Environmental enrichment alleviates cognitive and psychomotor alterations and increases adult hippocampal neurogenesis in cocaine withdrawn mice.

Cocaine is a widely used psychostimulant drug whose repeated exposure induces persistent cognitive/emotional dysregulation, which could be a predictor of relapse in users. However, there is scarce evidence on effective treatments to alleviate these symptoms. Environmental enrichment (EE) has been shown to be associated with improved synaptic function and cellular plasticity changes related to adult hippocampal neurogenesis (AHN), resulting in cognitive enhancement. Therefore, EE could mitigate the negative impact of chronic administration of cocaine in mice and reduce the emotional and cognitive symptoms present during cocaine abstinence. In this study, mice were chronically administered with cocaine for 14 days, and control mice received saline. After the last cocaine or saline dose, mice were submitted to control or EE housing conditions, and they stayed undisturbed for 28 days. Subsequently, mice were evaluated with a battery of behavioural tests for exploratory activity, emotional behaviour, and cognitive performance. EE attenuated hyperlocomotion, induced anxiolytic-like behaviour and alleviated cognitive impairment in spatial memory in the cocaine-abstinent mice. The EE protocol notably upregulated AHN in both control and cocaine-treated mice, though cocaine slightly reduced the number of immature neurons. Altogether, these results demonstrate that EE could enhance hippocampal neuroplasticity ameliorating the behavioural and cognitive consequences of repeated administration of cocaine. Therefore, environmental stimulation may be a useful strategy in the treatment cocaine addiction.

Advances in the Ongoing Battle against the Consequences of Peripheral Nerve Injuries.

A number of constraints to the full recovery of a peripheral nerve injury are being fought with a battery of novel promising tools. Anat Rec, 301:1606-1613, 2018. © 2018 Wiley Periodicals, Inc.

Neuronal tetraploidization in the cerebral cortex correlates with reduced cognition in mice and precedes and recapitulates Alzheimer's-associated neuropathology.

A controversy exists as to whether de novo-generated neuronal tetraploidy (dnNT) occurs in Alzheimer's disease. In addition, the presence of age-associated dnNT in the normal brain remains unexplored. Here we show that age-associated dnNT occurs in both superficial and deep layers of the cerebral cortex of adult mice, a process that is blocked in the absence of E2F1, a known regulator of cell cycle progression. This blockage correlates with improved cognition despite compromised neurogenesis in the adult hippocampus was confirmed in mice lacking the E2f1 gene. We also show that the human cerebral cortex contains tetraploid neurons. In normal humans, age-associated dnNT specifically occurs in the entorhinal cortex whereas, in Alzheimer, dnNT also affects association cortices prior to neurofibrillary tangle formation. Alzheimer-associated dnNT is likely potentiated by altered amyloid precursor protein (APP) processing as it is enhanced in the cerebral cortex of young APPswe/PS1deltaE9 mice, long before the first amyloid plaques are visible in their brains. In contrast to age-associated dnNT, enhanced dnNT in APPswe/PS1deltaE9 mice mostly affects the superficial cortical layers. The correlation of dnNT with reduced cognition in mice and its spatiotemporal course, preceding and recapitulating Alzheimer-associated neuropathology, makes this process a potential target for intervention in Alzheimer's disease.

Can Exercise Make You Smarter, Happier, and Have More Neurons? A Hormetic Perspective.

Exercise can make you smarter, happier and have more neurons depending on the dose (intensity) of the training program. It is well recognized that exercise protocols induce both positive and negative effects depending on the intensity of the exercise, among other key factors, a process described as a hormetic-like biphasic dose-response. However, no evidences have been reported till very recently about the biphasic response of some of the potential mediators of the exercise-induced actions. This hypothesis and theory will focus on the adult hippocampal neurogenesis (AHN) as a putative physical substrate for hormesis responses to exercise in the context of exercise-induced actions on cognition and mood, and on the molecular pathways which might potentially be mediating these actions.

The postnatal origin of adult neural stem cells and the effects of glucocorticoids on their genesis.

