Epigenetic mechanisms in alcohol- and adversity-induced developmental origins of neurobehavioral functioning.

The long-term effects of developmental alcohol and stress exposure are well documented in both humans and non-human animal models. Damage to the brain and attendant life-long impairments in cognition and increased risk for psychiatric disorders are debilitating consequences of developmental exposure to alcohol and/or psychological stress. Here we discuss evidence for a role of epigenetic mechanisms in mediating these consequences. While we highlight some of the common ways in which stress or alcohol impact the epigenome, we point out that little is understood of the epigenome's response to experiencing both stress and alcohol exposure, though stress is a contributing factor as to why women drink during pregnancy. Advancing our understanding of this relationship is of critical concern not just for the health and well-being of individuals directly exposed to these teratogens, but for generations to come.

Sex Differences in Early Postnatal Microglial Colonization of the Developing Rat Hippocampus Following a Single-Day Alcohol Exposure.

Microglia are involved in various homeostatic processes in the brain, including phagocytosis, apoptosis, and synaptic pruning. Sex differences in microglia colonization of the developing brain have been reported, but have not been established following alcohol insult. Developmental alcohol exposure represents a neuroimmune challenge that may contribute to cognitive dysfunction prevalent in humans with Fetal Alcohol Spectrum Disorders (FASD) and in rodent models of FASD. Most studies have investigated neuroimmune activation following adult alcohol exposure or following multiple exposures. The current study uses a single day binge alcohol exposure model (postnatal day [PD] 4) to examine sex differences in the neuroimmune response in the developing rat hippocampus on PD5 and 8. The neuroimmune response was evaluated through measurement of microglial number and cytokine gene expression at both time points. Male pups had higher microglial number compared to females in many hippocampal subregions on PD5, but this difference disappeared by PD8, unless exposed to alcohol. Expression of pro-inflammatory marker CD11b was higher on PD5 in alcohol-exposed (AE) females compared to AE males. After alcohol exposure, C-C motif chemokine ligand 4 (CCL4) was significantly increased in female AE pups on PD5 and PD8. Tumor necrosis factor-α (TNF-α) levels were also upregulated by AE in males on PD8. The results demonstrate a clear difference between the male and female neuroimmune response to an AE challenge, which also occurs in a time-dependent manner. These findings are significant as they add to our knowledge of specific sex-dependent effects of alcohol exposure on microglia within the developing brain.

Neurotrophins in the Brain: Interaction With Alcohol Exposure During Development.

Fetal alcohol spectrum disorders (FASDs) are a result of the teratogenic effects of alcohol on the developing fetus. Decades of research examining both individuals with FASDs and animal models of developmental alcohol exposure have revealed the devastating effects of alcohol on brain structure, function, behavior, and cognition. Neurotrophic factors have an important role in guiding normal brain development and cellular plasticity in the adult brain. This chapter reviews the current literature showing that alcohol exposure during the developmental period impacts neurotrophin production and proposes avenues through which alcohol exposure and neurotrophin action might interact. These areas of overlap include formation of long-term potentiation, oxidative stress processes, neuroinflammation, apoptosis and cell loss, hippocampal adult neurogenesis, dendritic morphology and spine density, vasculogenesis and angiogenesis, and behaviors related to spatial memory, anxiety, and depression. Finally, we discuss how neurotrophins have the potential to act in a compensatory manner as neuroprotective molecules that can combat the deleterious effects of in utero alcohol exposure.

Impact of exercise and a complex environment on hippocampal dendritic morphology, Bdnf gene expression, and DNA methylation in male rat pups neonatally exposed to alcohol.

Alcohol exposure in utero can result in Fetal Alcohol Spectrums Disorders (FASD). Measures of hippocampal neuroplasticity, including long-term potentiation, synaptic and dendritic organization, and adult neurogenesis, are consistently disrupted in rodent models of FASD. The current study investigated whether third trimester-equivalent binge-like alcohol exposure (AE) [postnatal days (PD) 4-9] affects dendritic morphology of immature dentate gyrus granule cells, and brain-derived neurotrophic factor (Bdnf) gene expression and DNA methylation in hippocampal tissue in adult male rats. To understand immediate impact of alcohol, DNA methylation was measured in the PD10 hippocampus. In addition, two behavioral interventions, wheel running (WR) and environmental complexity (EC), were utilized as rehabilitative therapies for alcohol-induced deficits. AE significantly decreased dendritic complexity of the immature neurons, demonstrating the long-lasting impact of neonatal alcohol exposure on dendritic morphology of immature neurons in the hippocampus. Both housing conditions robustly enhanced dendritic complexity in the AE animals. While Bdnf exon I DNA methylation was lower in the AE and sham-intubated animals compared with suckle controls on PD10, alterations to Bdnf DNA methylation and gene expression levels were not present at PD72. In control animals, exercise, but not exercise followed by housing in EC, resulted in higher levels of hippocampal Bdnf gene expression and lower DNA methylation. These studies demonstrate the long-lasting negative impact of developmental alcohol exposure on hippocampal dendritic morphology and support the implementation of exercise and complex environments as therapeutic interventions for individuals with FASD. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 708-725, 2017.

