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.

[1]  R. Gerlai,et al.  Early embryonic ethanol exposure impairs shoaling and the dopaminergic and serotoninergic systems in adult zebrafish. , 2011, Neurotoxicology and teratology.

[2]  Csaba Nyakas,et al.  Physical exercise leads to rapid adaptations in hippocampal vasculature: Temporal dynamics and relationship to cell proliferation and neurogenesis , 2009, Hippocampus.

[3]  C. McDonald,et al.  Alcohol exposure during adolescence impairs auditory fear conditioning in adult Long-Evans rats , 2006, Physiology & Behavior.

[4]  P. Clark,et al.  Voluntary wheel running enhances contextual but not trace fear conditioning , 2012, Behavioural Brain Research.

[5]  S. Kelly,et al.  Selective effects of perinatal ethanol exposure in medial prefrontal cortex and nucleus accumbens. , 2012, Neurotoxicology and teratology.

[6]  L. Reichardt,et al.  Neurotrophin-regulated signalling pathways , 2006, Philosophical Transactions of the Royal Society B: Biological Sciences.

[7]  H. van Praag,et al.  All about running: synaptic plasticity, growth factors and adult hippocampal neurogenesis. , 2013, Current topics in behavioral neurosciences.

[8]  Mal-Soon Shin,et al.  Treadmill exercise and methylphenidate ameliorate symptoms of attention deficit/hyperactivity disorder through enhancing dopamine synthesis and brain-derived neurotrophic factor expression in spontaneous hypertensive rats , 2011, Neuroscience Letters.

[9]  J. Ahlskog.  Does vigorous exercise have a neuroprotective effect in Parkinson disease? , 2011, Neurology.

[10]  A. Caspi,et al.  Is It Important to Prevent Early Exposure to Drugs and Alcohol Among Adolescents? , 2008, Psychological science.

[11]  K. Wisniewski,et al.  A clinical neuropathological study of the fetal alcohol syndrome. , 1983, Neuropediatrics.

[12]  B. Christie,et al.  Voluntary exercise alters the cytoarchitecture of the adult dentate gyrus by increasing cellular proliferation, dendritic complexity, and spine density , 2005, The Journal of comparative neurology.

[13]  J. Olney,et al.  Drug‐induced Apoptotic Neurodegeneration in the Developing Brain , 2002, Brain pathology.

[14]  Zhe Ying,et al.  Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition , 2004, The European journal of neuroscience.

[15]  T. Kusaka,et al.  Early postnatal ethanol exposure induces fluctuation in the expression of BDNF mRNA in the developing rat hippocampus. , 2008, Acta neurobiologiae experimentalis.

[16]  E. Franz,et al.  Effect of age on exercise-induced alterations in cognitive executive function: Relationship to cerebral perfusion , 2012, Experimental Gerontology.

[17]  J. Weinberg,et al.  Effects of prenatal ethanol exposure on hypothalamic-pituitary-adrenal function across the estrous cycle. , 2009, Alcoholism, clinical and experimental research.

[18]  M. Stanton,et al.  Neonatal alcohol exposure and the hippocampus in developing male rats: effects on behaviorally induced CA1 c-Fos expression, CA1 pyramidal cell number, and contextual fear conditioning , 2012, Neuroscience.

[19]  T. Tran,et al.  Choline supplementation mitigates trace, but not delay, eyeblink conditioning deficits in rats exposed to alcohol during development , 2012, Hippocampus.

[20]  F. Leslie,et al.  The effects of perinatal choline supplementation on hippocampal cholinergic development in rats exposed to alcohol during the brain growth spurt , 2012, Hippocampus.

[21]  L. Burd,et al.  Cost of fetal alcohol spectrum disorders , 2004, American journal of medical genetics. Part C, Seminars in medical genetics.

[22]  Paffenbarger Rs,et al.  Workshop on Epidemiologic and Public Health Aspects of Physical Activity and Exercise: a summary. , 1985 .

[23]  K. J. Lee,et al.  Effects of aerobic exercise training on cognitive function and cortical vascularity in monkeys , 2010, Neuroscience.

[24]  Joseph J. Sabia,et al.  Exercise and adolescent mental health: new evidence from longitudinal data. , 2010, The journal of mental health policy and economics.

[25]  Ernesta M Meintjes,et al.  Impaired delay and trace eyeblink conditioning in school-age children with fetal alcohol syndrome. , 2011, Alcoholism, clinical and experimental research.

[26]  S. Paul,et al.  Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-A beta antibody. , 2006, The Journal of clinical investigation.

[27]  Debbie A Lawlor,et al.  The effectiveness of exercise as an intervention in the management of depression: systematic review and meta-regression analysis of randomised controlled trials , 2001, BMJ : British Medical Journal.

