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Clinical evidence indicates that serotonin-1A receptor (5-HT1AR) gene polymorphisms are associated with anxiety disorders and deficits in cognition. In animal models, exercise (Ex) and environmental enrichment (EE) can change emotionality-related behaviours, as well as enhance some aspects of cognition and hippocampal neurogenesis. We investigated the effects of Ex and EE (which does not include running wheels) on cognition and anxiety-like behaviours in wild-type (WT) and 5-HT1AR knock-out (KO) mice. Using an algorithm-based classification of search strategies in the Morris water maze, we report for we believe the first time that Ex increased the odds for mice to select more hippocampal-dependent strategies. In the retention probe test, Ex (but not EE) corrected long-term spatial memory deficits displayed by KO mice. In agreement with these findings, only Ex increased hippocampal cell survival and BDNF protein levels. However, only EE (but not Ex) modified anxiety-like behaviours, demonstrating dissociation between improvements in cognition and innate anxiety. EE enhanced hippocampal cell proliferation in WT mice only, suggesting a crucial role for intact serotonergic signalling in mediating this effect. Together, these results demonstrate differential effects of Ex vs EE in a mouse model of anxiety with cognitive impairment. Overall, the 5-HT1AR does not seem to be critical for those behavioural effects to occur. These findings will have implications for our understanding of how Ex and EE enhance experience-dependent plasticity, as well as their differential impacts on anxiety and cognition.

Environmental factors interfere in the neural plasticity processes. Among these, malnutrition in the early stages of life stands out as one of the main non-genetic factors that can interfere in the morphofunctional development of the nervous system. Furthermore, sensory stimulation from enriched environments (EE) also interferes with neural development. These two factors can modify areas related to memory and learning as the hippocampus, through mechanisms related to the gene expression of brain-derived neurotrophic factor (BDNF). The BDNF may interfere in synaptic plasticity processes, such as memory. In addition, these changes in early life may affect the functioning of the hippocampus during adulthood through mechanisms mediated by BDNF. Therefore, this study aims to conduct a literature review on the effects of early malnutrition on memory and the relationship between the underlying mechanisms of EE, BDNF gene expression, and memory. In addition, there are studies that demonstrate the effect of EE reversal on exposure to changes in the functioning of hippocampal malnutrition in adult rats that were prematurely malnourished. Thereby, evidence from the scientific literature suggests that the mechanisms of synaptic plasticity in the hippocampus of adult animals are influenced by malnutrition and EE, and these alterations may involve the participation of BDNF as a key regulator in memory processes in the adult animal hippocampus.

Chronic stress causes dendritic atrophy of neurons within the hippocampus and medial prefrontal cortex. In this report, we show that chronic stress leads to reduced long-term potentiation in the pathway from the hippocampus to the medial prefrontal cortex of rats; and that such reduction is rescued by enriched housing environment. Connectivity between the hippocampus and medial prefrontal cortex is proposed to be an essential substrate that is often compromised in several psychiatric disorders. Our observations suggest that a short period of complexity in the housing environment has the potential to protect the functional integrity of this important connection. Ministry of Education (MOE) This study is supported by the Ministry of Education, Singapore (# RG 46/12) to RM.

Chronic cerebral ischemia (CCI) is one of the critical factors in the occurrence and development of vascular cognitive impairment (VCI). Apoptosis of nerve cells and changes in synaptic activity after CCI are the key factors to induce VCI. Synaptic stimulation up-regulates intraneuronal Ca2+ level through N-methyl-D-aspartic acid receptor (NMDAR) via induction of the activity-regulated inhibitor of death (AID) expression to produce active-dependent neuroprotection. Moreover, the regulation of synaptic plasticity could improve cognition and learning ability. Activin A (ActA), an exocrine protein of AID, can promote NMDAR phosphorylation and participate in the regulation of synaptic plasticity. We previously found that exogenous ActA can improve the cognitive function of rats with chronic cerebral ischemia and enhance the oxygenated glucose deprivation of intracellular Ca2+ level. In addition to NMDAR, the Wnt pathway is critical in the positive regulation of LTP through activation or inhibition. It plays an essential role in synaptic transmission and activity-dependent synaptic plasticity. The enriched environment can increase ActA expression during CCI injury. We speculated that the NMDAR-Ca2+-ActA signal pathway has a loop-acting mode, and the environmental enrichment could improve chronic cerebral ischemia cognitive impairment via NMDAR-Ca2+-ActA, Wnt/β-catenin pathway is involved in this process. For the hypothesis verification, this study intends to establish chronic cerebral hypoperfusion (CCH) rat model, explore the improvement effect of enriched environment on VCI, detect the changes in plasticity of synaptic morphology and investigate the regulatory mechanism NMDAR-Ca2+-ActA-Wnt/β-catenin signaling loop, providing a therapeutic method for the treatment of CCH.

—This review summarizes the data on plastic restructuring in animals under the influence of the enriched environment (EE). The EE includes three main components: sensory stimulation, social stimulation, and physical activity. Each of these components has its own peculiarities and specifics of influence but all of them have positive effects on the organism. The first part of this review summarizes the molecular-cellular mechanisms of EE influence on neurogenesis, neurotrophic factors, and synaptogenesis. The second part presents data on the effects of EE on plastic restructuring of synaptic transmission in hippocampal neurons, induction and maintenance of long-term potentiation and long-term depression of responses of neurons in the dentate gyrus and CA1 area of hippocampus, the neurochemical mechanisms of the EE influence, and the results of the use of transgenic animals. In the third and fourth parts, we consider the influence of EE on learning and memory in normal animals and in animals with disturbances of cognitive, emotional, and motor functions.

The decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Lifestyle interventions can improve brain function during aging, but their influence on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, we here show that experiencing a stimulus-rich environment counteracts age-related DNA methylation changes in the hippocampal dentate gyrus of mice. Specifically, environmental enrichment prevented the aging-induced CpG hypomethylation at target sites of the methyl-CpG-binding protein Mecp2, which is critical to neuronal function. The genes at which environmental enrichment counteracted aging effects have described roles in neuronal plasticity, neuronal cell communication and adult hippocampal neurogenesis and are dysregulated with age-related cognitive decline in the human brain. Our results highlight the stimulating effects of environmental enrichment on hippocampal plasticity at the level of DNA methylation and give molecular insights into the specific aspects of brain aging that can be counteracted by lifestyle interventions., Decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Here the authors provide evidence that environmental enrichment delays age-related DNA methylation alterations in the mouse hippocampus.