The relevance of adult neurogenesis in hippocampal function is well documented, as is the potential impact stress has on the adult neurogenic niche. Adult born neurons are generated from neural precursors in the dentate gyrus (DG), although the point in postnatal development that these cell precursors originate is not known. This is particularly relevant if we consider the effects stress may have on the development of neural precursors, and whether such effects on adult neurogenesis and behavior may persist in the long-term. We have analyzed the proportion of neural precursors in the adult murine hippocampus born on specific days during postnatal development using a dual birth-dating analysis, and we assessed their sensitivity to dexamethasone (DEX) on the peak day of cell generation. We also studied the consequences of postnatal DEX administration on adult hippocampal-dependent behavior. Postnatal day 6 (P6) is a preferred period for proliferating neural stem cells (NSCs) to become the precursors that remain in a proliferative state throughout adulthood. This window is independent of gender, the cell's location in the DG granule cell layer or their rostro-caudal position. DEX administration at P6 reduces the size of the adult NSC pool in the DG, which is correlated with poor learning/memory capacity and increased anxiety-like behavior. These results indicate that aNSCs are generated non-uniformly during postnatal development, with peak generation on day P6, and that stress receptor activation during the key period of postnatal NSC generation has a profound impact on both adult hippocampal neurogenesis and behavior.

Mifepristone prevents stress-induced apoptosis in newborn neurons and increases AMPA receptor expression in the dentate gyrus of C57/BL6 mice.

Chronic stress produces sustained elevation of corticosteroid levels, which is why it is considered one of the most potent negative regulators of adult hippocampal neurogenesis (AHN). Several mood disorders are accompanied by elevated glucocorticoid levels and have been linked to alterations in AHN, such as major depression (MD). Nevertheless, the mechanism by which acute stress affects the maturation of neural precursors in the dentate gyrus is poorly understood. We analyzed the survival and differentiation of 1 to 8 week-old cells in the dentate gyrus of female C57/BL6 mice following exposure to an acute stressor (the Porsolt or forced swimming test). Furthermore, we evaluated the effects of the glucocorticoid receptor (GR) antagonist mifepristone on the cell death induced by the Porsolt test. Forced swimming induced selective apoptotic cell death in 1 week-old cells, an effect that was abolished by pretreatment with mifepristone. Independent of its antagonism of GR, mifepristone also induced an increase in the percentage of 1 week-old cells that were AMPA(+). We propose that the induction of AMPA receptor expression in immature cells may mediate the neuroprotective effects of mifepristone, in line with the proposed antidepressant effects of AMPA receptor potentiators.

Antidepressant and proneurogenic influence of environmental enrichment in mice: protective effects vs recovery.

Physical-cognitive activity has long-lasting beneficial effects on the brain and on behavior. Environmental enrichment (EE) induces brain activity known to influence the behavior of mice, as measured in learned helplessness paradigms (forced swim test), and neurogenic cell populations in the hippocampal dentate gyrus. However, it is not completely clear whether the antidepressant and proneurogenic effects of EE are different in animals that are naive or pre-exposed to the stress inducing helplessness, and if this depends on the type of stressor. It also remains unclear whether differential effects are exerted on distinct neurogenic subpopulations. We found that EE has a protective effect in adult female mice (C57BL/6J) when exposed twice to the same stressor (forced swim test) but it has no influence on recovery. The repeated exposure to this stressor was analyzed together with the effects of EE on different neurogenic populations distinguished by age and differentiation state. Younger cells are more sensitive and responsive to the conditions, both the positive and negative effects. These results are relevant to identify the cell populations that are the targets of stress, depression, and enrichment, and that form part of the mechanism responsible for mood dysfunctions.

Multiple birthdating analyses in adult neurogenesis: a line-up of the usual suspects.

