The role of cannabinoids in adult neurogenesis Prenderville, Jack A; Kelly, Áine M; Downer, Eric J
British journal of pharmacology,
August 2015, Letnik:
172, Številka:
16
Journal Article
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The processes underpinning post‐developmental neurogenesis in the mammalian brain continue to be defined. Such processes involve the proliferation of neural stem cells and neural progenitor cells ...(NPCs), neuronal migration, differentiation and integration into a network of functional synapses within the brain. Both intrinsic (cell signalling cascades) and extrinsic (neurotrophins, neurotransmitters, cytokines, hormones) signalling molecules are intimately associated with adult neurogenesis and largely dictate the proliferative activity and differentiation capacity of neural cells. Cannabinoids are a unique class of chemical compounds incorporating plant‐derived cannabinoids (the active components of Cannabis sativa), the endogenous cannabinoids and synthetic cannabinoid ligands, and these compounds are becoming increasingly recognized for their roles in neural developmental processes. Indeed, cannabinoids have clear modulatory roles in adult neurogenesis, probably through activation of both CB1 and CB2 receptors. In recent years, a large body of literature has deciphered the signalling networks involved in cannabinoid‐mediated regulation of neurogenesis. This timely review summarizes the evidence that the cannabinoid system is intricately associated with neuronal differentiation and maturation of NPCs and highlights intrinsic/extrinsic signalling mechanisms that are cannabinoid targets. Overall, these findings identify the central role of the cannabinoid system in adult neurogenesis in the hippocampus and the lateral ventricles and hence provide insight into the processes underlying post‐developmental neurogenesis in the mammalian brain.
Abstract Physical activity has been reported to improve cognitive function in humans and rodents, possibly via a brain-derived neurotrophic factor (BDNF)-regulated mechanism. In this study of human ...subjects, we have assessed the effects of acute and chronic exercise on performance of a face–name matching task, which recruits the hippocampus and associated structures of the medial temporal lobe, and the Stroop word–colour task, which does not, and have assessed circulating concentrations of BDNF and IGF-1 in parallel. The results show that a short period of high-intensity cycling results in enhancements in performance of the face–name matching, but not the Stroop, task. These changes in cognitive function were paralleled by increased concentration of BDNF, but not IGF-1, in the serum of exercising subjects. 3 weeks of cycling training had no effect on cardiovascular fitness, as assessed by VO2 scores, cognitive function, or serum BDNF concentration. Increases in fitness, cognitive function and serum BDNF response to acute exercise were observed following 5 weeks of aerobic training. These data indicate that both acute and chronic exercise improve medial temporal lobe function concomitant with increased concentrations of BDNF in the serum, suggesting a possible functional role for this neurotrophic factor in exercise-induced cognitive enhancement in humans.
Highlights • Exercise elicits potent pro-cognitive and pro-neurogenic effects. • In AD mouse models, exercise reduces amyloid pathology and improves cognition. • Exercise-induced effects on ...neurogenesis and inflammation in AD are less explored. • Exercise can potentially slow down progression of AD.
•Exercised rats successfully completed challenging spatial task.•Exercised rats showed increase in KCl-stimulated BDNF release from dentate gyrus.•Exercised rats displayed increases in BDNF ...expression and cell division in dentate gyrus.•Exercised rats displayed activation of BDNF-stimulated signalling cascade.•BDNF injections mimicked effects of exercise on both memory and signalling events.
Exercise-induced improvements in learning are associated with neurotrophic and neurogenic changes in the dentate gyrus, but the intracellular signalling mechanisms that may mediate these improvements remain unknown. In the current study we investigate the effects of one week of forced exercise on spatial memory and analyse in parallel BDNF-stimulated signalling pathways in cells of the dentate gyrus. Additionally, we test whether a single intracerebroventricular (i.c.v.) injection of BDNF can mimic the observed cognitive and signalling changes. Male Wistar rats were assigned to exercised and sedentary groups and tested in a spatial task post-exercise. Tissue from the dentate gyrus was assessed for expression and release of BDNF, and for changes in expression and activation of TrkB, ERK and synapsin-1. In a separate set of experiments, male Wistar rats received a single i.c.v. injection of BDNF and were then tested in the same spatial learning task. Exercised and BDNF-treated (but not control) rats could successfully complete an object displacement task that tests spatial learning. Exercised rats and BDNF-treated rats displayed increases BDNF expression and ERK1 activation, while exercised rats showed increases in cell division, stimulated BDNF release, TrkB activation, and synapsin-1 expression in the dentate gyrus. We conclude that exercise-induced increases in BDNF in the dentate gyrus are sufficient to cause improvements in spatial memory by activating signalling cascades that enhance synaptic transmission in the hippocampus.