[28]  Walter J. Jermakowicz,et al.  Ethanol-Induced Caspase-3 Activation in the in Vivo Developing Mouse Brain , 2002, Neurobiology of Disease.

[29]  D. B. Moore,et al.  The role of neurotrophic factors, apoptosis-related proteins, and endogenous antioxidants in the differential temporal vulnerability of neonatal cerebellum to ethanol. , 2003, Alcoholism, clinical and experimental research.

[30]  Z. Bori,et al.  Long-term exercise treatment reduces oxidative stress in the hippocampus of aging rats , 2012, Neuroscience.

[31]  Tamar Licht,et al.  Reversible modulations of neuronal plasticity by VEGF , 2011, Proceedings of the National Academy of Sciences.

[32]  W. Greenough,et al.  Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[33]  C. Valenzuela,et al.  Behavioral effects of ethanol in cerebellum are age dependent: potential system and molecular mechanisms. , 2010, Alcoholism, clinical and experimental research.

[34]  M Chopp,et al.  VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. , 2000, The Journal of clinical investigation.

[35]  H. van Praag,et al.  Running throughout middle‐age improves memory function, hippocampal neurogenesis, and BDNF levels in female C57BL/6J mice , 2012, Developmental neurobiology.

[36]  Ho-youl Kang,et al.  Effects of Endurance Exercise and High-Fat Diet on Insulin Resistance and Ceramide Contents of Skeletal Muscle in Sprague-Dawley Rats , 2010, Korean diabetes journal.

[37]  Shane M. O'Mara,et al.  Aerobic exercise improves hippocampal function and increases BDNF in the serum of young adult males , 2011, Physiology & Behavior.

[38]  S. Maffi,et al.  Ethanol‐induced oxidative stress precedes mitochondrially mediated apoptotic death of cultured fetal cortical neurons , 2003, Journal of neuroscience research.

[39]  T. Jernigan,et al.  Abnormal development of the cerebellar vermis in children prenatally exposed to alcohol: size reduction in lobules I-V. , 1996, Alcoholism, clinical and experimental research.

[40]  Kathleen K. Sulik,et al.  Genesis of Alcohol-Induced Craniofacial Dysmorphism , 2005, Experimental biology and medicine.

[41]  H. Praag.  Exercise and the brain: something to chew on , 2009, Trends in Neurosciences.

[42]  S. M. Sumi,et al.  Brain malformations related to prenatal exposure to ethanol. , 1978, The Journal of pediatrics.

[43]  T. Pak,et al.  17β-Estradiol Is Required for the Sexually Dimorphic Effects of Repeated Binge-Pattern Alcohol Exposure on the HPA Axis during Adolescence , 2012, PloS one.

[44]  Henriette Pilegaard,et al.  Evidence for a release of brain‐derived neurotrophic factor from the brain during exercise , 2009, Experimental physiology.

[45]  T. Kaneko,et al.  The effects of moderate-, strenuous- and over-training on oxidative stress markers, DNA repair, and memory, in rat brain , 2005, Neurochemistry International.

[46]  C. Cotman,et al.  Estrogen and exercise interact to regulate brain‐derived neurotrophic factor mRNA and protein expression in the hippocampus , 2001, The European journal of neuroscience.

[47]  D. Walker,et al.  Ethanol-induced alterations in the expression of neurotrophic factors in the developing rat central nervous system. , 2000, Brain research. Developmental brain research.

[48]  Lisa M Saksida,et al.  ffects of environmental enrichment and voluntary exercise on neurogenesis , earning and memory , and pattern separation : BDNF as a critical variable ? , 2011 .

[49]  Gerd Kempermann,et al.  Experience-Induced Neurogenesis in the Senescent Dentate Gyrus , 1998, The Journal of Neuroscience.

[50]  G. Fan,et al.  Exercise impacts brain‐derived neurotrophic factor plasticity by engaging mechanisms of epigenetic regulation , 2011, The European journal of neuroscience.

[51]  E. Riley,et al.  Teratogenic Effects of Alcohol on Brain and Behavior , 2001, Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism.

[52]  J. Kaiser,et al.  Kinetics of serum brain-derived neurotrophic factor following low-intensity versus high-intensity exercise in men and women , 2012, Neuroreport.

[53]  J. Grisel,et al.  Locomotor sensitization to EtOH: contribution of β-Endorphin , 2012, Front. Mol. Neurosci..

[54]  B. Christie,et al.  Voluntary exercise induces adult hippocampal neurogenesis and BDNF expression in a rodent model of fetal alcohol spectrum disorders , 2011, The European journal of neuroscience.

