Magnetic resonance elastography captures a transient benefit of exercise intervention on forebrain stiffness in a rat model of fetal alcohol spectrum disorders.

BACKGROUND: Fetal alcohol spectrum disorders (FASD), a group of prevalent conditions resulting from prenatal alcohol exposure, affect the maturation of cerebral white matter as first identified with neuroimaging. However, traditional methods are unable to track subtle microstructural alterations to white matter. This preliminary study uses a highly sensitive and clinically translatable magnetic resonance elastography (MRE) protocol to assess brain tissue microstructure through its mechanical properties following an exercise intervention in a rat model of FASD. METHODS: Female rat pups were either alcohol-exposed (AE) via intragastric intubation of alcohol in milk substitute (5.25 g/kg/day) or sham-intubated (SI) on postnatal days (PD) four through nine to model alcohol exposure during the brain growth spurt. On PD 30, half of AE and SI rats were randomly assigned to either a wheel-running or standard cage for 12 days. Magnetic resonance elastography was used to measure whole brain and callosal mechanical properties at the end of the intervention (around PD 42) and at 1 month post-intervention, and findings were validated with histological quantification of oligoglia. RESULTS: Alcohol exposure reduced forebrain stiffness (p = 0.02) in standard-housed rats. The adolescent exercise intervention mitigated this effect, confirming that increased aerobic activity supports proper neurodevelopmental trajectories. Forebrain damping ratio was lowest in standard-housed AE rats (p < 0.01), but this effect was not mitigated by intervention exposure. At 1 month post-intervention, all rats exhibited comparable forebrain stiffness and damping ratio (p > 0.05). Callosal stiffness and damping ratio increased with age. With cessation of exercise, there was a negative rebound effect on the quantity of callosal oligodendrocytes, irrespective of treatment group, which diverged from our MRE results. CONCLUSIONS: This is the first application of MRE to measure the brain's mechanical properties in a rodent model of FASD. MRE successfully captured alcohol-related changes in forebrain stiffness and damping ratio. Additionally, MRE identified an exercise-related increase to forebrain stiffness in AE rats.

Monitoring lasting changes to brain tissue integrity through mechanical properties following adolescent exercise intervention in a rat model of Fetal Alcohol Spectrum Disorders.

Background: Fetal Alcohol Spectrum Disorders (FASD) encompass a group of highly prevalent conditions resulting from prenatal alcohol exposure. Alcohol exposure during the third trimester of pregnancy overlapping with the brain growth spurt is detrimental to white matter growth and myelination, particularly in the corpus callosum, ultimately affecting tissue integrity in adolescence. Traditional neuroimaging techniques have been essential for assessing neurodevelopment in affected youth; however, these methods are limited in their capacity to track subtle microstructural alterations to white matter, thus restricting their effectiveness in monitoring therapeutic intervention. In this preliminary study we use a highly sensitive and clinically translatable Magnetic Resonance Elastography (MRE) protocol for assessing brain tissue microstructure through its mechanical properties following an exercise intervention in a rat model of FASD. Methods: Rat pups were divided into two groups: alcohol-exposed (AE) pups which received alcohol in milk substitute (5.25 g/kg/day) via intragastric intubation on postnatal days (PD) four through nine during the rat brain growth spurt (Dobbing and Sands, 1979), or sham-intubated (SI) controls. In adolescence, on PD 30, half AE and SI rats were randomly assigned to either a modified home cage with free access to a running wheel or to a new home cage for 12 days (Gursky and Klintsova, 2017). Previous studies conducted in the lab have shown that 12 days of voluntary exercise intervention in adolescence immediately ameliorated callosal myelination in AE rats (Milbocker et al., 2022, 2023). MRE was used to measure longitudinal changes to mechanical properties of the whole brain and the corpus callosum at intervention termination and one-month post-intervention. Histological quantification of precursor and myelinating oligoglia in corpus callosum was performed one-month post-intervention. Results: Prior to intervention, AE rats had lower forebrain stiffness in adolescence compared to SI controls ( p = 0.02). Exercise intervention immediately mitigated this effect in AE rats, resulting in higher forebrain stiffness post-intervention in adolescence. Similarly, we discovered that forebrain damping ratio was lowest in AE rats in adolescence ( p < 0.01), irrespective of intervention exposure. One-month post-intervention in adulthood, AE and SI rats exhibited comparable forebrain stiffness and damping ratio (p > 0.05). Taken together, these MRE data suggest that adolescent exercise intervention supports neurodevelopmental "catch-up" in AE rats. Analysis of the stiffness and damping ratio of the body of corpus callosum revealed that these measures increased with age. Finally, histological quantification of myelinating oligodendrocytes one-month post-intervention revealed a negative rebound effect of exercise cessation on the total estimate of these cells in the body of corpus callosum, irrespective of treatment group which was not convergent with noninvasive MRE measures. Conclusions: This is the first application of MRE to measure changes in brain mechanical properties in a rodent model of FASD. MRE successfully captured alcohol-related changes to forebrain stiffness and damping ratio in adolescence. These preliminary findings expand upon results from previous studies which used traditional diffusion neuroimaging to identify structural changes to the adolescent brain in rodent models of FASD (Milbocker et al., 2022; Newville et al., 2017). Additionally, in vivo MRE identified an exercise-related alteration to forebrain stiffness that occurred in adolescence, immediately post-intervention.