When an object conditioned stimulus (CS) is paired with a food unconditioned stimulus (US), anticipatory goal-directed action directed at the US location (goal tracking) is accompanied by behavior directed at the object CS (sign tracking). Sign-tracking behavior appears to be compulsive and habit-like and predicts increased vulnerability to the addictive potential of drugs in animal models. A large body of the literature also suggests that environmental enrichment protects against the development of addiction-prone phenotypes. Thus, we investigated whether compulsive-like sign tracking develops in environmentally enriched rats trained directly in their enriched home environment. We demonstrate that adolescent enriched-housed male Sprague-Dawley rats readily sign track a 5% ethanol bottle CS in their home environment and at a rate higher than adolescent standard-housed rats. We also show that enriched adolescent rats sign track less than enriched adult-trained rats and that acute isolation stress affects sign- and goal-tracking performance of adolescents and adults differently. Sign tracking increased more in the adult than the adolescent rats. Whereas the younger rats showed a decrease in goal tacking after the final stressor manipulation, the adults showed increased goal tracking. Our results are consistent with recent studies, which suggest that although sign tracking performance is compulsive-like, it is not as inflexible and habit-like as previously assumed. Testing in an enriched home environment with object CSs having greater affordance than "neutral" lever CSs may provide greater ecological relevance for investigating the development and expression of adaptive and compulsive-like behaviors in translational research.

Gestational stress can increase postpartum depression in women. To treat maternal depression, fluoxetine (FLX) is most commonly prescribed. While FLX may be effective for the mother, at high doses it may have adverse effects on the fetus. As environmental enrichment (EE) can reduce maternal stress effects, we hypothesized that a subthreshold dose of FLX increases the impact of EE to reduce anxiety and depression-like behavior in postpartum dams exposed to gestational stress. We evaluated this hypothesis in mice and to assess underlying mechanisms we additionally measured hypothalamic–pituitary–adrenal (HPA) axis function and brain levels of the hormone oxytocin, which are thought to be implicated in postpartum depression. Gestational stress increased anxiety- and depression-like behavior in postpartum dams. This was accompanied by an increase in HPA axis function and a decrease in whole-brain oxytocin levels in dams. A combination of FLX and EE remediated the behavioral, HPA axis and oxytocin changes induced by gestational stress. Central administration of an oxytocin receptor antagonist prevented the remediating effect of FLX + EE, indicating that brain oxytocin contributes to the effect of FLX + EE. These findings suggest that oxytocin is causally involved in FLX + EE mediated remediation of postpartum stress-related behaviors, and HPA axis function in postpartum dams.

Synaptic deficit-induced excitation and inhibition (E/I) imbalance have been implicated in the pathogenesis of schizophrenia. Using in vivo two-photon microscopy, we examined the dynamic plasticity of dendritic spines of pyramidal neurons (PNs) and "en passant" axonal bouton of parvalbumin-expressing interneurons (PVINs) in the frontal association (FrA) cortex in two adolescent mouse models with schizophrenia-like behaviors. Simultaneous imaging of PN dendritic spines and PV axonal boutons showed that repeated exposure to N-methyl-D-aspartate receptor (NMDAR) antagonist MK801 during adolescence disrupted the normal developmental balance of excitatory and inhibitory synaptic structures. This MK801-induced structural E/I imbalance significantly correlated with animal recognition memory deficits and could be ameliorated by environmental enrichment (EE). In addition, selective chemogenetic activation of PVINs in the FrA mimicked the effects of EE on both synaptic plasticity and animal behavior, while selective inhibition of PVIN abolished EE's beneficial effects. Electrophysiological recordings showed that chronic MK801 treatment significantly suppressed the frequency of mEPSC/mIPSC ratio of layer (L) 2/3 PNs and significantly reduced the resting membrane potential of PVINs, the latter was rescued by selective activation of PVINs. Such manipulations of PVINs also showed similar effects in PV-Cre; ErbB4fl/fl animal model with schizophrenia-like behaviors. EE or selective activation of PVINs in the FrA restored behavioral deficits and structural E/I imbalance in adolescent PV-Cre; ErbB4fl/fl mice, while selective inhibition of PVINs abolished EE's beneficial effects. Our findings suggest that the PVIN activity in the FrA plays a crucial role in regulating excitatory and inhibitory synaptic structural dynamics and animal behaviors, which may provide a potential therapeutic target for schizophrenia treatment.

Adverse environments during early life may lead to different neurophysiological and behavioral consequences, including depression and learning and memory deficits that persist into adulthood. Previously, we demonstrated that exposure to an enriched environment during adolescence mitigates the cognitive impairment observed after maternal separation in a task-specific manner. However, underlying neural mechanisms are still not fully understood. The current study examines the effects of neonatal maternal separation (MS) and postweaning environmental enrichment (EE) on spatial learning and memory performance in a short version of the Barnes Maze, active and passive behaviors in the forced swim test, and on TrkB/BDNF receptor expression in the hippocampus. Our results revealed that MS impaired acquisition learning and that enriched rats performed better than non-enriched rats in acquisition trials, regardless of early conditions. During the probe, enriched-housed rats demonstrated better performance than those reared in standard conditions. No significant differences between groups were found in the forced swim test. Both MS and EE increase full-length TrkB expression, and the combination of MS and EE treatment caused the highest levels of this protein expression. Similarly, truncated TrkB expression was higher in the MS/EE group. Animal facility rearing (AFR) non-enriched groups present the lowest activation of phosphorylated Erk, a canonical downstream kinase of TrkB signaling. Taken together, our results demonstrate the importance of enriched environment as an intervention to ameliorate the effects of maternal separation on spatial learning and memory. TrkB/BDNF signaling could mediate neuroplastic changes related to learning and memory during exposure to enriched environment.

Rationale: Stroke is a leading cause of adult disability worldwide, but no drug provides functional recovery during the repair phase. Accumulating evidence demonstrates that environmental enrichment (EE) promotes stroke recovery by enhancing network excitability. However, the complexities of utilizing EE in a clinical setting limit its translation. Methods: We used multifaceted approaches combining electrophysiology, chemogenetics, optogenetics, and floxed mice in a mouse photothrombotic stroke model to reveal the key target of EE-mediated stroke recovery. Results: EE reduced tonic gamma-aminobutyric acid (GABA) inhibition and facilitated phasic GABA inhibition in the peri-infarct cortex, thereby promoting network excitability and stroke recovery. These beneficial effects depended on GAT-1, a GABA transporter regulating both tonic and phasic GABA signaling, as EE positively regulated GAT-1 expression, trafficking, and function. Furthermore, GAT-1 was necessary for EE-induced network plasticity, including structural neuroplasticity, input synaptic strengthening in the peri-infarct cortex, output synaptic strengthening in the corticospinal tract, and sprouting of uninjured corticospinal axons across the midline into the territory of denervated spinal cord, and functional recovery from stroke. Moreover, restoration of GAT-1 function in the peri-infarct cortex by its overexpression showed similar beneficial effects on stroke recovery as EE exposure. Conclusion: GAT-1 is a key molecular substrate of the effects of EE on network excitability and consequent stroke recovery and can serve as a novel therapeutic target for stroke treatment during the repair phase.