[55]  Brian E Bernier,et al.  Previous Ethanol Experience Enhances Synaptic Plasticity of NMDA Receptors in the Ventral Tegmental Area , 2011, The Journal of Neuroscience.

[56]  C. Guerri,et al.  Intermittent ethanol exposure increases long-lasting behavioral and neurochemical effects of MDMA in adolescent mice , 2011, Psychopharmacology.

[57]  A. Klintsova,et al.  Postnatal binge‐like alcohol exposure reduces spine density without affecting dendritic morphology in rat mPFC , 2008, Synapse.

[58]  R. Hellweg,et al.  Voluntary exercise induces anxiety‐like behavior in adult C57BL/6J mice correlating with hippocampal neurogenesis , 2009, Hippocampus.

[59]  John T. Green,et al.  The effects of two forms of physical activity on eyeblink classical conditioning , 2011, Behavioural Brain Research.

[60]  K. Partanen,et al.  Brain perfusion SPECT and MRI in foetal alcohol syndrome , 1999, Developmental medicine and child neurology.

[61]  F. Gage,et al.  Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus , 1999, Nature Neuroscience.

[62]  Evgenia Cherouveim,et al.  Frontal cerebral cortex blood flow, oxygen delivery and oxygenation during normoxic and hypoxic exercise in athletes , 2011, The Journal of physiology.

[63]  Luc Vanhees,et al.  Physical activity and enhanced fitness to improve cognitive function in older people without known cognitive impairment. , 2008, The Cochrane database of systematic reviews.

[64]  S. Maier,et al.  Freewheel Running Prevents Learned Helplessness/Behavioral Depression: Role of Dorsal Raphe Serotonergic Neurons , 2003, The Journal of Neuroscience.

[65]  P. L. Larsen.  Aging and resistance to oxidative damage in Caenorhabditis elegans. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[66]  W. Greenough,et al.  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. , 2012, Alcoholism, clinical and experimental research.

[67]  A. Bauman,et al.  Epidemiology of physical activity participation among New South Wales school students , 2002, Australian and New Zealand journal of public health.

[68]  Victor Swayze,et al.  Brain function in fetal alcohol syndrome assessed by single photon emission computed tomography. , 2002, South Dakota journal of medicine.

[69]  M. Stanton,et al.  Neonatal alcohol exposure disrupts hippocampal neurogenesis and contextual fear conditioning in adult rats , 2011, Brain Research.

[70]  R. Sircar,et al.  Adolescent rats exposed to repeated ethanol treatment show lingering behavioral impairments. , 2005, Alcoholism, clinical and experimental research.

[71]  B. McCool.  Ethanol modulation of synaptic plasticity , 2011, Neuropharmacology.

[72]  Shigehiko Ogoh,et al.  The distribution of blood flow in the carotid and vertebral arteries during dynamic exercise in humans , 2011, The Journal of physiology.

[73]  B. Gualano,et al.  Effects of acute physical exercise on executive functions: a comparison between aerobic and strength exercise. , 2012, Journal of sport & exercise psychology.

[74]  A. Hayar,et al.  Developmental alterations in olivary climbing fiber distribution following postnatal ethanol exposure in the rat , 2010, Neuroscience.

[75]  H. Moser,et al.  Dendritic anomalies in disorders associated with mental retardation. , 1999, Cerebral cortex.

[76]  Dan J Stein,et al.  Exercise normalizes altered expression of proteins in the ventral hippocampus of rats subjected to maternal separation , 2012, Experimental physiology.

[77]  G. Johnson,et al.  Ethanol-Induced Face-Brain Dysmorphology Patterns Are Correlative and Exposure-Stage Dependent , 2012, PloS one.

[78]  R. Sircar,et al.  Repeated ethanol treatment in adolescent rats alters cortical NMDA receptor. , 2006, Alcohol.

[79]  Fernando Cadaveira,et al.  Executive functioning and alcohol binge drinking in university students. , 2012, Addictive behaviors.

[80]  Florence F. Roussotte,et al.  Abnormal cortical thickness alterations in fetal alcohol spectrum disorders and their relationships with facial dysmorphology. , 2012, Cerebral cortex.

[81]  W. Greenough,et al.  Differential rearing effects on rat visual cortex synapses. I. Synaptic and neuronal density and synapses per neuron , 1985, Brain Research.

[82]  D. Bucci,et al.  Physical exercise during adolescence versus adulthood: differential effects on object recognition memory and brain-derived neurotrophic factor levels , 2011, Neuroscience.

[83]  J. Olney,et al.  Neurotransmitters and apoptosis in the developing brain. , 2001, Biochemical pharmacology.