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.

Representation of prefrontal axonal efferents in the thalamic nucleus reuniens in a rodent model of fetal alcohol exposure during third trimester.

Alcohol exposure (AE) during the prenatal period could result in fetal alcohol spectrum disorders (FASDs), one of many deficits of which is impaired executive functioning (EF). EF relies on the coordination of activity between the medial prefrontal cortex (mPFC) and hippocampus (HPC) by the thalamic nucleus reuniens (Re), a structure that has been shown to be damaged following high-dose AE in a rodent model of third trimester exposure. Notably, mPFC neurons do not project directly to HPC, but rather communicate with it via a disynaptic pathway where the first cortical axons synapse on neurons in Re, which in turn send axons to make contacts with hippocampal cells. This experiment investigated the effect of binge AE (5.25 g/kg/day, two doses 2 h apart) during postnatal days 4-9 on the length of medial prefrontal axonal projections within Re in Long Evans rat. AE reduced the cumulative length of mPFC-originating axon terminals in Re in female rats, with male rats exhibiting shorter cumulative lengths when compared to female procedural control animals. Additionally, Re volume was decreased in AE animals, a finding that reproduced previously reported data. This experiment helps us better understand how early life AE affects prefrontal-thalamic-hippocampal connectivity that could underlie subsequent EF deficits.

Reduced and delayed myelination and volume of corpus callosum in an animal model of Fetal Alcohol Spectrum Disorders partially benefit from voluntary exercise.

1 in 20 live births in the United States is affected by prenatal alcohol exposure annually, creating a major public health crisis. The teratogenic impact of alcohol on physical growth, neurodevelopment, and behavior is extensive, together resulting in clinical disorders which fall under the umbrella term of Fetal Alcohol Spectrum Disorders (FASD). FASD-related impairments to executive function and perceptual learning are prevalent among affected youth and are linked to disruptions to corpus callosum growth and myelination in adolescence. Targeted interventions that support neurodevelopment in FASD-affected youth are nonexistent. We evaluated the capacity of an adolescent exercise intervention, a stimulator of myelinogenesis, to upregulate corpus callosum myelination in a rat model of FASD (third trimester-equivalent alcohol exposure). This study employs in vivo diffusion tensor imaging (DTI) scanning to investigate the effects of: (1) neonatal alcohol exposure and (2) an adolescent exercise intervention on corpus callosum myelination in a rodent model of FASD. DTI scans were acquired twice longitudinally (pre- and post-intervention) in male and female rats using a 9.4 Tesla Bruker Biospec scanner to assess alterations to corpus callosum myelination noninvasively. Fractional anisotropy values as well as radial/axial diffusivity values were compared within-animal in a longitudinal study design. Analyses using mixed repeated measures ANOVA's confirm that neonatal alcohol exposure in a rodent model of FASD delays the trajectory of corpus callosum growth and myelination across adolescence, with a heightened vulnerability in the male brain. Alterations to corpus callosum volume are correlated with reductions to forebrain volume which mediates an indirect relationship between body weight gain and corpus callosum growth. While we did not observe any significant effects of voluntary aerobic exercise on corpus callosum myelination immediately after completion of the 12-day intervention, we did observe a beneficial effect of exercise intervention on corpus callosum volume growth in all rats. In line with clinical findings, we have shown that prenatal alcohol exposure leads to hypomyelination of the corpus callosum in adolescence and that the severity of damage is sexually dimorphic. Further, exercise intervention improves corpus callosum growth in alcohol-exposed and control rats in adolescence.

