BACKGROUND: Prenatal alcohol exposure (PAE) has serious physical consequences for children such as behavioral disabilities, growth disorders, neuromuscular problems, impaired motor coordination, and decreased muscle tone. However, it is not known whether loss of muscle strength occurs, and which interventions will effectively mitigate physical PAE impairments. We aimed to investigate whether physical alteration persists during adolescence and whether exercise is an effective intervention.
RESULTS: Using paradigms to evaluate different physical qualities, we described that early adolescent PAE animals have significant alterations in agility and strength, without alterations in balance and coordination compared to CTRL animals. We evaluated the effectiveness of 3 different exercise protocols for 4 weeks: Enrichment environment (EE), Endurance exercise (EEX), and Resistance exercise (REX). The enriched environment significantly improved the strength in the PAE group but not in the CTRL group whose strength parameters were maintained even during exercise. Resistance exercise showed the greatest benefits in gaining strength, and endurance exercise did not.
CONCLUSIONS: PAE induced a significant decrease in strength compared to CTRL in PND21. Resistance exercise is the most effective to reverse the effects of PAE on muscular strength. Our data suggests that individualized, scheduled, and supervised training of resistance is more beneficial than endurance or enriched environment exercise for adolescents FASD.

Ethanol (EtOH) intake and noise exposure are particularly concerning among human adolescents because the potential to harm brain. Unfortunately, putative underlying mechanisms remain to be elucidated. Moreover, implementing non-pharmacological strategies, such as enriched environments (EE), would be pertinent in the field of neuroprotection. This study aims to explore possible underlying triggering mechanism of hippocampus-dependent behaviors in adolescent animals of both sexes following ethanol intake, noise exposure, or a combination of both, as well as the impact of EE. Adolescent Wistar rats of both sexes were subjected to an intermittent voluntary EtOH intake paradigm for one week. A subgroup of animals was exposed to white noise for two hours after the last session of EtOH intake. Some animals of both groups were housed in EE cages. Hippocampal-dependent behavioral assessment and hippocampal oxidative state evaluation were performed. Results show that different hippocampal-dependent behavioral alterations might be induced in animals of both sexes after EtOH intake and sequential noise exposure, that in some cases are sex-specific. Moreover, hippocampal oxidative imbalance seems to be one of the potential underlying mechanisms. Additionally, most behavioral and oxidative alterations were prevented by EE. These findings suggest that two frequently found environmental agents may impact behavior and oxidative pathways in both sexes in an animal model. In addition, EE resulted a partially effective neuroprotective strategy. Therefore, it could be suggested that the implementation of a non-pharmacological approach might also potentially provide neuroprotective advantages against other challenges. Finally, considering its potential for translational human benefit might be worth.

Here, we explored the impact of prolonged environmental enrichment (EE) on behavioral, neurochemical, and epigenetic changes in the serotonin transporter gene in mice subjected to a two-hit schizophrenia model. The methodology involved administering the viral mimetic PolyI:C to neonatal Swiss mice as a first hit during postnatal days (PND) 5-7, or a sterile saline solution as a control. At PND21, mice were randomly assigned either to standard environment (SE) or EE housing conditions. Between PND35-44, the PolyI:C-treated group was submitted to various unpredictable stressors, constituting the second hit. Behavioral assessments were conducted on PND70, immediately after the final EE exposure. Following the completion of behavioral assessments, we evaluated the expression of proteins in the hippocampus that are indicative of microglial activation, such as Iba-1, as well as related to neurogenesis, including doublecortin (Dcx). We also performed methylation analysis on the serotonin transporter gene (Slc6a4) to investigate alterations in serotonin signaling. The findings revealed that EE for 50 days mitigated sensorimotor gating deficits and working memory impairments in two-hit mice and enhanced their locomotor and exploratory behaviors. EE also normalized the overexpression of hippocampal Iba-1 and increased the expression of hippocampal Dcx. Additionally, we observed hippocampal demethylation of the Slc6a4 gene in the EE-exposed two-hit group, indicating epigenetic reprogramming. These results contribute to the growing body of evidence supporting the protective effects of long-term EE in counteracting behavioral disruptions caused by the two-hit schizophrenia model, pointing to enhanced neurogenesis, diminished microglial activation, and epigenetic modifications of serotonergic pathways as underlying mechanisms.