The mechanisms of long-term memory formation and ways to improve it (in the case of its impairment) remain an extremely difficult problem yet to be solved. Over the recent years, much attention has been paid to microRNAs in this regard. MicroRNAs are unique endogenous non-coding RNAs about 22 nucleotides in length; each can regulate translation of hundreds of messenger RNA targets, thereby controlling entire gene networks. MicroRNAs are widely represented in the central nervous system. A large number of studies are currently being conducted to investigate the role of microRNAs in the brain functioning. A number of microRNAs have been shown to be involved in the process of synaptic plasticity, as well as in the long-term memory formation. Disruption of microRNA biogenesis leads to significant cognitive dysfunctions. Moreover, impaired microRNA biogenesis is one of the causes of the pathogenesis of mental disorders, neurodegenerative illnesses and senile dementia, which are often accompanied by deterioration in the learning ability and by memory impairment. Optimistic predictions are made that microRNAs can be used as targets for therapeutic treatment and for diagnosing the above pathologies. The importance of applications related to microRNAs significantly raises interest in studying their functions in the brain. Thus, this review is focused on the role of microRNAs in cognitive processes. It describes microRNA biogenesis and the role of miRNAs in the regulation of gene expression, as well as the latest achievements in studying the functional role of microRNAs in learning and in long-term memory formation, depending on the activation or inhibition of their expression. The review presents summarized data on the effect of impaired microRNA biogenesis on long-term memory formation, including those associated with sleep deprivation. In addition, analysis is provided of the current literature related to the prospects of improving cognitive processes by influencing microRNA biogenesis via the use of CRISPR/Cas9 technologies and active mental and physical exercises.Механизмы формирования долговременной памяти и способы ее улучшения (в случае нарушения) остаются сложнейшей нерешенной проблемой. В последние годы большое внимание в этой связи уделяется микроРНК. МикроРНК являются уникальными эндогенными некодирующими РНК длиной около 22 нуклеотидов, каждая из которых может регулировать трансляцию сотен матричных РНК, тем самым управляя целыми сетями генов. МикроРНК широко представлены в центральной нервной системе. В настоящее время значительное количество исследований посвящено изучению роли микроРНК в функционировании мозга. Показано, что целый ряд микроРНК вовлечен в процесс синаптической пластичности, а также в формирование долговременной памяти. При этом нарушение биогенеза микроРНК приводит к значительным когнитивным дисфункциям. Более того, нарушение биогенеза микроРНК является одной из причин патогенеза заболеваний, связанных с психическими расстройствами, нейродегенеративными патологиями и старческой деменцией, которые часто сопровождаются ухудшением способности к обучению и нарушением памяти. Высказываются оптимистичные прогнозы, что микроРНК могут быть использованы в качестве мишеней для терапевтического лечения и диагностики данных патологий. Важное прикладное значение микроРНК увеличивает интерес к изучению их функций в работе мозга. Представленный обзор посвящен роли микроРНК в когнитивных процессах. Описаны биогенез микроРНК и роль микроРНК в регуляции экспрессии генов. Рассмотрены последние достижения в изучении функциональной роли микроРНК в обучении и формировании долговременной памяти, в зависимости от активации или ингибирования их экспрессии, и о влиянии нарушения биогенеза микроРНК на формирование долговременной памяти. Небольшой раздел посвящен влиянию депривации сна на когнитивные процессы, зависимые от микроРНК. Кроме того, приведен анализ текущей литературы, связанной с перспективами улучшения когнитивных функций посредством влияния на биогенез микроРНК путем применения CRISPR/Cas9 технологий и активных умственных и физических нагрузок.

Social and environmental factors impact cancer and energy balance profoundly. Years ago, our lab established the existence of a novel brain-fat interaction we termed the "hypothalamic-sympathoneural-adipocyte (HSA) axis", through which complex environmental stimuli provided by an enriched environment regulate body composition, energy balance, and development of cancer. We have spent a significant portion of the past decade to further characterize the broad health benefits of an enriched environment (for example, leanness, enhanced immune function, and cancer resistance), and to identify mediators in the brain and periphery along the HSA axis. This review summarizes our recent work regarding the interface between endocrinology, immunology, cancer biology, aging, and neuroscience. We will discuss the interplay between these systemic phenomena and how the HSA axis can be targeted for regulation of cancer and aging.

Neuroinflammation and oxidative stress are major mechanisms of post-stroke cognitive impairment (PSCI) neural injury and decreased spatial and memory capacity. Enriched environment (EE) is an effective method to improve cognitive dysfunction. However, the regulation by EE of neuroinflammation, oxidative stress and associated mechanisms in animal models remains unclear.In this study, a rat PSCI model was established by middle cerebral artery occlusion (MCAO). Rats were randomly divided into the control group, standard environment (SE) group and EE group for 28 days. A Morris water-maze test was used to measure cognitive function at 7, 14 and 28 days after MCAO. Rats were sacrificed on the 28th day. Quantitative PCR, immunohistochemistry and ELISA were respectively used to detect mRNA expression of NF-E2-related factor 2 (Nrf2) and Nrf2 response genes, the expression of IL-1β and levels of proinflammatory cytokines in the hippocampus.EE improved mNSS scores and cognitive ability in PSCI rats. EE increased mRNA expression of the Nrf2 and Nrf2 response genes, including heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1). EE significantly decreased the level of malondialdehyde (MDA) and increased the levels of superoxide dismutase (SOD) and glutathione (GSH), in the hippocampus of PSCI rats. EE reduced the number of IL-1β positive cells in the hippocampus, and IL-1β levels in the hippocampus and serum. EE increased GFAP-positive astrocytes in the hippocampus, and BDNF levels in the hippocampus and serum.EE can improve cognitive function in PSCI rats by inhibiting neuroinflammation and oxidative stress.

The structure of neurons in the central auditory system is vulnerable to various kinds of acoustic exposures during the critical postnatal developmental period. Here we explored long-term effects of exposure to an acoustically enriched environment (AEE) during the third and fourth weeks of the postnatal period in rat pups. AEE consisted of a spectrally and temporally modulated sound of moderate intensity, reinforced by a behavioral paradigm. At the age of 3-6 months, a Golgi-Cox staining was used to evaluate the morphology of neurons in the inferior colliculus (IC), the medial geniculate body (MGB), and the auditory cortex (AC). Compared to controls, rats exposed to AEE showed an increased mean dendritic length and volume and the soma surface in the external cortex and the central nucleus of the IC. The spine density increased in both the ventral and dorsal divisions of the MGB. In the AC, the total length and volume of the basal dendritic segments of pyramidal neurons and the number and density of spines on these dendrites increased significantly. No differences were found on apical dendrites. We also found an elevated number of spines and spine density in non-pyramidal neurons. These results show that exposure to AEE during the critical developmental period can induce permanent changes in the structure of neurons in the central auditory system. These changes represent morphological correlates of the functional plasticity, such as an improvement in frequency tuning and synchronization with temporal parameters of acoustical stimuli.