Rat Model of Late Gestational Alcohol Exposure Produces Similar Life-Long Changes in Thalamic Nucleus Reuniens Following Moderate- Versus High-Dose Insult.

AIMS: Recent studies have recognized that thalamic nucleus reuniens (Re) undergoes substantial neuron loss following alcohol exposure (AE) during the brain growth spurt (BGS). As all previous studies have utilized high-dose AE paradigms, we tested whether moderate-dose AE is capable of damaging Re to a similar degree as high-dose AE. METHODS: We used a rat model of third-trimester binge AE (relative to human pregnancy) to administer ethanol to rat pups at either a high (5.25 g/kg/day) or moderate (3.00 g/kg/day) dose during the BGS (postnatal days [PD] 4-9) via intragastric intubation. In adulthood (i.e. PD72), we quantified the volume of Re as well as the total number of neurons and non-neuronal cells in the nucleus (which were further divided into microglia versus 'other' non-neurons), using unbiased stereological estimation of cells identified with immunofluorescent markers (i.e. nuclear label Hoechst, neuron-specific protein NeuN, and microglia-specific protein Iba1). Data were analyzed both between-treatment and correlated with peak blood alcohol concentration (BAC). RESULTS AND CONCLUSIONS: We observed significant neuronal and non-neuronal cell loss in both the high-dose and moderate-dose AE groups (relative to both procedural control and typically-developing control groups), which mediated reductions in Re volume. Outcomes did not correlate with peak BAC, further supporting that Re is vulnerable to AE-induced neurodegeneration at lower doses than previously suspected. Given the role that Re has in coordinating prefrontal cortex and hippocampus, the current study highlights the role that thalamic damage may play in the range of behavioral alterations observed in Fetal Alcohol Spectrum Disorders.

Glia-Driven Brain Circuit Refinement Is Altered by Early-Life Adversity: Behavioral Outcomes.

Early-life adversity (ELA), often clinically referred to as "adverse childhood experiences (ACE)," is the exposure to stress-inducing events in childhood that can result in poor health outcomes. ELA negatively affects neurodevelopment in children and adolescents resulting in several behavioral deficits and increasing the risk of developing a myriad of neuropsychiatric disorders later in life. The neurobiological mechanisms by which ELA alters neurodevelopment in childhood have been the focus of numerous reviews. However, a comprehensive review of the mechanisms affecting adolescent neurodevelopment (i.e., synaptic pruning and myelination) is lacking. Synaptic pruning and myelination are glia-driven processes that are imperative for brain circuit refinement during the transition from adolescence to adulthood. Failure to optimize brain circuitry between key brain structures involved in learning and memory, such as the hippocampus and prefrontal cortex, leads to the emergence of maladaptive behaviors including increased anxiety or reduced executive function. As such, we review preclinical and clinical literature to explore the immediate and lasting effects of ELA on brain circuit development and refinement. Finally, we describe a number of therapeutic interventions best-suited to support adolescent neurodevelopment in children with a history of ELA.

Changes in Representation of Thalamic Projection Neurons within Prefrontal-Thalamic-Hippocampal Circuitry in a Rat Model of Third Trimester Binge Drinking.