[84]  A. Klintsova,et al.  Postnatal binge‐like alcohol exposure decreases dendritic complexity while increasing the density of mature spines in mPFC Layer II/III pyramidal neurons , 2010, Synapse.

[85]  L. Lanfumey,et al.  Effect of enhanced voluntary physical exercise on brain levels of monoamines in Huntington disease mice , 2011, PLoS currents.

[86]  M. Kim,et al.  Protective effect of pyruvate against ethanol-induced apoptotic neurodegeneration in the developing rat brain , 2011, Neuropharmacology.

[87]  C. Cotman,et al.  Dietary and Behavioral Interventions Protect against Age Related Activation of Caspase Cascades in the Canine Brain , 2011, PloS one.

[88]  M. Stanton,et al.  Effects of exercise and environmental complexity on deficits in trace and contextual fear conditioning produced by neonatal alcohol exposure in rats. , 2013, Developmental psychobiology.

[89]  A F Kramer,et al.  Social relations, physical activity, and well-being in older adults. , 2000, Preventive medicine.

[90]  Jayanth Ramadoss,et al.  Chronic ethanol increases fetal cerebral blood flow specific to the ethanol‐sensitive cerebellum under normoxaemic, hypercapnic and acidaemic conditions: ovine model , 2007, Experimental physiology.

[91]  J. Buscemi,et al.  Moderators of the Relationship Between Physical Activity and Alcohol Consumption in College Students , 2011, Journal of American college health : J of ACH.

[92]  J. Rhodes,et al.  Aerobic exercise is the critical variable in an enriched environment that increases hippocampal neurogenesis and water maze learning in male C57BL/6J mice , 2012, Neuroscience.

[93]  R. Napper,et al.  Acute and long-term Purkinje cell loss following a single ethanol binge during the early third trimester equivalent in the rat. , 2012, Alcoholism, clinical and experimental research.

[94]  E. Shooter,et al.  BDNF overexpression increases dendrite complexity in hippocampal dentate gyrus , 2002, Neuroscience.

[95]  J. Bertrand,et al.  Medical expenditures of children in the United States with fetal alcohol syndrome. , 2011, Neurotoxicology and teratology.

[96]  E P Riley,et al.  A decrease in the size of the basal ganglia in children with fetal alcohol syndrome. , 1996, Alcoholism, clinical and experimental research.

[97]  T. Jirikowic,et al.  Children with fetal alcohol spectrum disorders: problem behaviors and sensory processing. , 2008, The American journal of occupational therapy : official publication of the American Occupational Therapy Association.

[98]  P. Clark,et al.  Adult hippocampal neurogenesis and c-Fos induction during escalation of voluntary wheel running in C57BL/6J mice , 2010, Behavioural Brain Research.

[99]  C. Cotman,et al.  Exercise-induced noradrenergic activation enhances memory consolidation in both normal aging and patients with amnestic mild cognitive impairment. , 2012, Journal of Alzheimer's disease : JAD.

[100]  D. Harman.  Aging: a theory based on free radical and radiation chemistry. , 1956, Journal of gerontology.

[101]  Gil-Young An,et al.  Treadmill exercise represses neuronal cell death in an aged transgenic mouse model of Alzheimer's disease , 2011, Neuroscience Research.

[102]  N. Perrone-Bizzozero,et al.  Opposite effects of acute ethanol exposure on GAP-43 and BDNF expression in the hippocampus versus the cerebellum of juvenile rats. , 2011, Alcohol.

[103]  L. Spear,et al.  Chronic tolerance to the social consequences of ethanol in adolescent and adult Sprague-Dawley rats. , 2007, Neurotoxicology and teratology.

[104]  V. Petkov,et al.  [Lipid peroxidation changes in the brain in fetal alcohol syndrome]. , 1992, Biulleten' eksperimental'noi biologii i meditsiny.

[105]  Myoung-Hwa Lee,et al.  Maternal ethanol administration inhibits 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in the dorsal raphe of rat offspring , 2005, Brain and Development.

[106]  J. Beck,et al.  High exercise levels are related to favorable sleep patterns and psychological functioning in adolescents: a comparison of athletes and controls. , 2010, The Journal of adolescent health : official publication of the Society for Adolescent Medicine.

[107]  R. Traystman,et al.  Newborn Cerebrovascular Responses after First Trimester Moderate Maternal Ethanol Exposure in Sheep , 1997, Pediatric Research.

[108]  S. Knecht,et al.  High impact running improves learning , 2007, Neurobiology of Learning and Memory.

[109]  I. Goudarzi,et al.  Neuroprotective effects of the 17β-estradiol against ethanol-induced neurotoxicity and oxidative stress in the developing male rat cerebellum: Biochemical, histological and behavioral changes , 2011, Pharmacology Biochemistry and Behavior.