Impaired cognitive functioning is a core feature of schizophrenia, and is hypothesized to be due to myelination as well as interneuron defects during adolescent prefrontal cortex (PFC) development. Here we report that in the apomorphine-susceptible (APO-SUS) rat model, which has schizophrenia-like features, a myelination defect occurred specifically in parvalbumin interneurons. The adult rats displayed medial PFC (mPFC)-dependent cognitive inflexibility, and a reduced number of mature oligodendrocytes and myelinated parvalbumin inhibitory axons in the mPFC. In the developing mPFC, we observed decreased myelin-related gene expression that persisted into adulthood. Environmental enrichment applied during adolescence restored parvalbumin interneuron hypomyelination as well as cognitive inflexibility. Collectively, these findings highlight that impairment of parvalbumin interneuron myelination is related to schizophrenia-relevant cognitive deficits., Dysfunction of GABAergic neurons in the prefrontal cortex has been reported in schizophrenia. Here, the authors use the apomorphine-susceptible rat, which displays some schizophrenia-like behaviors, and show that interneurons in the medial prefrontal cortex are hypomyelinated, which may contribute to this behavioral phenotype.

Adverse experiences early in life are associated with the development of psychiatric illnesses. The hippocampus is likely to play pivotal role in generating these effects: it undergoes significant development during childhood and is extremely reactive to stress. In rodent models, stress in the pre-pubertal period impairs adult hippocampal neurogenesis (AHN) and behaviours which rely on this process. In normal adult animals, environmental enrichment (EE) is a potent promoter of AHN and hippocampal function. Whether exposure to EE during adolescence can restore normal hippocampal function and AHN following pre-pubertal stress (PPS) is unknown. We investigated EE as a treatment for reduced AHN and hippocampal function following PPS in a rodent model. Stress was administered between post-natal days (PND) 25–27, EE from PND 35 to early adulthood, when behavioural testing and assessment of AHN took place. PPS enhanced fear reactions to a conditioned stimulus (CS) following a trace fear protocol and reduced the survival of 4-week-old adult-born neurons throughout the adult hippocampus. Furthermore, we show that fewer adult-born neurons were active during recall of the CS stimulus following PPS. All effects were reversed by EE. Our results demonstrate lasting effects of PPS on the hippocampus and highlight the utility of EE during adolescence for restoring normal hippocampal function. EE during adolescence is a promising method of enhancing impaired hippocampal function resulting from early life stress, and due to multiple benefits (low cost, few side effects, widespread availability) should be more thoroughly explored as a treatment option in human sufferers of childhood adversity.

Traumatic brain injury (TBI) during critical periods of early-life brain development can affect the normal formation of brain networks responsible for a range of complex social behaviors. Because of the protracted nature of brain and behavioral development, deficits in cognitive and socioaffective behaviors may not become evident until late adolescence and early adulthood, when such skills are expected to reach maturity. In addition, multiple pre- and post-injury factors can interact with the effects of early brain insult to influence long-term outcomes. In recent years, with advancements in magnetic-resonance-based neuroimaging techniques and analysis, studies of the pediatric population have revealed a link between neurobehavioral deficits, such as social dysfunction, with white matter damage. In this review, in which we focus on contributions from Australian researchers to the field, we have highlighted pioneering longitudinal studies in pediatric TBI, in relation to social deficits specifically. We also discuss the use of advanced neuroimaging and novel behavioral assays in animal models of TBI in the immature brain. Together, this research aims to understand the relationship between injury consequences and ongoing brain development after pediatric TBI, which promises to improve prediction of the behavioral deficits that emerge in the years subsequent to early-life injury.

Memory is an important cognitive function in humans. Exercise and environmental enrichment (EE) exposure have positive effects on memory function via improved neurogenesis through expression of growth factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Exercise and environmental enrichment have independently been shown to increase BDNF and NGF, but the effect of the combination of these treatments has not been widely studied. This experimental study aims to analyse the effect of aerobic exercise, EE exposure, and combination of aerobic exercise and EE exposure on memory function. This study used twenty 7-month old male Wistar rats that were given treatment for 8 weeks. Memory function was tested using forced alternation Y-maze. Hippocampal expression of BDNF and NGF were also assessed. The results showed the combination group has highest performance in memory function test and also the highest level of hippocampal BDNF and NGF (P

Hypoxic damage to the developing brain due to preterm birth causes many anatomical changes, including damage to the periventricular white matter. This results in the loss of glial cells, significant disruptions in myelination, and thereby cognitive and behavioral disabilities seen throughout life. Encouragingly, these neurological morbidities can be improved by environmental factors; however, the underlying cellular mechanisms remain unknown. We found that early and continuous environmental enrichment selectively enhances endogenous repair of the developing white matter by promoting oligodendroglial maturation, myelination, and functional recovery after perinatal brain injury. These effects require increased exposure to socialization, physical activity, and cognitive enhancement of surroundings—a complete enriched environment. Using RNA-sequencing, we identified oligodendroglial-specific responses to hypoxic brain injury, and uncovered molecular mechanisms involved in enrichment-induced recovery. Together, these results indicate that myelin plasticity induced by modulation of the neonatal environment can be targeted as a therapeutic strategy for preterm birth., Hypoxic brain damage associated with premature birth causes lasting neurological impairments. Here, the authors use environmental enrichment to rescue white matter dysmaturation following hypoxia, while identifying a critical window of intervention and oligodendrocyte-specific changes in gene expression.

BACKGROUND: Prenatal ethanol exposure (PE) impairs midbrain dopaminergic (DA) neuron function, which might contribute to various cognitive and behavioral deficits, including attention deficits and increased addiction risk, often observed in individuals with fetal alcohol spectrum disorders (FASD). Currently, the underlying mechanisms for PE-induced deficits are unclear. Prenatal ethanol exposure could lead to neuroinflammation by activating microglia, which play an important role in synaptic function. In the present study, we investigated PE effects on microglial activation and DA neuron density and morphology in the ventral tegmental area (VTA). Since postnatal environmental enrichment can reduce neuroinflammation and ameliorate several PE-induced behavioral deficits, we examined if a postnatal environmental intervention strategy using neonatal handling and post-weaning complex housing could reverse PE effects on VTA DA neurons and microglia. METHODS: Pregnant rats received 0 or 6 g/kg/day ethanol with two intragastric intubation on gestation days 8 – 20. After birth, rats were reared in the standard laboratory or enriched condition. Male adult rats (8–12 weeks old) were used for immunocytochemistry. RESULTS: The results showed that PE decreased VTA DA neuron body size in standardly housed rats. Moreover, there was a significant decrease in numbers of VTA microglial branches and junctions in PE rats, suggesting morphological activation of microglia and possible neuroinflammation. The PE effects on microglia were normalized by postnatal environmental intervention, which also decreased the numbers of microglial branches and junctions in control animals, possibly via reduced stress. CONCLUSIONS: Our findings show an association between PE-induced morphological activation of microglia and impaired DA neuron morphology in the VTA. Importantly, postnatal environmental intervention rescues possible PE-induced microglial activation. These data support that environmental intervention can be effective in ameliorating cognitive and behavioral deficits associated with VTA DA neuron dysfunctions, such as attention deficits and increased addiction risk.