Alcohol exposure (AE) during the third trimester of pregnancy-a period known as the brain growth spurt (BGS)-could result in a diagnosis of a fetal alcohol spectrum disorder (FASD), a hallmark of which is impaired executive functioning (EF). Coordinated activity between prefrontal cortex and hippocampus is necessary for EF and thalamic nucleus reuniens (Re), which is required for prefrontal-hippocampal coordination, is damaged following high-dose AE during the BGS. The current experiment utilized high-dose AE (5.25 g/kg/day) during the BGS (i.e., postnatal days 4-9) of Long-Evans rat pups. AE reduces the number of neurons in Re into adulthood and selectively alters the proportion of Re neurons that simultaneously innervate both medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC). The AE-induced change unique to Re→(mPFC + vHPC) projection neurons (neuron populations that innervate either mPFC or vHPC individually were unchanged) is not mediated by reduction in neuron number. These data are the first to examine mPFC-Re-HPC circuit connectivity in a rodent model of FASD, and suggest that both short-term AE-induced neuron loss and long-term changes in thalamic connectivity may be two distinct (but synergistic) mechanisms by which developmental AE can alter mPFC-Re-vHPC circuitry and impair EF throughout the lifespan.

Midline Thalamic Damage Associated with Alcohol-Use Disorders: Disruption of Distinct Thalamocortical Pathways and Function.

The thalamus, a significant part of the diencephalon, is a symmetrical and bilateral central brain structure. The thalamus is subdivided into three major groups of nuclei based on their function: sensorimotor nuclei (or principal/relay nuclei), limbic nuclei and nuclei bridging these two domains. Anatomically, nuclei within the thalamus are described by their location, such as anterior, medial, lateral, ventral, and posterior. In this review, we summarize the role of medial and midline thalamus in cognition, ranging from learning and memory to flexible adaptation. We focus on the discoveries in animal models of alcohol-related brain damage, which identify the loss of neurons in the medial and midline thalamus as drivers of cognitive dysfunction associated with alcohol use disorders. Models of developmental ethanol exposure and models of adult alcohol-related brain damage and are compared and contrasted, and it was revealed that there are similar (anterior thalamus) and different (intralaminar [adult exposure] versus ventral midline [developmental exposure]) thalamic pathology, as well as disruptions of thalamo-hippocampal and thalamo-cortical circuits. The final part of the review summarizes approaches to recover alcohol-related brain damage and cognitive and behavioral outcomes. These approaches include pharmacological, nutritional and behavioral interventions that demonstrated the potential to mitigate alcohol-related damage. In summary, the medial/midline thalamus is a significant contributor to cognition function, which is also sensitive to alcohol-related brain damage across the life span, and plays a role in alcohol-related cognitive dysfunction.

Examination of cortically projecting cholinergic neurons following exercise and environmental intervention in a rodent model of fetal alcohol spectrum disorders.

BACKGROUND: Up to 1 in 5 infants in the United States are exposed to alcohol prenatally, resulting in neurodevelopmental deficits categorized as fetal alcohol spectrum disorders (FASD). Choline supplementation ameliorates some deficits, suggesting that alcohol exposure (AE) perturbs cholinergic neurotransmission and development. Behavioral interventions, which upregulate cholinergic neurotransmission, rescue cognitive deficits in rodent models of FASD. METHODS: We investigated the impacts of two interventions (either wheel-running (WR) or "super intervention," WR plus exposure to a complex environment) on cholinergic neuronal morphology in the nucleus basalis of Meynert (NBM), the source of cortical cholinergic input, and prefrontal cortex (PFC) in a rodent model of FASD. One third of the total 47 male pups received intragastric intubation of ethanol in milk substitute during postnatal days (PD) 4-9. Another third served as sham-intubated procedural controls while the final third served as suckle controls. Rats from each group were exposed to either intervention during PD 30-72. Choline acetyltransferase (ChAT+ ) and acetylcholinesterase staining were used to quantify cholinergic neuron number, soma volume, and axon number. RESULTS: Our data indicate a main effect of postnatal treatment on ChAT+ neuron number in NBM in adulthood. Post hoc analysis demonstrates that ChAT+ neuron number is reduced in AE compared to suckle control rodents (p < .01). CONCLUSIONS: We examined the cytoarchitectonics of cholinergic neurons in NBM and PFC in adulthood following early postnatal AE and two interventions. We show that AE reduces ChAT+ neuron number in NBM, and this is not mitigated by either intervention.