[110]  T. Ikeda,et al.  Sex differences in the benefits of rehabilitative training during adolescence following neonatal hypoxia–ischemia in rats , 2010, Experimental Neurology.

[111]  L. Johnston,et al.  Exercise and substance use among American youth, 1991-2009. , 2011, American journal of preventive medicine.

[112]  W. Greenough,et al.  The effects of exercise on adolescent hippocampal neurogenesis in a rat model of binge alcohol exposure during the brain growth spurt , 2009, Brain Research.

[113]  K. Nixon,et al.  Adolescent binge alcohol exposure alters hippocampal progenitor cell proliferation in rats: Effects on cell cycle kinetics , 2011, The Journal of comparative neurology.

[114]  D. B. Matthews,et al.  Effects of ethanol on hippocampal function during adolescence: a look at the past and thoughts on the future. , 2010, Alcohol.

[115]  R. Mortara,et al.  Early exercise promotes positive hippocampal plasticity and improves spatial memory in the adult life of rats , 2012, Hippocampus.

[116]  Shameena Bake,et al.  Ethanol exposure during pregnancy persistently attenuates cranially directed blood flow in the developing fetus: evidence from ultrasound imaging in a murine second trimester equivalent model. , 2012, Alcoholism, clinical and experimental research.

[117]  T. Teasdale,et al.  Cognitive and Social Development in Preschool Children Born to Women Using Substances , 2012, Journal of addictive diseases.

[118]  Social problem solving in children with fetal alcohol spectrum disorders. , 2012, Journal of population therapeutics and clinical pharmacology = Journal de la therapeutique des populations et de la pharamcologie clinique.

[119]  A. Navarro,et al.  Beneficial effects of moderate exercise on mice aging: survival, behavior, oxidative stress, and mitochondrial electron transfer. , 2004, American journal of physiology. Regulatory, integrative and comparative physiology.

[120]  E P Riley,et al.  Brain dysmorphology in individuals with severe prenatal alcohol exposure , 2001, Developmental medicine and child neurology.

[121]  W. Greenough,et al.  Binge‐like postnatal alcohol exposure triggers cortical gliogenesis in adolescent rats , 2009, The Journal of comparative neurology.

[122]  M. Murray,et al.  Exercise Induces Cortical Plasticity after Neonatal Spinal Cord Injury in the Rat , 2009, The Journal of Neuroscience.

[123]  E. Levine,et al.  BDNF enhancement of postsynaptic NMDA receptors is blocked by ethanol , 2005, Synapse.

[124]  A. Sun,et al.  Ethanol-Induced Cell Death by Lipid Peroxidation in PC12 Cells , 1997, Neurochemical Research.

[125]  M. Morris,et al.  Voluntary exercise and palatable high-fat diet both improve behavioural profile and stress responses in male rats exposed to early life stress: Role of hippocampus , 2010, Psychoneuroendocrinology.

[126]  F. Volkmar,et al.  Effects of rearing complexity on dendritic branching in frontolateral and temporal cortex of the rat. , 1973, Experimental neurology.

[127]  Matteo Cesari,et al.  Predictors of Combined Cognitive and Physical Decline , 2005, Journal of the American Geriatrics Society.

[128]  C. Guerri,et al.  Changes in histone acetylation in the prefrontal cortex of ethanol-exposed adolescent rats are associated with ethanol-induced place conditioning , 2012, Neuropharmacology.

[129]  R. Sircar,et al.  Repeated ethanol exposure affects the acquisition of spatial memory in adolescent female rats , 2009, Behavioural Brain Research.

[130]  N. K. Popova,et al.  Ameliorative effect of BDNF on prenatal ethanol and stress exposure-induced behavioral disorders , 2011, Neuroscience Letters.

[131]  Maryam Soleimani,et al.  Executive functioning and working memory deficits on the CANTAB among children with prenatal alcohol exposure. , 2011, Journal of population therapeutics and clinical pharmacology = Journal de la therapeutique des populations et de la pharamcologie clinique.

[132]  W. Greenough,et al.  Therapeutic motor training increases parallel fiber synapse number per Purkinje neuron in cerebellar cortex of rats given postnatal binge alcohol exposure: preliminary report. , 1997, Alcoholism, clinical and experimental research.

[133]  P. Meikle,et al.  Consumption of a high‐fat diet, but not regular endurance exercise training, regulates hypothalamic lipid accumulation in mice , 2012, The Journal of physiology.

[134]  Arthur F. Kramer,et al.  Basal Ganglia Volume Is Associated with Aerobic Fitness in Preadolescent Children , 2010, Developmental Neuroscience.