Environmental enrichment is known to be beneficial for cognitive improvement. In many animal models of neurological disorders and brain injury, EE has also demonstrated neuroprotective benefits in neurodegenerative diseases and in improving recovery after stroke or traumatic brain injury. The exact underlying mechanism for these phenomena has been unclear. Recent findings have now indicated that neuronal activity elicited by environmental enrichment induces Ca2+ influx in dorsal root ganglion neurons results in lasting enhancement of CREB-binding protein-mediated histone acetylation. This, in turn, increases the expression of pro-regeneration genes and promotes axonal regeneration. This mechanism associated with neuronal activity elicited by environmental enrichment-mediated pathway is one of several epigenetic mechanisms which modulate axon regeneration upon injury that has recently come to light. The other prominent mechanisms, albeit not yet directly associated with environmental enrichment, include DNA methylation/demethylation and N6-methyladenosine modification of transcripts. In this brief review, I highlight recent work that has shed light on the epigenetic basis of environmental enrichment-based axon regeneration, and discuss the mechanism and pathways involved. I further speculate on the implications of the findings, in conjunction with the other epigenetic mechanisms, that could be harness to promote axon regeneration upon injury.

Experience powerfully influences neuronal function and cognitive performance, but the cellular and molecular events underlying the experience-dependent enhancement of mental ability have remained elusive. In particular, the mechanisms that couple the external environment to the genomic changes underpinning this improvement are unknown. To address this, we have used male mice harboring an inactivating mutation of mitogen- and stress-activated protein kinase 1 (MSK1), a brain-derived neurotrophic factor (BDNF)-activated enzyme downstream of the mitogen-activated protein kinase (MAPK) pathway. We show that MSK1 is required for the full extent of experience-induced improvement of spatial memory, for the expansion of the dynamic range of synapses, exemplified by the enhancement of hippocampal long-term potentiation (LTP) and long-term depression (LTD), and for the regulation of the majority of genes influenced by enrichment. In addition, and unexpectedly, we show that experience is associated with an MSK1-dependent downregulation of key MAPK and plasticity-related genes, notably of EGR1/Zif268 and Arc/Arg3.1, suggesting the establishment of a novel genomic landscape adapted to experience. By coupling experience to homeostatic changes in gene expression MSK1, represents a prime mechanism through which the external environment has an enduring influence on gene expression, synaptic function, and cognition. SIGNIFICANCE STATEMENT Our everyday experiences strongly influence the structure and function of the brain. Positive experiences encourage the growth and development of the brain and support enhanced learning and memory and resistance to mood disorders such as anxiety. While this has been known for many years, how this occurs is not clear. Here, we show that many of the positive aspects of experience depend on an enzyme called mitogen- and stress-activated protein kinase 1 (MSK1). Using male mice with a mutation in MSK1, we show that MSK1 is necessary for the majority of gene expression changes associated with experience, extending the range over which the communication between neurons occurs, and for both the persistence of memory and the ability to learn new task rules.

Innate behavioral biases such as human handedness are a ubiquitous form of inter-individual variation that are not strictly hardwired into the genome and are influenced by diverse internal and external cues. Yet, genetic and environmental factors modulating behavioral variation remain poorly understood, especially in vertebrates. To identify genetic and environmental factors that influence behavioral variation, we take advantage of larval zebrafish light-search behavior. During light-search, individuals preferentially turn in leftward or rightward loops, in which directional bias is sustained and non-heritable. Our previous work has shown that bias is maintained by a habenula-rostral PT circuit and genes associated with Notch signaling. Here we use a medium-throughput recording strategy and unbiased analysis to show that significant individual to individual variation exists in wildtype larval zebrafish turning preference. We classify stable left, right, and unbiased turning types, with most individuals exhibiting a directional preference. We show unbiased behavior is not due to a loss of photo-responsiveness but reduced persistence in same-direction turning. Raising larvae at elevated temperature selectively reduces the leftward turning type and impacts rostral PT neurons, specifically. Exposure to conspecifics, variable salinity, environmental enrichment, and physical disturbance does not significantly impact inter-individual turning bias. Pharmacological manipulation of Notch signaling disrupts habenula development and turn bias individuality in a dose dependent manner, establishing a direct role of Notch signaling. Last, a mutant allele of a known Notch pathway affecter gene, gsx2, disrupts turn bias individuality, implicating that brain regions independent of the previously established habenula-rostral PT likely contribute to inter-individual variation. These results establish that larval zebrafish is a powerful vertebrate model for inter-individual variation with established neural targets showing sensitivity to specific environmental and gene signaling disruptions. Our results provide new insight into how variation is generated in the vertebrate nervous system.

Strongly affecting human and animal physiology, sounds and vibration are critical environmental factors whose complex role in behavioral and brain functions necessitates further clinical and experimental studies. Zebrafish are a promising model organism for neuroscience research, including probing the contribution of auditory and vibration stimuli to neurobehavioral processes. Here, we summarize mounting evidence on the role of sound and vibration in zebrafish behavior and brain function, and outline future directions of translational research in this field. With the growing environmental exposure to noise and vibration, we call for more active use of zebrafish models for probing neurobehavioral and bioenvironmental consequences of acute and long-term exposure to sounds and vibration in complex biological systems.

Environmental enrichment is used to increase social and physical stimulation for animals in captivity which can lead to enhanced cognition. Fundamental to the positive effect enrichment has on the brain is that it provides opportunities for captive animals to recognize and discriminate between different stimuli in the environment. In the wild, being able to discriminate between novel or familiar stimuli has implications for survival, for example finding food, hiding from predators, or even choosing a mate. The novel object recognition (NOR) test is a cognitive task that is used extensively in the rodent literature to assess object recognition and memory, where the amount of time an animal spends exploring a novel vs. familiar object is quantified. Enrichment has been shown to enhance object recognition in rodents. More recently, the use of the NOR test has been applied to another animal model, zebrafish (Danio rerio), however, the effects of enrichment have not yet been explored. In the current study we looked at the effects of enrichment on object recognition in zebrafish using the NOR test. Adult zebrafish were housed in either enriched conditions (gravel substrate, plastic plants, shelter, heater and a filter) or plain conditions (heater and filter only) for 6 months before behavioral NOR tests were conducted. Enriched fish showed a preference for a novel object over a familiar one at a distance but did not show a preference during close inspection. Control fish did not show a preference at either distance. Our results suggest that enrichment can enhance zebrafish ability to discriminate between novel and familiar objects, but distance from the object may be an important factor. Future research is needed to determine whether any enhancements in object recognition are a result of an increase in sensory stimulation from being reared with enrichment, or whether it is due to a reduction in stress reactivity.