Postnatal alcohol exposure and adolescent exercise have opposite effects on cerebellar microglia in rat.

Developmental alcohol exposure results in altered neuroimmune function in both humans and rodents. Given the critical role for the principle neuroimmune cell, microglia, in maintaining synaptic form and function, microglial dysfunction in the cerebellum may be an important mechanism underlying the aberrant cerebellar connectivity observed in rodent models of fetal alcohol spectrum disorders. Using an established rodent model of alcohol exposure during human third-trimester fetal development, we examine the cerebellum of male and female Long Evans rats to determine the impact of early postnatal alcohol exposure on cerebellar microglia, and the potential therapeutic effects of an adolescent intervention consisting of voluntary exercise (running). All cerebelli were examined at postnatal day 42 (i.e., late adolescence), and microglia were labeled with Iba1, a microglia-specific protein. Early postnatal alcohol exposure caused an increase in microglial density throughout cerebellum and a reduction in cerebellar volume, and a reduction in the proportion of fully ramified (often called "resting state") microglia selective to lobules 1-4. In contrast, adolescent exercise decreased microglial density throughout cerebellum and increased cerebellar volume, while activating microglia (as indicated by increases in amoeboid microglia, and reductions in fully and partially ramified microglia) selectively in lobules 1-4. These results suggest that adolescent exercise may be a suitable intervention to ameliorate alcohol-induced neuroimmune dysfunction as it alters microglia density and cerebellar volume in opposite to the effects of developmental alcohol exposure. Importantly, exercise intervention can be flexibly implemented well after the time window of vulnerability to alcohol.

Single-day Postnatal Alcohol Exposure Induces Apoptotic Cell Death and Causes long-term Neuron Loss in Rodent Thalamic Nucleus Reuniens.

Fetal alcohol spectrum disorders (FASD) constitute a prevalent, yet preventable, developmental disorder worldwide. While a wealth of research demonstrates that altered function of hippocampus (HPC) and prefrontal cortex may underlie behavioral impairments in FASD, only one published paper to date has examined the impact of developmental alcohol exposure (AE) on the region responsible for coordinated prefrontal-hippocampal activity: thalamic nucleus reuniens (Re). In the current study, we used a rodent model of human third trimester AE to examine both the acute and lasting impact of a single-day AE on Re. We administered 5.25 g/kg of ethanol to male and female Long Evans rat pups on postnatal day (PD) 7. We used unbiased stereological estimation to evaluate cell death or cell loss at three time points: 12 h after alcohol administration; 4 days after alcohol administration (i.e., PD11); in adulthood (i.e.,PD 72). AE on PD7 increased apoptotic cell death in Re on PD7, and caused short-term cell loss on PD11. This relationship between short-term cell death versus cell number suggests that alcohol-related cell loss is driven by induction of apoptosis. In adulthood, alcohol-exposed animals displayed permanent cell loss (mediating volume loss in the Re), which included a reduction in neuron number (relative to procedural controls). Both procedural controls and alcohol exposed animals displayed a deficit in non-neuronal cell number relative to typically-developing controls, suggesting that Re cell populations may be vulnerable to early life stress as well as AE in an insult- and cell type-dependent manner.

Proceedings of the 2018 annual meeting of the Fetal Alcohol Spectrum Disorders study group.

The 2018 Fetal Alcohol Spectrum Disorders Study Group (FASDSG) meeting was entitled "Sex Differences and Vulnerability." The theme reflected the ongoing NIH initiative to address sex differences in both clinical and preclinical research. The first keynote speaker, Jill Becker, Ph.D., addressed sex differences in addiction in preclinical studies. The second keynote speaker, Meeyoung Min, Ph.D., discussed effects of gender on adolescent outcomes in poly-drug exposed children. The conference presented updates from three government agencies, a discussion panel of new data on FASD prevalence, and short presentations by junior and senior investigators showcasing late-breaking FASD research. The conference was capped by the presentation of Dr. Sarah Mattson, Ph.D., the recipient of the 2018 Henry Rosett award for career-long contributions to the field.

Nucleus reuniens of the midline thalamus of a rat is specifically damaged after early postnatal alcohol exposure.