[135]  H. Aizenstein,et al.  Caudate asymmetry: a neurobiological marker of moderate prenatal alcohol exposure in young adults. , 2010, Neurotoxicology and teratology.

[136]  Gerd Kempermann,et al.  Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus , 2006, Neurobiology of Aging.

[137]  E. Bennett,et al.  CEREBRAL EFFECTS OF ENVIRONMENTAL COMPLEXITY AND TRAINING AMONG ADULT RATS. , 1964, Journal of comparative and physiological psychology.

[138]  C. Vadász,et al.  Ethanol triggers sphingosine 1‐phosphate elevation along with neuroapoptosis in the developing mouse brain , 2012, Journal of neurochemistry.

[139]  P. J. Jones,et al.  Placental blood flow in rats fed alcohol before and during gestation. , 1981, Life sciences.

[140]  Hossein Sharafi,et al.  The Effect of Resistance Exercise on p53, Caspase-9, and Caspase-3 in Trained and Untrained Men , 2012, Journal of strength and conditioning research.

[141]  Kai-Yu Tong,et al.  The Effects of Voluntary, Involuntary, and Forced Exercises on Brain-Derived Neurotrophic Factor and Motor Function Recovery: A Rat Brain Ischemia Model , 2011, PloS one.

[142]  J. Kleim,et al.  Synaptogenesis and FOS Expression in the Motor Cortex of the Adult Rat after Motor Skill Learning , 1996, The Journal of Neuroscience.

[143]  M. Saito,et al.  Elevation of GM2 ganglioside during ethanol‐induced apoptotic neurodegeneration in the developing mouse brain , 2012, Journal of neurochemistry.

[144]  J. Searcy,et al.  Reversal of Glial and Neurovascular Markers of Unhealthy Brain Aging by Exercise in Middle-Aged Female Mice , 2011, PloS one.

[145]  S. Belcher,et al.  Early postnatal ethanol exposure selectively decreases BDNF and truncated TrkB-T2 receptor mRNA expression in the rat cerebellum. , 2001, Brain research. Molecular brain research.

[146]  W. Greenough,et al.  Persistent impairment of hippocampal neurogenesis in young adult rats following early postnatal alcohol exposure. , 2007, Alcoholism, clinical and experimental research.

[147]  J. Juraska,et al.  Effects of ethanol during adolescence on the number of neurons and glia in the medial prefrontal cortex and basolateral amygdala of adult male and female rats , 2012, Brain Research.

[148]  Christopher D Molteno,et al.  Impaired eyeblink conditioning in children with fetal alcohol syndrome. , 2008, Alcoholism, clinical and experimental research.

[149]  B. Christie,et al.  Anxiety- and depression-like behaviors are accompanied by an increase in oxidative stress in a rat model of fetal alcohol spectrum disorders: Protective effects of voluntary physical exercise , 2012, Neuropharmacology.

[150]  Mal-Soon Shin,et al.  Treadmill exercise inhibits traumatic brain injury-induced hippocampal apoptosis , 2010, Physiology & Behavior.

[151]  W. Greenough,et al.  Therapeutic effects of complex motor training on motor performance deficits induced by neonatal binge-like alcohol exposure in rats I. Behavioral results , 1998, Brain Research.

[152]  Christopher J. Fox,et al.  Voluntary exercise rescues deficits in spatial memory and long‐term potentiation in prenatal ethanol‐exposed male rats , 2005, The European journal of neuroscience.

[153]  D. B. Matthews,et al.  The effect of chronic intermittent ethanol exposure on spatial memory in adolescent rats: The dissociation of metabolic and cognitive tolerances , 2012, Brain Research.

[154]  V. Felipo,et al.  Ebselen prevents chronic alcohol-induced rat hippocampal stress and functional impairment. , 2007, Alcoholism, clinical and experimental research.

[155]  D. Corbett,et al.  Brain-Derived Neurotrophic Factor Contributes to Recovery of Skilled Reaching After Focal Ischemia in Rats , 2009, Stroke.

[156]  S. A. Marshall,et al.  Adolescent binge alcohol exposure induces long-lasting partial activation of microglia , 2011, Brain, Behavior, and Immunity.

[157]  Jason S. Snyder,et al.  The effects of exercise and stress on the survival and maturation of adult‐generated granule cells , 2009, Hippocampus.

[158]  T. Foster,et al.  Comparison of lifelong and late life exercise on oxidative stress in the cerebellum , 2009, Neurobiology of Aging.

[159]  Chia-Liang Tsai,et al.  Effects of acute exercise on executive function: a study with a Tower of London Task. , 2011, Journal of sport & exercise psychology.

[160]  C. Kirstein,et al.  Alcohol during adolescence selectively alters immediate and long-term behavior and neurochemistry. , 2010, Alcohol.