Senescence affects various aspects of sleep, and it remains unclear how sleep-related neuronal network activity is altered by senescence. Here, we recorded local field potential signals from multiple brain regions covering the forebrain in young (10-week-old) and aged (2-year-old) mice. Interregional LFP correlations across these brain regions showed smaller differences between awake and sleep states in aged mice. Multivariate analyses with machine learning algorithms with uniform manifold approximation and projection (UMAP) and robust continuous clustering (RCC) demonstrated that these LFP correlational patterns in aged mice less represented awake/sleep states than those in young mice. By housing aged mice in an enriched environment, the LFP patterns were restored to those observed in young mice. Our results demonstrate senescence-induced changes in neuronal activity at the network level and provide insight into the prevention of pathological symptoms associated with sleep disturbance in senescence.

Background: Cocaine use disorder is associated with compulsive drug-seeking and drug-taking, whereas relapse may be induced by several factors, including stress, drug-related places, people, and cues. Recent observations strongly support the involvement of the N-methyl-D-aspartate (NMDA) receptors in cocaine use disorders and abstinence, whereas withdrawal in different environments may affect the intensification of relapse. Methods: The aim of this study was to examine the GluN2B subunit expression and its association with the postsynaptic density protein 95 (PSD95) in several brain structures in rats with a history of cocaine self-administration and housed either in an enriched environment or in an isolated condition. Furthermore, a selective antagonist of the GluN2B subunit—CP 101,606 (10 and 20 mg/kg) administered during exposure to cocaine or a drug-associated conditional stimulus (a cue) was used to evaluate seeking behavior in rats. Results: In rats previously self-administering cocaine, we observed an increase in the GluN2B expression in the total homogenate from the dorsal hippocampus under both enriched environment and isolation. Cocaine abstinence under isolation conditions increased the GluN2B and GluN2B/PSD95 complex levels in the PSD fraction of the prelimbic cortex in rats previously self-administering cocaine. Administration of CP 101,606 attenuated cue-induced cocaine-seeking behavior only in isolation-housed rats. Conclusion: In summary, in this study we showed region-specific changes in both the expression of GluN2B subunit and NMDA receptor trafficking during cocaine abstinence under different housing conditions. Furthermore, we showed that the pharmacological blockade of the GluN2B subunit may be useful in attenuating cocaine-seeking behavior.

Perioperative neurocognitive disorders (PND) encompass short-term delirium and long-term cognitive dysfunction. Aging increases the susceptibility to PND, yet the neural mechanism is not known. In this study, we monitored the dynamic changes of neuronal activity in the prelimbic cortex before and after surgery. We found that anesthesia combined with surgery, but not anesthesia alone, induced a prolonged decrease in neuronal activity during the post-operation period in the aged mice, but not in the adult mice. The prolonged decrease in neuronal activity was accompanied by surgery-induced microglial activation and proinflammatory cytokines expression. Importantly, we found that the enriched environment (EE) completely prevented both the prolonged neural inhibition and neuroinflammation, and improved cognitive function in the aged mice. These results indicate that the prolonged neural inhibition correlated to PND and that EE before the surgery could effectively alleviate the surgery- induced cognitive dysfunction.

Sensation seeking is a multidimensional phenotype that predicts the development of drug addiction in humans and addiction-like drug seeking in rodents. Several lines of evidence suggest that chronic stress increases sensation seeking and addiction-like drug seeking through common genetic mechanisms. Discovery and characterization of these mechanisms would reveal how chronic stress interacts with the genome to influence sensation seeking and how drugs of abuse hijack these fundamental reward mechanisms to drive addiction. To this end, we tested the hypothesis that chronic isolation housing stress (relative to environmental enrichment) influences operant sensation seeking as a function of strain, sex, or their interaction. To determine if the BXD recombinant inbred panel could be used to identify genetic and epigenetic mechanisms underlying any identified gene-by-environment interactions, we used mice from the two BXD founder strains. Following 10 weeks of differential housing, we assessed operant sensation seeking using several reinforcement schedules. The primary finding from this study was that DBA/2J but not C57BL/6J mice were significantly vulnerable to an isolation-induced increase (relative to environmental enrichment) in sensation seeking during extinction when the sensory reward was no longer available; this effect was significantly more robust in females. These data reveal a previously unknown isolation-induced effect on extinction of operant sensation seeking that is sex-dependent, addiction-relevant, and that can be dissected using the BXD recombinant inbred panel.

Enriched environment (EE) is an important animal experimental paradigm to decipher gene-environment interaction. It is thought to be efficient in aiding recovery from certain metabolism disorders or cognitive impairments. Recently, the effects of EE during adolescence in mice gradually draw much attention. We first established an EE model in adolescent mice, dissected lipid metabolism, and further examined baseline level of anxiety and depression by multiple behavioral tests, including open field test (OFT), elevated zero maze (EZM), tail suspension test (TST), and forced swimming test (FST). EE mice exhibited lower weights, lower cholesterol than standard housing (SH) mice. Behaviorally, EE mice traveled more distance and had higher velocity than SH mice in OFT and EZM. Besides, EE mice showed reduced anxiety levels in OFT and EZM. Furthermore, EE mice also had less immobility time than SH mice in TST and FST. Thus, these results suggest that EE during adolescence has metabolic and behavioral benefits in mice.

Enriched environment (EE) is a complex containing social, cognitive, and motor stimuli. Exposure to EE can promote functional recovery after ischemia/reperfusion (I/R) injury. However, the underlying mechanisms remained unclear. Pyroptosis has recently been identified and demonstrated a significant role in ischemic stroke. The purpose of this study was to explore the effect of EE on neuronal pyroptosis after cerebral I/R injury. In the current study, middle cerebral artery occlusion/reperfusion (MCAO/R) was applied to establish the cerebral I/R injury model. Behavior tests including the modified Neurological Severity Scores (mNSS) and the Morris Water Maze (MWM) were performed. The infarct volume was evaluated by Nissl staining. To evaluate the levels of pyroptosis-related proteins, the levels of GSDMD-N and nod-like receptor protein 1/3 (NLRP1/3) inflammasome-related proteins were examined. The mRNA levels of IL-1β and IL-18 were detected by Quantitative Real-Time PCR (qPCR). The secretion levels of IL-1β and IL-18 were analyzed by ELISA. Also, the expression of p65 and p-p65 were detected. The results showed that EE treatment improved functional recovery, reduced infarct volume, attenuated neuronal pyroptosis after cerebral I/R injury. EE treatment also suppressed the activities of NLRP1/NLRP3 inflammasomes. These may be affected by inhabiting the NF-κB p65 signaling pathway. Our findings suggested that neuronal pyroptosis was probably the neuroprotective mechanism that EE treatment rescued neurological deficits after I/R injury.