Individuals diagnosed with fetal alcohol spectrum disorders often show behavioral impairments in executive functioning. Mechanistic studies have implicated coordination between the prefrontal cortex and the hippocampus (through thalamic nucleus reuniens) as essential for such executive functions. This study is the first to report the long-term neuroanatomical alterations to the ventral midline thalamus after alcohol exposure on postnatal days 4-9 (a rodent model of binge drinking during the third-trimester of human pregnancy). Alcohol added to a milk formula was administered to female Long-Evans rat pups on postnatal days 4-9 (5.25 g/kg/day of ethanol, intragastric intubation). Control animals were intubated without the administration of liquid. In adulthood, brains were immunohistochemically labeled for a neuronal marker (NeuN) conjugated with Cy3 fluorophore and stained with Hoechst33342 to visualize nuclei. Total non-neuronal cell number (NeuN/Hoechst) and neuron number (NeuN/Hoechst), and total volume were estimated using unbiased stereology in two neighboring midline thalamic nuclei: reuniens and rhomboid. Estimates were analyzed using linear mixed modeling to account for animal and litter as clustering variables. A 21% reduction in the total neuron number (resulting in altered neuron-to-non-neuron ratio) and an 18% reduction in total volume were found exclusively in thalamic nucleus reuniens in rats exposed to ethanol. Non-neuronal cell number was not changed in reuniens. No ethanol-induced changes on any measures were observed in rhomboid nucleus. These specific neuroanatomical alterations provide a necessary foundation for further examination of circuit-level alterations that occur in fetal alcohol spectrum disorder.

Proceedings of the 2017 annual meeting of the Fetal Alcohol Spectrum Disorders study group.

The 2017 Fetal Alcohol Spectrum Disorders Study Group (FASDSG) meeting was titled "Prenatal alcohol exposure in the context of multiple factors affecting brain development." The theme was reflected in the interactions between members of the Teratology Society and the FASDSG this year. The first keynote speaker, Elaine Faustman, Ph.D., was a liaison between the societies and spoke about systems biology and the multiple genetic and environmental influences on development. The second keynote speaker, Rebecca Knickmeyer, Ph.D., discussed population neuroscience and multiple influences on brain development. The conference presented updates from three government agencies and short presentations by junior and senior investigators showcasing late-breaking FASD research. The conference was capped by Dr. John Hannigan, Ph.D., the recipient of the 2017 Henry Rosett award for career-long contributions to the field.

Proceedings of the 2016 annual meeting of the Fetal Alcohol Spectrum Disorders Study Group.

The 2016 Fetal Alcohol Spectrum Disorders Study Group (FASDSG) meeting was titled "Rehabilitation in FASD: Potential Interventions and Challenges". During the previous decades, studies with human subjects and animal models have improved much of our understanding of the mechanisms underlying FASD, putting the scientific community in a good position to test hypotheses that can lead to potential therapeutic interventions. During the conference, two keynote speakers addressed potential interventions used in different fields and their applicability to FASD research. The conference also included updates from several government agencies, short presentations by junior and senior investigators that showcased the latest in FASD research, and award presentations. The conference was closed by a talk by Dr. Charles Goodlett, the recipient of the 2016 Henry Rosett award.

Wheel Running and Environmental Complexity as a Therapeutic Intervention in an Animal Model of FASD.

Aerobic exercise (e.g., wheel running (WR) extensively used in animal research) positively impacts many measures of neuroplastic potential in the brain, such as rates of adult neurogenesis, angiogenesis, and expression of neurotrophic factors in rodents. This intervention has also been shown to mitigate behavioral and neuroanatomical aspects of the negative impacts of teratogens (i.e., developmental exposure to alcohol) and age-related neurodegeneration in rodents. Environmental complexity (EC) has been shown to produce numerous neuroplastic benefits in cortical and subcortical structures and can be coupled with wheel running to increase the proliferation and survival of new cells in the adult hippocampus. The combination of these two interventions provides a robust "superintervention" (WR-EC) that can be implemented in a range of rodent models of neurological disorders. We will discuss the implementation of WR/EC and its constituent interventions for use as a more powerful therapeutic intervention in rats using the animal model of prenatal exposure to alcohol in humans. We will also discuss which elements of the procedures are absolutely necessary for the interventions and which ones may be altered depending on the experimenter's question or facilities.