Neonatal binge alcohol exposure increases microglial activation in the developing rat hippocampus.

Aberrant activation of the developing immune system can have long-term negative consequences on cognition and behavior. Teratogens, such as alcohol, activate microglia, the brain's resident immune cells, which could contribute to the lifelong deficits in learning and memory observed in humans with Fetal Alcohol Spectrum Disorders (FASD) and in rodent models of FASD. The current study investigates the microglial response of the brain 24 h following neonatal alcohol exposure (postnatal days (PDs) 4-9, 5.25 g/kg/day). On PD10, microglial cell counts and area of cell territory were assessed using unbiased stereology in the hippocampal subfields CA1, CA3 and dentate gyrus (DG), and hippocampal expression of pro- and anti-inflammatory genes was analyzed. A significant decrease in microglial cell counts in CA1 and DG was found in alcohol-exposed and sham-intubated (SI) animals compared to undisturbed suckle controls (SCs), suggesting overlapping effects of alcohol exposure and intubation alone on the neuroimmune response. Cell territory was decreased in alcohol-exposed animals in CA1, CA3, and DG compared to controls, suggesting the microglia have shifted to a more activated state following alcohol treatment. Furthermore, both alcohol-exposed and SI animals had increased levels of pro-inflammatory cytokines IL-1ß, TNF-α, CD11b, and CCL4; in addition, CCL4 was significantly increased in alcohol-exposed animals compared to SI as well. Alcohol-exposed animals also showed increased levels of anti-inflammatory cytokine TGF-ß compared to both SI and SCs. In summary, the number and activation of microglia in the neonatal hippocampus are both affected in a rat model of FASD, along with increased gene expression of pro- and anti-inflammatory cytokines. This study shows that alcohol exposure during development induces a neuroimmune response, potentially contributing to long-term alcohol-related changes to cognition, behavior and immune function.

Effects of developmental alcohol exposure vs. intubation stress on BDNF and TrkB expression in the hippocampus and frontal cortex of neonatal rats.

Third trimester-equivalent alcohol exposure causes significant deficits in hippocampal and cortical neuroplasticity, resulting in alterations to dendritic arborization, hippocampal adult neurogenesis, and performance on learning tasks. The current study investigated the impact of neonatal alcohol exposure (postnatal days 4-9, 5.25 g/kg/day) on expression of brain-derived neurotrophic factor (BDNF) and the tropomyosin-related kinase B (TrkB) receptor in the hippocampal and frontal cortex of infant Long-Evans rats. Levels of BDNF protein were increased in the hippocampus, but not frontal cortex, of alcohol-exposed rats 24h after the last dose, when compared with undisturbed (but not sham-intubated) control animals. BDNF protein levels showed a trend toward increase in hippocampus of sham-intubated animals as well, suggesting an effect of the intubation procedure. TrkB protein was increased in the hippocampus of alcohol-exposed animals compared to sham-intubated pups, indicating an alcohol-specific effect on receptor expression. In addition, expression of bdnf total mRNA in alcohol-exposed and sham-intubated pups was enhanced in the hippocampus; however, there was a differential effect of alcohol and intubation stress on exon I- and IV-specific mRNA transcripts. Further, plasma corticosterone was found to be increased in both alcohol-exposed and sham-intubated pups compared to undisturbed animals. Upregulation of BDNF could potentially represent a neuroprotective mechanism activated following alcohol exposure or stress. The results suggest that alcohol exposure and stress have both overlapping and unique effects on BDNF, and highlight the need for the stress of intubation to be taken into consideration in studies that implement this route of drug delivery.

Understanding age effects associated with changes in secondary health conditions in a Canadian spinal cord injury cohort.