Environmental enrichment produces beneficial effects in the brain at genetic, molecular, cellular and behavior levels, and has long been studied as a therapeutic intervention for a wide variety of neurological disorders. However, the complexity of applying a robust environmental enrichment paradigm makes clinical use difficult. Accordingly, there has been increased interest in developing environmental enrichment mimetics, also known as enviromimetics. Here we review the benefits of environmental enrichment for migraine treatment, and discuss the potential of using extracellular vesicles derived from interferon gamma-stimulated dendritic cells as an effective mimetic.

Significance Stroke is the second leading cause of death and the most frequent cause of disability in adults. After stroke, most ischemic neurons die and a few neurons live, leading to brain dysfunction; yet, genes involved in both neuronal survival and death remain poorly understood. Here, we found that the activity-dependent transcription factor Npas4 is essential for acquisition of neuronal tolerance to ischemia. Moreover, a systematic search for Npas4-downstream genes identified Gem, which encodes Ras-related small GTPase that mediates neuroprotective effects of Npas4. Gem suppresses the membrane localization of voltage-gated Ca2+ channels to inhibit excess Ca2+ influx, thereby protecting neurons from excitotoxic death. Our findings suggest that Gem expression via Npas4 promotes neuroprotection and neuroplasticity in injured and healthy brains, respectively., Ischemic stroke, which results in loss of neurological function, initiates a complex cascade of pathological events in the brain, largely driven by excitotoxic Ca2+ influx in neurons. This leads to cortical spreading depolarization, which induces expression of genes involved in both neuronal death and survival; yet, the functions of these genes remain poorly understood. Here, we profiled gene expression changes that are common to ischemia (modeled by middle cerebral artery occlusion [MCAO]) and to experience-dependent activation (modeled by exposure to an enriched environment [EE]), which also induces Ca2+ transients that trigger transcriptional programs. We found that the activity-dependent transcription factor Npas4 was up-regulated under MCAO and EE conditions and that transient activation of cortical neurons in the healthy brain by the EE decreased cell death after stroke. Furthermore, both MCAO in vivo and oxygen-glucose deprivation in vitro revealed that Npas4 is necessary and sufficient for neuroprotection. We also found that this protection involves the inhibition of L-type voltage-gated Ca2+ channels (VGCCs). Next, our systematic search for Npas4-downstream genes identified Gem, which encodes a Ras-related small GTPase that mediates neuroprotective effects of Npas4. Gem suppresses the membrane localization of L-type VGCCs to inhibit excess Ca2+ influx, thereby protecting neurons from excitotoxic death after in vitro and in vivo ischemia. Collectively, our findings indicate that Gem expression via Npas4 is necessary and sufficient to promote neuroprotection in the injured brain. Importantly, Gem is also induced in human cerebral organoids cultured under an ischemic condition, revealing Gem as a new target for drug discovery.

Lifestyle is one of the most powerful instruments shaping mankind; the lifestyle includes many aspects of interactions with the environment, from nourishment and education to physical activity and quality of sleep. All these factors taken in complex affect neuroplasticity and define brain performance and cognitive longevity. In particular, physical exercise, exposure to enriched environment and dieting act through complex modifications of microglial cells, which change their phenotype and modulate their functional activity thus translating lifestyle events into remodelling of brain homoeostasis and reshaping neural networks ultimately enhancing neuroprotection and cognitive longevity.

The opioid epidemic is a rapidly evolving societal issue driven, in part, by a surge in synthetic opioid use. A rise in fentanyl use among pregnant women has led to a 40-fold increase in the number of perinatally-exposed infants in the past decade. These children are more likely to develop mood- and somatosensory-related conditions later in life, suggesting that fentanyl may permanently alter neural development. Here, we examined the behavioral and synaptic consequences of perinatal fentanyl exposure in adolescent male and female C57BL/6J mice and assessed the therapeutic potential of environmental enrichment to mitigate these effects. Dams were given ad libitum access to fentanyl (10 µg/mL, per os) across pregnancy and until weaning (PD 21). Perinatally-exposed adolescent mice displayed hyperactivity (PD 45), enhanced sensitivity to anxiogenic environments (PD 46), and sensory maladaptation (PD 47) – sustained behavioral effects that were completely normalized by environmental enrichment (PD 21-45). Additionally, environmental enrichment normalized the fentanyl-induced changes in the frequency of miniature excitatory postsynaptic currents of layer 2/3 neurons in the primary somatosensory cortex (S1). We also demonstrate that fentanyl impairs short- and long-term potentiation in S1 layer 2/3 neurons which, instead, exhibit a sustained depression of synaptic transmission that is restored by environmental enrichment. On its own, environmental enrichment suppressed long-term depression of control S1 neurons from vehicle-treated mice subjected to standard housing conditions. These results demonstrate that the lasting effects of fentanyl can be ameliorated with a non-invasive intervention introduced during early development.Significance StatementIllicit use of fentanyl accounts for a large proportion of opioid-related overdose deaths. Children exposed to opioids during development have a higher risk of developing neuropsychiatric disorders later in life. Here, we employ a preclinical model of perinatal fentanyl exposure that recapitulates these long-term impairments and show, for the first time, that environmental enrichment can reverse deficits in somatosensory circuit function and behavior. These findings have the potential to directly inform and guide ongoing efforts to mitigate the consequences of perinatal opioid exposure.

Increase in the quality of life, combined with drug strategies, has been studied as possibilities for improving memory and delaying the onset of neurodegenerative diseases. A previous study published by the group of the authors has shown that microdose lithium and enriched environment can improve memory in both mice and humans. To elucidate this relationship better, this study aimed to evaluate whether the chronic combination of these two strategies could increase healthy aging in Senescence Accelerated Mouse-Prone 8 (SAMP8). Animals were submitted to either one or both of these strategies until the age of 10 months when they were anesthetized and killed and their hippocampus was extracted. The untreated SAMP-8 group exhibited worse memory and reduced neuronal density with greater neurodegeneration and increased amyloid-β plaque density compared with the control group. Moreover, significant alterations in proteins related to long-term potentiation, such as, synaptophysin and brain-derived neurotrophic factor (BDNF), were observed in this group. The strategies used in the study maintained long-term memory, reduced anxiety, and increased neuroprotection. Both strategies were efficient in reducing neurodegeneration and increasing parameters related to memory maintenance. In many experiments, the combination of the two strategies was more effective in improving healthy aging. This study sheds light on the combination of strategies that choose to improve the quality of life and drugs with low side effects. Moreover, it opens perspectives for a new field of study for healthy aging.