Analyzing the variation in different subpopulations of newborn neurons is central to the study of adult hippocampal neurogenesis. The acclaimed working hypothesis that different subpopulations of newborn, differentiating neurons could be playing different roles arouses great interest. Therefore, the physiological and quantitative analysis of neuronal subpopulations at different ages is critical to studies of neurogenesis. Such approaches allow cells of different ages to be identified by labeling them according to their probable date of birth. Until very recently, only neurons born at one specific time point could be identified in each experimental animal. However the introduction of different immunohistochemically compatible markers now enables multiple subpopulations of newborn neurons to be analyzed in the same animal as in a line-up, revealing the relationships between these subpopulations in response to specific influences or conditions. This review summarizes the current research carried out using these techniques and outlines some of the key applications.

Differential regulation of the variations induced by environmental richness in adult neurogenesis as a function of time: a dual birthdating analysis.

Adult hippocampal neurogenesis (AHN) augments after environmental enrichment (EE) and it has been related to some of the anxiolytic, antidepressant and neuroprotective effects of EE. Indeed, it has been suggested that EE specifically modulates hippocampal neurogenic cell populations over the course of time. Here we have used dual-birthdating to study two subpopulations of newborn neuron in mice (Mus musculus): those born at the beginning and at the end of enrichment. In this way, we demonstrate that while short-term cell survival is upregulated after an initial 1 week period of enrichment in 2 month old female mice, after long-term enrichment (2 months) neither cell proliferation nor the survival of the younger newly born cell populations are distinguishable from that observed in non-enriched control mice. In addition, we show that the survival of older newborn neurons alone (i.e. those born at the beginning of the enrichment) is higher than in controls, due to the significantly lower levels of cell death. Indeed, these parameters are rapidly adjusted to the sudden cessation of the EE conditions. These findings suggest both an early selective, long-lasting effect of EE on the neurons born in the initial stages of enrichment, and a quick response when the environment again becomes impoverished. Therefore, EE induces differential effects on distinct subpopulations of newborn neurons depending on the age of the immature cells and on the duration of the EE itself. The interaction of these two parameters constitutes a new, specific regulation of these neurogenic populations that might account for the long-term enrichment's behavioral effects.

Blockade of insulin-like growth factor-I has complex effects on structural plasticity in the hippocampus.

Physical exercise enhances adult neurogenesis in the hippocampus. Running induces the uptake of blood insulin-like growth factor-I (IGF-I) into the brain. A causal link between these two phenomena has been reported; running-induced increases in adult neurogenesis can be blocked by peripheral infusion of anti-IGF-I. Running also alters other aspects of hippocampal structure, including dendritic spine density. It remains unclear, however, whether these effects are also mediated through an IGF-I mechanism. To examine this possibility, we blocked peripheral IGF-I and examined adult neurogenesis and dendritic spine density in treadmill running mice. Two weeks of running resulted in an increase in cell proliferation in the dentate gyrus (DG) as well as an increase in dendritic spine density on DG granule cells and basal dendrites of CA1 pyramidal neurons, while having no effect on apical or basal dendritic spine density of CA3 pyramidal neurons. IGF-I blockade reduced cell proliferation in both sedentary and running mice, but by contrast, this treatment had no effect on granule cell or CA3 pyramidal cell dendritic spine density in sedentary or running mice. However, IGF-I antibody treatment seemed to prevent the running-induced increase in spine density on basal dendrites of CA1 pyramidal cells. These results suggest that IGF-I exerts a complex influence over hippocampal structure and that its effects are not restricted to those induced by running.

Growth factors as mediators of exercise actions on the brain.

Physical exercise has long been recognized as highly beneficial for brain and body health. The molecular mechanisms responsible for translation of exercise stimuli in the brain have claimed attention due to mounting evidence for the neuroprotective actions of the exercise and its positive effects in preventing both ageing and neurodegenerative disease. These molecular mediators are currently under investigation with new tools able to yield deep insights into the neurobiology of exercise. In the present work we focus on the evidence pertaining to the mediation of exercise effects by insulin-like growth factor 1 (IGF1), as recent reports suggest that this growth factor shows brain area-specific, temporal rank-sensitive, and behavioural task-dependent features in response to exercise.