[This corrects the article DOI: 10.3389/fnbeh.2023.1251144.].

Learning and memory are affected by novel enriched environment, a condition where animals play and interact with a variety of toys and conspecifics. Exposure of animals to the novel enriched environments improves memory by altering neural plasticity during natural sleep, a process called memory consolidation. The hippocampus, a pivotal brain region for learning and memory, generates high-frequency oscillations called ripples during sleep, which is required for memory consolidation. Naturally occurring sleep shares characteristics in common with general anesthesia in terms of extracellular oscillations, guaranteeing anesthetized animals suitable to examine neural activity in a sleep-like state. However, it is poorly understood whether the preexposure of animals to the novel enriched environment modulates neural activity in the hippocampus under subsequent anesthesia. To ask this question, we allowed mice to freely explore the novel enriched environment or their standard environment, anesthetized them, and recorded local field potentials in the hippocampal CA1 area. We then compared the characteristics of hippocampal ripples between the two groups and found that the amplitude of ripples and the number of successive ripples were larger in the novel enriched environment group than in the standard environment group, suggesting that the afferent synaptic input from the CA3 area to the CA1 area was higher when the animals underwent the novel enriched environment. These results underscore the importance of prior experience that surpasses subsequent physical states from the neurophysiological point of view.

Spinal cord injury (SCI) leads to motor and sensory impairment below the site of injury, thereby necessitating rehabilitation. An enriched environment (EE) increases social interaction and locomotor activity in a mouse model, similar to human rehabilitation. However, the impact of EE on presynaptic plasticity in gene expression levels remains unclear. Hence, this study aimed to investigate the therapeutic potential of EE in an SCI mouse model. Mice with spinal cord contusion were divided into two groups: those housed in standard cages (control) and those in EE conditions (EE). Each group was housed separately for either 2- or 8-weeks post-injury, after which RNA sequencing was performed and compared to a sham group (receiving only a dorsal laminectomy). The synaptic vesicle cycle (SVC) pathway and related genes showed significant downregulation after SCI at both time points. Subsequently, we investigated whether exposure to EE for 2- and 8-weeks post-SCI could modulate the SVC pathway and its related genes. Notably, exposure to EE for 8 weeks resulted in a marked reversal effect of SVC-related gene expression, along with stimulation of axon regeneration and mitigation of locomotor activity loss. Thus, prolonged exposure to EE increased presynaptic activity, fostering axon regeneration and functional improvement by modulating the SVC in the SCI mouse model. These findings suggest that EE exposure proves effective in inducing activity-dependent plasticity, offering a promising therapeutic approach akin to rehabilitation training in patients with SCI.

Sepsis-associated encephalopathy (SAE) is a frequent complication of severe systemic infection resulting in delirium, premature death, and long-term cognitive impairment. We closely mimicked SAE in a murine peritoneal contamination and infection (PCI) model. We found long-lasting synaptic pathology in the hippocampus including defective long-term synaptic plasticity, reduction of mature neuronal dendritic spines, and severely affected excitatory neurotransmission. Genes related to synaptic signaling, including the gene for activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) and members of the transcription-regulatory EGR gene family, were downregulated. At the protein level, ARC expression and mitogen-activated protein kinase signaling in the brain were affected. For targeted rescue we used adeno-associated virus-mediated overexpression of ARC in the hippocampus in vivo. This recovered defective synaptic plasticity and improved memory dysfunction. Using the enriched environment paradigm as a non-invasive rescue intervention, we found improvement of defective long-term potentiation, memory, and anxiety. The beneficial effects of an enriched environment were accompanied by an increase in brain-derived neurotrophic factor (BDNF) and ARC expression in the hippocampus, suggesting that activation of the BDNF-TrkB pathway leads to restoration of the PCI-induced reduction of ARC. Collectively, our findings identify synaptic pathomechanisms underlying SAE and provide a conceptual approach to target SAE-induced synaptic dysfunction with potential therapeutic applications to patients with SAE.