[161]  B. Christie,et al.  Exercise-induced changes in dendritic structure and complexity in the adult hippocampal dentate gyrus , 2006, Neuroscience.

[162]  C. Guerri,et al.  Mechanisms involved in the neurotoxic, cognitive, and neurobehavioral effects of alcohol consumption during adolescence. , 2010, Alcohol.

[163]  Sarah-Jayne Blakemore,et al.  Adolescence: a foundation for future health , 2012, The Lancet.

[164]  R. Paffenbarger,et al.  Workshop on Epidemiologic and Public Health Aspects of Physical Activity and Exercise: a summary. , 1985, Public health reports.

[165]  Arthur F. Kramer,et al.  Interactive effects of fitness and hormone treatment on brain health in postmenopausal women , 2007, Neurobiology of Aging.

[166]  H. Budde,et al.  Molecular aspects involved in swimming exercise training reducing anhedonia in a rat model of depression , 2011, Neuroscience.

[167]  S. Rossi,et al.  Early exposure to ethanol or red wine and long-lasting effects in aged mice. A study on nerve growth factor, brain-derived neurotrophic factor, hepatocyte growth factor, and vascular endothelial growth factor , 2012, Neurobiology of Aging.

[168]  Charles H Hillman,et al.  Acute cardiovascular exercise and executive control function. , 2003, International journal of psychophysiology : official journal of the International Organization of Psychophysiology.

[169]  C. Vadász,et al.  Involvement of ceramide in ethanol‐induced apoptotic neurodegeneration in the neonatal mouse brain , 2010, Journal of neurochemistry.

[170]  R. Room,et al.  Alcohol and public health , 2005, The Lancet.

[171]  David Buckley,et al.  Prevalence and epidemiologic characteristics of FASD from various research methods with an emphasis on recent in-school studies. , 2009, Developmental disabilities research reviews.

[172]  Sérgio Gomes da Silva,et al.  Physical exercise during the adolescent period of life increases hippocampal parvalbumin expression , 2010, Brain and Development.

[173]  B. Christie,et al.  Altered adult hippocampal neuronal maturation in a rat model of fetal alcohol syndrome , 2011, Brain Research.

[174]  Jennifer D. Thomas,et al.  Choline supplementation and DNA methylation in the hippocampus and prefrontal cortex of rats exposed to alcohol during development. , 2012, Alcoholism, clinical and experimental research.

[175]  F. Gomez-Pinilla,et al.  Exercise influences hippocampal plasticity by modulating brain-derived neurotrophic factor processing , 2011, Neuroscience.

[176]  M. Giese,et al.  Intensive Coordinative Training Improves Motor Performance in Degenerative Cerebellar Disease Editorial, Page Xxx , 2022 .

[177]  T. Sather,et al.  Voluntary exercise influences behavioral development in rats exposed to alcohol during the neonatal brain growth spurt. , 2008, Behavioral neuroscience.

[178]  Y. Shaham,et al.  Running is the neurogenic and neurotrophic stimulus in environmental enrichment. , 2011, Learning & memory.

[179]  R. Paz,et al.  Fetal alcohol spectrum disorder-associated depression: Evidence for reductions in the levels of brain-derived neurotrophic factor in a mouse model , 2008, Pharmacology Biochemistry and Behavior.

[180]  B. Christie,et al.  Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways , 2006, Hippocampus.

[181]  L. Iyer,et al.  Depletion of central BDNF in mice impedes terminal differentiation of new granule neurons in the adult hippocampus , 2008, Molecular and Cellular Neuroscience.

[182]  L. Lanfumey,et al.  Early exposure to ethanol differentially affects ethanol preference at adult age in two inbred mouse strains , 2012, Neuropharmacology.

[183]  J. Pei,et al.  Executive function and memory in children with Fetal Alcohol Spectrum Disorder , 2011, Child neuropsychology : a journal on normal and abnormal development in childhood and adolescence.

[184]  Sarah E. Jacobson,et al.  Deficits in trace fear conditioning in a rat model of fetal alcohol exposure: dose-response and timing effects. , 2009, Alcohol.

[185]  C. Valenzuela,et al.  Repeated third trimester-equivalent ethanol exposure inhibits long-term potentiation in the hippocampal CA1 region of neonatal rats. , 2010, Alcohol.

[186]  P. Hunt,et al.  Deficits in trace fear conditioning induced by neonatal alcohol persist into adulthood in female rats. , 2013, Developmental psychobiology.

[187]  Csaba Nyakas,et al.  The effects of training and detraining on memory, neurotrophins and oxidative stress markers in rat brain , 2006, Neurochemistry International.