With regard to future experimental directions, they caution the reliance upon BMI as a means of categorizing study participants, arguing that without gathering relevant information on dietary pattern ...across groups, key information about the relationship between weight, diet and cognition may be overlooked. ...Lang et al. focus on perhaps the most popular and fundamental tool used in experimental learning and memory research in their masterful overview of the development of assessments of cognitive function in the laboratory mouse. The increasing use and biological relevance of experimental settings that control for the effects of the laboratory cage environment on physical activity and social and cognitive enrichment is discussed, along with the importance of efforts to mimic the environment more naturally experienced by the mouse in the wild.
•The age-related switch to glycolysis in microglia is attenuated by exercise.•Glycolytic microglia are functionally impaired.•Exercise ameliorates expression of senescent markers in microglia from ...aged mice.
Microglial activation and neuroinflammatory changes are characteristic of the aged brain and contribute to age-related cognitive impairment. Exercise improves cognitive function in aged animals, perhaps because of a modulatory effect on microglial activation. Recent evidence indicates that inflammatory microglia are glycolytic, driven by an increase in 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), an enzyme that is described as the master regulator of glycolysis. Here we investigated whether microglia from aged animals exhibited a glycolytic signature and whether exercise exerted a modulatory effect on this metabolic profile. Young (4 month-old) and aged (18 month-old) mice were trained for 10 days on a treadmill. One day before sacrifice, animals were assessed in the novel object recognition and the object displacement tests. Animals were sacrificed after the last bout of exercise, microglial cells were isolated, cultured for 5 days and assessed for metabolic profile. Performance in both behavioural tests was impaired in sedentary aged animals and exercise attenuated this age-related effect. A significant increase in glycolysis, glycolytic capacity and PFKFB3 was observed in microglia from aged animals and exercise ameliorated these effects, while it also increased the phagocytic capacity of cells. The senescent markers, β-galactosidase and p16INK4A, were increased in microglia from sedentary aged mice, and expression of these markers was significantly decreased by exercise. The data demonstrate that the exercise-related improved cognition is orchestrated by a normalization of the metabolic profile and functionality of microglia.
To critically review current knowledge on the positive and negative predictive value of blood biomarkers for concussion; to illustrate the clinical and biological contexts that help evaluate the use ...of these markers in sport-related traumatic brain injuries (TBIs).
This systematic review was performed in accordance with PRISMA guidelines. We reviewed the measurement, clinical utility, endpoint, and biological significance of blood biomarkers in concussion.
A total of 4352 publications were identified. Twenty-six articles relating to blood biomarkers were included in the review. Four common blood biomarkers, namely S100B, tau, neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP), were examined. Overall, the studies showed S100B measurement and use, either acutely or at several time points, can distinguish injured from noninjured patients with an uncertain degree of utility in predicting mortality. At present, S100B has largely become an acceptable biomarker of TBI; however, studies have begun to highlight the need to incorporate clinical symptoms instead of S100B concentration in isolation on the basis of inconsistent results and lack of specificity across published studies. Further research is needed to evaluate and validate the use of tau, NSE, and GFAP as a diagnostic aid in the management of concussion and TBI.
At present, blood biomarkers have only a limited role in the evaluation and management of concussion. Although several biomarkers of brain injury have been identified, continued research is required. S100B holds promise as the most clinically useful diagnostic biomarker. Blood biomarkers, in combination with other clinical data, such as head computed tomography, would maximize the diagnostic accuracy. The methodological limitations evident in blood biomarker research results in the need for the clinical utility of blood biomarker use in concussion to be further explored.
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