Anxiety and depression are the most common mental health disorders worldwide, each affecting around 30% stroke survivors. These complications not only affect the functional recovery and quality of life in stroke patients, but also are distressing for caregivers. However, effective treatments are still lacking. Enriched environment (EE), characterized with novel and multi-dimensional stimulation, has been reported to exert therapeutic effects on physical and cognitive function. In addition, EE also had potential positive effects on emotional disorders after ischemic stroke; however, the underling mechanisms have not been well elucidated. This study aimed to explore the effectiveness of EE on emotional disorders after cerebral ischemia and its underling mechanism. Sensorimotor cortical infarction was induced by photothrombosis with stable infarct location and volume, resulting in motor dysfunction, anxiety and depression-like behaviors in mice, with decreased ALFF and ReHo values and decreased c-fos expression in the infarction area and adjacent regions. Seven days\' EE treatment significantly improved motor function of contralateral forelimb and exhibited anxiolytic and antidepressant effects in infarcted mice. Compared to the mice housing in a standard environment, those subjected to acute EE stimulation had significantly increased ALFF and ReHo values in the bilateral somatosensory cortex (S1, S2), dorsal dentate gyrus (dDG), dorsal CA1 of hippocampus (dCA1), lateral habenular nucleus (LHb), periaqueductal gray (PAG), ipsilateral primary motor cortex (M1), retrosplenial cortex (RSC), parietal association cortex (PtA), dorsal CA3 of hippocampus (dCA3), claustrum (Cl), ventral pallidum (VP), amygdala (Amy), and contralateral auditory cortex (Au). Some of, but not all, the ipsilateral brain regions mentioned above showed accompanying increases in c-fos expression with the most significant changes in the dDG. The number of FosB positive cells in the dDG, decreased in infarcted mice, was significantly increased after chronic EE treatment. Chemogenetic activation of dDG neurons reduced anxiety and depressive-like behaviors in infarcted mice, while neuronal inhibition resulted in void of the anxiolytic and antidepressant effects of EE. Altogether, these findings indicated that dDG neurons may mediate EE-triggered anxiolytic and antidepressant effects in cortical infarcted mice.

Impaired decision-making constitutes a fundamental issue in numerous psychiatric disorders. Extensive research has established that early life adversity (ELA) increases vulnerability to psychiatric disorders later in life. ELA in human neonates is associated with changes in cognitive, emotional, as well as reward-related processing. Maternal separation (MS) is an established animal model of ELA and has been shown to be associated with decision-making deficits. On the other hand, enriched environment (EE) and intranasal oxytocin (OT) administration have been demonstrated to have beneficial effects on decision-making in humans or animals. Given these considerations, our investigation sought to explore the impact of brief exposure to EE and intranasal OT administration on the decision-making abilities of adolescent rats that had experienced MS during infancy. The experimental protocol involved subjecting rat pups to the MS regimen for 180 min per day from postnatal day (PND) 1 to PND 21. Then, from PND 22 to PND 34, the rats were exposed to EE and/or received intranasal OT (2 μg/μl) for seven days. The assessment of decision-making abilities, using a rat gambling task (RGT), commenced during adolescence. Our findings revealed that MS led to impaired decision-making and a decreased percentage of advantageous choices. However, exposure to brief EE or intranasal OT administration mitigated the deficits induced by MS and improved the decision-making skills of maternally-separated rats. Furthermore, combination of these treatments did not yield additional benefits. These results suggest that EE and OT may hold promise as therapeutic interventions to enhance certain aspects of cognitive performance.

Neuronal plasticity is a crucial mechanism for an adapting nervous system to change. It is shown to be regulated by perineuronal nets (PNNs), the condensed forms of the extracellular matrix (ECM) around neuronal bodies. By assessing the changes in the number, intensity, and structure of PNNs, the ultrastructure of the PNN mesh, and the expression of inhibitory and excitatory synaptic inputs on these neurons, we aimed to clarify the role of an ECM glycoprotein, tenascin-C (TnC), in the dorsal hippocampus. To enhance neuronal plasticity, TnC-deficient (TnC-/-) and wild-type (TnC+/+) young adult male mice were reared in an enriched environment (EE) for 8 weeks. Deletion of TnC in TnC-/- mice showed an ultrastructural reduction of the PNN mesh and an increased inhibitory input in the dentate gyrus (DG), and an increase in the number of PNNs with a rise in the inhibitory input in the CA2 region. EE induced an increased inhibitory input in the CA2, CA3, and DG regions; in DG, the change was also followed by an increased intensity of PNNs. No changes in PNNs or synaptic expression were found in the CA1 region. We conclude that the DG and CA2 regions emerged as focal points of alterations in PNNs and synaptogenesis with EE as mediated by TnC.