Housing in Environmental Complexity Following Wheel Running Augments Survival of Newly-Generated Hippocampal Neurons in a Rat Model of Binge Alcohol Exposure during the Third Trimester Equivalent

Background Binge-like alcohol exposure in neonatal rats during the brain growth spurt causes deficits in adult neurogenesis in the hippocampal dentate gyrus (DG). Previous data from our lab demonstrated that twelve days of voluntary wheel-running (WR) beginning on postnatal day (PD) 30 significantly increased the number of newly-generated cells evident in the DG on PD42 in both alcohol-exposed and control rats, but 30 days later a sustained beneficial effect of WR was evident only in control rats. This study tested the hypothesis that housing rats in environmental complexity (EC) following WR would promote survival of the newly-generated cells stimulated by WR, particularly in alcohol-exposed rats. Methods On PD4-9, pups were intubated with alcohol in a binge-like manner (5.25g/kg/day), sham-intubated, or reared normally. In Experiment 1, animals were either assigned to WR during PD30-42 or were socially housed (SH). On PD42, animals were injected with bromodeoxyuridine (BrdU; 200mg/kg) and perfused two hours later to confirm the WR-induced stimulation of proliferation. In Experiment 2, all animals received WR on PD30-42 and were injected with BrdU on the last full day of WR. On PD42, animals were randomly assigned either to EC (WR/EC) or SH (WR/SH) for 30 days and subsequently perfused and brains were processed for immunohistochemical staining to identify BrdU+, Ki67+ and BrdU+/NeuN+ labeled cells in DG. Results In Exp. 1, WR exposure significantly increased the number of proliferating cells in all three postnatal conditions. In Exp. 2, the alcohol-exposed rats given WR/SH had significantly fewer BrdU+ cells compared to control rats given WR/SH. However, WR/EC experience significantly increased the number of surviving BrdU+ cells in both the alcohol-exposed and sham-intubated groups compared to WR/SH rats of the same neonatal treatment. Approximately 80% of the surviving BrdU+ cells in the DG across the conditions were co-labeled with NeuN. Conclusions WR followed by EC could provide a behavioral model for developing interventions in humans to ameliorate hippocampal-dependent impairments associated with fetal alcohol spectrum disorders

Long-Term Consequences of Developmental Alcohol Exposure on Brain Structure and Function: Therapeutic Benefits of Physical Activity

Developmental alcohol exposure both early in life and during adolescence can have a devastating impact on normal brain structure and functioning, leading to behavioral and cognitive impairments that persist throughout the lifespan. This review discusses human work as well as animal models used to investigate the effect of alcohol exposure at various time points during development, as well as specific behavioral and neuroanatomical deficits caused by alcohol exposure. Further, cellular and molecular mediators contributing to these alcohol-induced changes are examined, such as neurotrophic factors and apoptotic markers. Next, this review seeks to support the use of aerobic exercise as a potential therapeutic intervention for alcohol-related impairments. To date, few interventions, behavioral or pharmacological, have been proven effective in mitigating some alcohol-related deficits. Exercise is a simple therapy that can be used across species and also across socioeconomic status. It has a profoundly positive influence on many measures of learning and neuroplasticity; in particular, those measures damaged by alcohol exposure. This review discusses current evidence that exercise may mitigate damage caused by developmental alcohol exposure and is a promising therapeutic target for future research and intervention strategies

Exercise in Adolescence Enhances Callosal White Matter Refinement in the Female Brain in a Rat Model of Fetal Alcohol Spectrum Disorders

A total of 1 in 20 infants born annually are exposed to alcohol prenatally, which disrupts neurodevelopment and results in several disorders categorized under the umbrella term Fetal Alcohol Spectrum Disorders (FASD). Children and adolescents affected by FASD exhibit delayed maturation of cerebral white matter, which contributes to deficits in executive function, visuospatial processing, sensory integration, and interhemispheric communication. Research using animal models of FASD have uncovered that oligoglia proliferation, differentiation, and survival are vulnerable to alcohol teratogenesis in the male brain due in part to the activation of the neuroimmune system during gestation and infancy. A comprehensive investigation of prenatal alcohol exposure on white matter development in the female brain is limited. This study demonstrated that the number of mature oligodendrocytes and the production of myelin basic protein were reduced first in the female corpus callosum following alcohol exposure in a rat model of FASD. Analysis of myelin-related genes confirmed that myelination occurs earlier in the female corpus callosum compared to their counterparts, irrespective of postnatal treatment. Moreover, dysregulated oligodendrocyte number and myelin basic protein production was observed in the male and female FASD brain in adolescence. Targeted interventions that support white matter development in FASD-affected youth are nonexistent. The capacity for an adolescent exercise intervention to upregulate corpus callosum myelination was evaluated: we discovered that volunteer exercise increases the number of mature oligodendrocytes in alcohol-exposed female rats. This study provides critical evidence that oligoglia differentiation is difficult but not impossible to induce in the female FASD brain in adolescence following a behavioral intervention

Fragile X mental retardation protein is necessary for neurotransmitter-activated protein translation at synapses

Fragile X mental retardation is caused by absence of the RNA-binding protein fragile X mental retardation protein (FMRP), encoded by the FMR1 gene. There is increasing evidence that FMRP regulates transport and modulates translation of some mRNAs. We studied neurotransmitter-activated synaptic protein synthesis in fmr1-knockout mice. Synaptoneurosomes from knockout mice did not manifest accelerated polyribosome assembly or protein synthesis as it occurs in wild-type mice upon stimulation of group I metabotropic glutamate receptors. Direct activation of protein kinase C did not compensate in the knockout mouse, indicating that the FMRP-dependent step is further along the signaling pathway. Visual cortices of young knockout mice exhibited a lower proportion of dendritic spine synapses containing polyribosomes than did the cortices of wild-type mice, corroborating this finding in vivo. This deficit in rapid neurotransmitter-controlled local translation of specific proteins may contribute to morphological and functional abnormalities observed in patients with fragile X syndrome