Proceedings of the 2015 Annual Meeting of the Fetal Alcohol Spectrum Disorders Study Group.

The 2015 Fetal Alcohol Spectrum Disorders Study Group (FASDSG) meeting was titled "Basic Mechanisms and Translational Implications." Despite decades of basic science and clinical research, our understanding of the mechanisms by which ethanol affects fetal development is still in its infancy. The first keynote presentation focused on the role of heat shock protein pathways in the actions of ethanol in the developing brain. The second keynote presentation addressed the use of magnetoencephalography to characterize brain function in children with FASD. The conference also included talks by representatives from several government agencies, short presentations by junior and senior investigators that showcased the latest in FASD research, and award presentations. An important part of the meeting was the presentation of the 2015 Henry Rosett award to Dr. Michael Charness in honor of his achievements in research on FASD.

Activity and social behavior in a complex environment in rats neonatally exposed to alcohol.

Environmental complexity (EC) is a powerful, stimulating paradigm that engages animals through a variety of sensory and motor pathways. Exposure to EC (30 days) following 12 days of wheel running preserves hippocampal neuroplasticity in male rats neonatally exposed to alcohol during the third-trimester equivalent (binge-like exposure on postnatal days [PD] 4-9). The current experiment investigates the importance of various components of EC (physical activity, exploration, social interaction, novelty) and examines whether neonatal alcohol exposure affects how male rats interact with their environment and other male rats. Male pups were assigned to 1 of 3 neonatal conditions from PD 4-9: suckle control (SC), sham-intubated (SI), or alcohol-exposed (AE, 5.25 g/kg/day). From PD 30-42 animals were housed with 24-h access to a voluntary running wheel. The animals were then placed in EC from PD 42-72 (9 animals/cage, counterbalanced by neonatal condition). During EC, the animals were filmed for five 30-min sessions (PD 42, 48, 56, 64, 68). For the first experiment, the videos were coded for distance traveled in the cage, overall locomotor activity, time spent near other animals, and interaction with toys. For the second experiment, the videos were analyzed for wrestling, mounting, boxing, grooming, sniffing, and crawling over/under. AE animals were found to be less active and exploratory and engaged in fewer mounting behaviors compared to control animals. Results suggest that after exposure to wheel running, AE animals still have deficits in activity and social behaviors while housed in EC compared to control animals with the same experience.

Rehabilitation training using complex motor learning rescues deficits in eyeblink classical conditioning in female rats induced by binge-like neonatal alcohol exposure.

BACKGROUND: Effective treatments for the behavioral and cognitive deficits in children with fetal alcohol spectrum disorders (FASD) are lacking, and translational approaches using animal models can help develop rational interventions. One such model, binge-like alcohol exposure in neonatal rats during the period of brain development comparable with that of the human third trimester, causes structural and functional damage to the cerebellum and disrupts cerebellar-dependent eyeblink classical conditioning. The eyeblink conditioning deficits first demonstrated in this rat model predicted the similar deficits subsequently demonstrated in children with FASD. METHODS: The current study extends this translational approach by testing the hypothesis that rehabilitation training involving 20 days of training on traversal of an obstacle course (complex motor learning) would ameliorate the deficits on classical conditioning of eyeblink responses produced by the neonatal alcohol exposure. We have previously shown that this training stimulates cerebellar synaptic plasticity and improves alcohol-induced deficits on motor coordination tasks. RESULTS: The current studies found that rehabilitation training significantly attenuated alcohol-induced deficits in acquisition of eyeblink conditioning in females but not in males. These results are consistent with normalization of cerebellar-dependent learning, at least in alcohol-exposed females. CONCLUSIONS: These findings extend previous studies in this model suggesting that rehabilitation of adolescents with FASD using training with complex motor learning tasks could be effective in ameliorating functional impairments associated with cerebellar damage. Eyeblink classical conditioning deficits are now well documented in children with FASD and could serve as an evaluation measure to continue to develop therapeutic interventions such as complex motor learning.