normal aging individuals. One way in which cognitive function is affected in cases of POD is through activation of the inflammatory cascade following surgery or injury. There is compelling evidence that immune challenges (surgery and/or injury) associated with POD trigger the release of pro-inflammatory cytokines into both the periphery and central nervous system. Thus, it is possible that cognitive impairments following an inflammatory episode may lead to more severe forms of dementia and AD pathogenesis. Here we will discuss the inflammation associated with POD, and highlight the advantages of using POD as a model to study inflammation-evoked cognitive impairment. We will explore the possibility that advancing age and immune challenges may provide mechanistic evidence correlating early life POD with AD. We will review and propose neural mechanisms by which cognitive impairments occur in cases of POD, and discuss how POD may augment the onset of AD.

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Environmental enrichment improves learning and memory and long-term potentiation in young adult rats through a mechanism requiring mGluR5 signaling and sustained activation of p70s6k

Cited by 74 publications

References 36 publications

Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders

Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders

Exercise increases mTOR signaling in brain regions involved in cognition and emotional behavior

Neuroinflammatory challenges compromise neuronal function in the aging brain: Postoperative cognitive delirium and Alzheimer’s disease

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