STUDY DESIGN: Longitudinal cohort. OBJECTIVES: To determine whether changes in secondary health conditions (SHC) associated with spinal cord injury (SCI) were effectively modeled from a longitudinal or cross-sectional perspective, and whether the changes in SHCs were attributable to age or years post-injury (YPI). SETTING: Toronto Rehabilitation Institute, Lyndhurst Centre. METHODS: Telephone survey methods were used to collect data on (1) demographics, (2) impairment, (3) health status, and (4) self-reported SHCs at two time intervals (1995-1997; 2003-2004) from 344 adults with SCI. Generalized estimating equations were applied to model the longitudinal and cross-sectional effects. RESULTS: Health status decreased over time (P<0.0005), whereas the number of SHCs increased (P<0.0001). Regardless of age or YPI, the longitudinal component of aging better predicted SHC occurrence and was associated with spasticity [odds ratio, OR=1.055 (95% confidence interval, CI, 1.018 to 1.093, P<0.01)], kidney problems [OR=1.154 (95% CI, 1.084 to 1.229, P<0.0001)], cardiac problems [OR=1.168 (95% CI, 1.060 to 1.286, P<0.01)], high blood pressure [OR=1.121 (95% CI, 1.058 to 1.188, P<0.0001)], chronic pain [OR=1.058 (95% CI, 1.021 to 1.096, P<0.01)], and arthritis/joint pain [OR=1.113 (95% CI, 1.075 to 1.152, P<0.0001)]. CONCLUSION: Within a relatively short period of time, persons with SCI experienced substantive declines in health. The findings suggest that a longitudinal perspective is more sensitive for predicting the risk of self-reported SHCs than a cross-sectional one.

Predicting life satisfaction after spinal cord injury in a Canadian sample.

STUDY DESIGN: Cross-sectional, survey. OBJECTIVES: To extend current theoretical models predicting life satisfaction post-spinal cord injury (SCI). Our primary model predicting life satisfaction as measured by the Satisfaction with Life Scale (SWLS) examined demographic characteristics, elements of the International Classification of Functioning and subjective and objective measures of health. A second model was developed to examine factors that are associated with successful community participation as measured by the Reintegration to Normal Living Index (RNL). In addition, the effects of psychological distress and chronic pain on life satisfaction and community participation were examined. SETTING: Toronto Rehabilitation Institute, Spinal Cord Rehabilitation Program, Lyndhurst Centre. METHODS: Prospective data collection via semi-structured telephone interview on an established SCI Canadian sample. RESULTS: In predicting life satisfaction, our model accounted for 35.3% of the variance with demographic characteristics, objective and subjective health, and community participation significantly contributing to the model. In particular, psychological complications, current health rating and community participation were the only variables that made significant contributions in predicting life satisfaction. With regards to community participation, the presence of psychological complications and number of medical complications were associated with decreased reintegration. Increased time since injury onset, higher health ratings and being employed were positively related to RNL. CONCLUSION: It would appear that factors involving functional decline and aging are associated with lower participation but not life satisfaction. Further, models predicting quality of life should incorporate measures of psychological functioning.

Exploring the comparative responsiveness of a core set of outcome measures in a school-based conductive education programme.

BACKGROUND: Conductive education (CE) is a holistic educational system that uses an active cognitive approach to teach individuals with motor disorders to become more functional participants in daily activities. While CE's popularity continues to grow in North America and Europe, its effectiveness has not been established. The lack of definition of responsive outcome measures for evaluation of CE programmes has limited the interpretability of conclusions from earlier studies evaluating effectiveness. OBJECTIVE: To determine which measures from a core set were most responsive to physical, functional and psychosocial changes associated with a school-based CE programme. METHODS: This was a one-group before and after data collection design using an 8-month follow-up period. We enrolled a referral sample of nine children with cerebral palsy in Kindergarten or Grade 1 (Gross Motor Function Classification System levels 3, 4 or 5). The study took place within a school-based CE programme at a Canadian children's rehabilitation centre. Children participated in a CE full-day class for an entire school year. Physical, functional, psychosocial and participation measures included: Gross Motor Function Measure (GMFM), Quality of Upper Extremity Skills Test (QUEST), Peabody Developmental Motor Scales, Paediatric Evaluation of Disability Inventory (PEDI), Pictorial Scale of Perceived Competence and Social Acceptance for Young Children, Individualized Educational Plan, and Goal Attainment Scaling (GAS). Four children from the study's second year were also evaluated on the Impact on Family Scale (IFS), GAS and School Function Assessment. RESULTS: The Gross Motor Function Measure, QUEST, PEDI (Caregiver Assistance) and IFS were most responsive to change. GAS was useful in documenting and quantifying goals. Problems were encountered in evaluating self-esteem and school participation. CONCLUSIONS: Several strong measures of outcome were identified. Further work is needed to find valid and sensitive psychosocial and school participation measures for these young children.

Independent living long-term outcome variables in spinal cord injury: a replication of DeJong.

Most independent living (IL) literature focused on describing rather than measuring or evaluating the newly developing IL phenomenon in the rehabilitation field. Gerben DeJong, however, recognized the need to quantify important IL components for research purposes. In the late 1970s he devised a ranking instrument to assess Living Arrangement and Productivity Status of adults with spinal cord injury. As there were few other IL researchers at the time, DeJong's instrument received little attention. Currently, however, IL research is becoming more prominent. The present study is a replication of DeJong's early work. It supports the current relevance of DeJong's conceptual framework, but suggests changes to the specific classification schemes for quantifying long-term IL outcomes of Living Arrangement and Productivity Status for individuals with spinal cord injury.