OBJECTIVE: Cognitive and memory impairments are common sequelae after stroke, yet how middle cerebral artery (MCA) stroke chronically affects the neural activity of the hippocampus, a brain region critical for memory but remote from the stroke epicenter, is poorly understood. Environmental enrichment (EE) improves cognition following stroke; however, the electrophysiology that underlies this behavioral intervention is still elusive. APPROACH: We recorded extracellular local field potentials simultaneously from sensorimotor cortex and hippocampus in rats during urethane anesthesia following MCA occlusion and subsequent EE treatment. MAIN RESULTS: We found that MCA stroke significantly impacted the electrophysiology in the hippocampus, in particular it disrupted characteristics of sharp-wave associated ripples (SPW-Rs) altered brain state, and disrupted phase amplitude coupling (PAC) within the hippocampus and between the cortex and hippocampus. Importantly, we show that EE mitigates stroke-induced changes to SPW-R characteristics but does not restore hippocampal brain state or PAC. SIGNIFICANCE: These results begin to uncover the complex interaction between cognitive deficit following stroke and EE treatment, providing a testbed to assess different strategies for therapeutics following stroke.

The environment of an organism can convey a powerful influence over its biology. Environmental enrichment (EE), as a eustress model, has been used extensively in neuroscience to study neurogenesis and brain plasticity. EE has also been used as an intervention for the treatment and prevention of neurological and psychiatric disorders with limited clinical application. By contrast, the effects of EE on the immune system are relatively less investigated. Recently, accumulating evidence has demonstrated that EE can robustly impact immune function. In this review, we summarize the major components of EE, the impact of EE on natural killer (NK) cells, EE’s immunoprotective roles in cancer, and the underlying mechanisms of EE-induced NK cell regulation. Moreover, we discuss opportunities for translational application based on insights from animal research of EE-induced NK cell regulation.

Cerebellar reserve refers to the capacity of the cerebellum to compensate for tissue damage or loss of function resulting from many different etiologies. When the inciting event produces acute focal damage (e.g., stroke, trauma), impaired cerebellar function may be compensated for by other cerebellar areas or by extracerebellar structures (i.e., structural cerebellar reserve). In contrast, when pathological changes compromise cerebellar neuronal integrity gradually leading to cell death (e.g., metabolic and immune-mediated cerebellar ataxias, neurodegenerative ataxias), it is possible that the affected area itself can compensate for the slowly evolving cerebellar lesion (i.e., functional cerebellar reserve). Here, we examine cerebellar reserve from the perspective of the three cornerstones of clinical ataxiology: control of ocular movements, coordination of voluntary axial and appendicular movements, and cognitive functions. Current evidence indicates that cerebellar reserve is potentiated by environmental enrichment through the mechanisms of autophagy and synaptogenesis, suggesting that cerebellar reserve is not rigid or fixed, but exhibits plasticity potentiated by experience. These conclusions have therapeutic implications. During the period when cerebellar reserve is preserved, treatments should be directed at stopping disease progression and/or limiting the pathological process. Simultaneously, cerebellar reserve may be potentiated using multiple approaches. Potentiation of cerebellar reserve may lead to compensation and restoration of function in the setting of cerebellar diseases, and also in disorders primarily of the cerebral hemispheres by enhancing cerebellar mechanisms of action. It therefore appears that cerebellar reserve, and the underlying plasticity of cerebellar microcircuitry that enables it, may be of critical neurobiological importance to a wide range of neurological/neuropsychiatric conditions.

Early postnatal experience has a profound influence on the development of organisms. In this integration, we provide a novel framework of the neurobehavioral pathways through which positive early postnatal experience acts to enhance adult reward sensitivity. The heterogeneity of the construct of reward and the underlying neurotransmitter systems (i.e., dopamine in incentive reward, opioids in consummatory reward, and oxytocin in orienting the reward systems to social cues) are first described as a means of organizing the discussion. Then, for each neurotransmitter system, their early postnatal ontogenesis is depicted for identifying potential sensitive periods for the effects of early experience. This is followed by the presentation of a model of the neurobehavioral foundation of two main forms of positive early postnatal experience that, with their essential components – novelty and positive tactile stimulation, facilitate the development of incentive and consummatory reward systems. Next, a detailed analysis of the major effects of positive early prewean and postwean experience on the neural and behavioral functioning of each neurotransmitter system is reviewed. The data support the neurobehavioral model presented, which theorizes that essential components of positive early experience enhance incentive and consummatory reward sensitivities through early activation of particular neural pathways. These activity-dependent effects are sustained via structural modifications of underlying neural circuitries.

Background:Aging is an unavoidable, physiological process that reduces the complexity and the plasticity of the synaptic contacts in Central Nervous System (CNS), having profound implications for human well-being. The term “cognitive reserve” refers to central cellular adaptations that augment the resilience of human brain to damage and aging. The term “Cognitive training” indicates the cultural, social and physical stimulations proposed as add-on therapy for the cure of central neurological diseases. “Cognitive training” reinforces the “cognitive reserve” permitting to counteract brain impairments and rejuvenating synaptic complexity. The research has begun investigating the clinical impact of the “cognitive training” in aged people, but additional work is needed to definitively assess its effectiveness. In particular, there is a need to understand, from a preclinical point of view, whether “cognitive training” promotes compensatory effects or, alternatively, if it elicits genuine recovery of neuronal defects. Although the translation from rodent studies to the clinical situation could be difficult, the results from pre-clinical models are of high clinical relevance, since they should allow a better understanding of the effects of environmental interventions in aging-associated chronic derangements in mammals.Conclusion:Data in literature and the recent results obtained in our laboratory concerning the impact of environmental stimulation on the presynaptic release of noradrenaline, glutamate and gamma amino butyric acid (GABA) suggest that these neurotransmitters undergo different adaptations during aging and that they are differently tuned by “cognitive training”. The impact of “cognitive training” on neurotransmitter exocytosis might account for the cellular events involved in reinforcement of “cognitive reserve” in young and old animals.

Accumulation of alpha-synuclein protein aggregates is the hallmark neuropathologic feature of synucleinopathies such as Parkinson's disease. Rare point mutations and multiplications in SNCA, the gene encoding alpha-synuclein, as well as other genetic alterations are linked to familial Parkinson's disease cases with high penetrance and hence constitute major genetic risk factors for Parkinson's disease. However, the preponderance of cases seems sporadic, most likely based on a complex interplay between genetic predispositions, aging processes and environmental influences. Deciphering the impact of these environmental factors and their interactions with the individual genetic background in humans is challenging and often requires large cohorts, complicated study designs, and longitudinal set-ups. In contrast, rodent models offer an ideal system to study the influence of individual environmental aspects under controlled genetic background and standardized conditions. In this review, we highlight findings from studies examining effects of environmental enrichment mimicking stimulation of the brain by its physical and social surroundings as well as of environmental stressors on brain health in the context of Parkinson's disease. We discuss possible internal molecular transducers of such environmental cues in Parkinson's disease rodent models and emphasize their potential in developing novel avenues to much-needed therapies for this still incurable disease. This article is part of the Special Issue "Synuclein". peerReviewed