[188]  J. Dobbing,et al.  Comparative aspects of the brain growth spurt. , 1979, Early human development.

[189]  L. Spear.  The adolescent brain and age-related behavioral manifestations , 2000, Neuroscience & Biobehavioral Reviews.

[190]  L. Costa,et al.  Ethanol inhibits muscarinic receptor-induced axonal growth in rat hippocampal neurons. , 2009, Alcoholism, clinical and experimental research.

[191]  T. Mikami,et al.  Regular exercise cures depression-like behavior via VEGF-Flk-1 signaling in chronically stressed mice , 2012, Neuroscience.

[192]  B. Christie,et al.  Voluntary exercise does not enhance long-term potentiation in the adolescent female dentate gyrus , 2011, Neuroscience.

[193]  Sok Park,et al.  Maternal exercise reduces hyperthermia-induced apoptosis in developing mouse brain , 2011, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[194]  V. Russell,et al.  Effect of exercise on dopamine neuron survival in prenatally stressed rats , 2009, Metabolic Brain Disease.

[195]  B. Christie,et al.  Prenatal ethanol exposure enhances NMDAR‐dependent long‐term potentiation in the adolescent female dentate gyrus , 2012, Hippocampus.

[196]  B. Ames,et al.  Chronically and acutely exercised rats: biomarkers of oxidative stress and endogenous antioxidants. , 2000, Journal of applied physiology.

[197]  Bonnie J. Nagel,et al.  Aerobic fitness relates to learning on a virtual Morris Water Task and hippocampal volume in adolescents , 2012, Behavioural Brain Research.

[198]  D. K. Williams,et al.  Purkinje cell vulnerability to developmental ethanol exposure in the rat cerebellum. , 1999, Alcoholism, clinical and experimental research.

[199]  Jay L Alberts,et al.  Forced, Not Voluntary, Exercise Improves Motor Function in Parkinson's Disease Patients , 2009, Neurorehabilitation and neural repair.

[200]  W. Mayhan.  Responses of cerebral arterioles during chronic ethanol exposure. , 1992, The American journal of physiology.

[201]  Joanne Weinberg,et al.  Hippocampal cell proliferation is reduced following prenatal ethanol exposure but can be rescued with voluntary exercise , 2006, Hippocampus.

[202]  Adriana Galvan,et al.  The adolescent brain. , 2008, Developmental review : DR.

[203]  M. Shin,et al.  Effect of postnatal treadmill exercise on c-Fos expression in the hippocampus of rat pups born from the alcohol-intoxicated mothers , 2008, Brain and Development.

[204]  S. Billinger,et al.  Exercise and Executive Function in Individuals With Chronic Stroke: A Pilot Study , 2011, Journal of neurologic physical therapy : JNPT.

[205]  Attenuation of oxidative stress, neuroinflammation, and apoptosis by curcumin prevents cognitive deficits in rats postnatally exposed to ethanol , 2012, Psychopharmacology.

[206]  R. Kirk,et al.  Effect of acute ethanol and acute allopregnanolone on spatial memory in adolescent and adult rats. , 2011, Alcohol.

[207]  A. Kramer,et al.  Be smart, exercise your heart: exercise effects on brain and cognition , 2008, Nature Reviews Neuroscience.

[208]  W. Greenough,et al.  Differential rearing effects on rat visual cortex synapses. III. Neuronal and glial nuclei, boutons, dendrites, and capillaries , 1987, Brain Research.

[209]  W. Koch,et al.  Ethanol protects from injury due to ischemia and reperfusion by increasing vascularity via vascular endothelial growth factor. , 2012, Alcohol.

[210]  R. Tsuji,et al.  Effects of postnatal ethanol exposure on neurotrophic factors and signal transduction pathways in rat brain , 2008, Journal of applied toxicology : JAT.

[211]  T. Pak,et al.  Binge-Pattern Alcohol Exposure during Puberty Induces Long-Term Changes in HPA Axis Reactivity , 2011, PloS one.

[212]  F. Crews,et al.  Periadolescent ethanol exposure reduces adult forebrain ChAT+IR neurons: correlation with behavioral pathology , 2011, Neuroscience.

[213]  C. Cotman,et al.  Exercise: a behavioral intervention to enhance brain health and plasticity , 2002, Trends in Neurosciences.

[214]  C. Humpel,et al.  Effects of long-term moderate ethanol and cholesterol on cognition, cholinergic neurons, inflammation, and vascular impairment in rats , 2012, Neuroscience.

[215]  M. Stanton,et al.  Dose-dependent deficits in dual interstimulus interval classical eyeblink conditioning tasks following neonatal binge alcohol exposure in rats. , 2008, Alcoholism, clinical and experimental research.