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Alcohol and the Developing Brain: Neuroanatomical Studies

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Alcohol and the Developing Brain: Neuroanatomical Studies Alcohol and the Developing Brain: Neuroanatomical Studies Document Transcript

  • Alcohol and the Developing Brain: Neuroanatomical Studies Wei-Jung A. Chen, Ph.D., Susan E. Maier, Ph.D., Scott E. Parnell, and James R. West, Ph.D. One of the distinguishing features of prenatal alcohol exposure is impaired cognitive and behavioral function resulting from damage to the central nervous system. Information available from the small number of autopsied cases in humans indicates that the offspring of mothers who abused alcohol during pregnancy have various neuroanatomical alterations ranging from gross reductions in brain size to cellular alterations. Recent neuroimaging technology provides the most powerful tool for assessing the neurotoxic effects of fetal alcohol exposure in living organisms and for exploring the relationship between behavioral dysfunction and brain damage at the regional level. Recently, ani­ mal research has suggested that the damaging effects of alcohol exposure during brain development could be prevented or attenuated by various pharmacological manipulations or by complex motor training. These promising findings provide directions for developing future prevention or interven­ tion strategies. KEY WORDS: prenatal alcohol exposure; neuroimaging; neurotoxicity; fetal alcohol effects; brain damage; cognitive development; AODR (alcohol and other drug related) behavioral problem; prevention strategy; drug therapy; CNS function; cell adhesion molecules; mitochondriaP renatal alcohol exposure adversely tion of symptoms known as fetal alcohol in the communications among cells. affects the developing anatomical syndrome (FAS). The criteria for diag- These alterations can have a long-term structures of the body and brain, nosing FAS include facial dysmorphology, detrimental impact on behavioral andleading to a range of physical, cognitive, growth retardation, and central nervous cognitive development.and behavioral effects. The term “anatom- system (CNS) dysfunction. Facial dys­ical structures” encompasses both the morphology results from anatomicalcomponents of the major body systems changes occurring during weeks 4 to 8 Human Neuroanatomical(e.g., heart, blood vessels, bones, muscles) of gestational development that affect Studiesand the cellular and molecular structures how tissues merge under the facialwithin these major components. Any prominences. Of all anomalies associ- Since FAS was defined several decadesalterations to the body’s anatomical ated with FAS, growth retardation is ago, researchers have learned a signifi­structures, regardless of the level at which the most obvious form of anatomical cant amount about the nature of thethey occur (gross or microscopic), may change. People who are not professionallynegatively affect an organism’s function. trained to analyze facial dysmorphologyThis article reviews changes in brain can easily recognize this anomaly WEI-JUNG A. CHEN, PH.D., is an assis­anatomy (i.e., neuroanatomy) that occur because the weight and size of FAS tant professor; SUSAN E. MAIER, PH.D.,following developmental (prenatal and/or infants are distinctly smaller than nor- is a research assistant professor; SCOTT E.early postnatal) alcohol exposure in both mal. Anatomical alterations associated PARNELL is a graduate student; andhumans and animal models. It also dis- with CNS dysfunction may range from JAMES R. WEST, PH.D., is a distin­cusses promising techniques to prevent gross reduction in brain volume (i.e., guished professor; all in the Department ofor reverse alcohol-induced neuroanatom- microencephaly), to deficits in cell Human Anatomy and Medicalical changes. number in a particular brain region, Neurobiology, College of Medicine, Texas The most serious consequence of to cellular modifications of individual A&M University System Health Scienceprenatal alcohol exposure is a constella- nerve cells (i.e., neurons), to alterations Center, College Station, Texas.174 Alcohol Research & Health
  • Alcohol and the Developing Brain xxx xxx xxx xxx xxx xxx xxxbehavioral, cognitive, and physical fea­ Neuroimaging pants from this study were examinedtures of FAS and related diagnoses. Until further using positron emission tomog­ In recent years, researchers have usedrecently, not much was known about raphy (PET). These scans revealed both anatomical MRI and functionalthe actual anatomical injury to the brains changes in metabolic rate in the thala­of children with FAS and the relationships MRI to determine the nature of brain mus and the head of the caudatebetween risk factors and behavioral/ injury in living offspring with FAS. nucleus (two brain structures impor­cognitive outcomes and brain injury. Early seminal MRI studies by Riley tant for communication within theThis information could only be acquired and colleagues (reviewed by Roebuck brain) (Clark et al. 2000). The authorsat autopsy, and because FAS generally is et al. 1998) showed reductions in the suggest that the functional findingsnot life threatening, there were few cases volume of several brain regions in chil­ may be related to the regional vulnera­available for study. Researchers had to dren who were affected by heavy1 bility of the brain to prenatal alcoholuse caution when reviewing the autopsy maternal drinking. These studies were exposure, which is consistent with thedata derived from children with FAS significant because they showed a conclusion of an earlier PET studywho died for reasons other than accidents reduction in the size of specific brain (Hannigan et al. 1995).because brain tissues may be severely regions independent of any reduction More recently, Bookstein and col­affected by other life-threatening diseases. in total brain volume. leagues (2002a,b) explored the relation­Therefore, researchers had to rely on More recently, Archibald and col­ ship between the shape of the corpusanimal models to address most of these leagues (2001) found that, in children callosum in adolescents and adultsquestions. Now that magnetic resonance with FAS, the fibers carrying informa­ (assessed with MRI) exposed to alcoholimaging (MRI) and functional MRI tion between brain cells (i.e., white prenatally and the degree of their cog­(fMRI) are available for use with living matter) appear to be more susceptible nitive impairment, to see if the shapesubjects, researchers are generating new to reductions in volume than the outer, of the corpus callosum was an indicatordata that can lead to a better understand­ convoluted layer of brain tissue called of heavy in utero alcohol exposure.ing of brain and behavior relationships the cerebral cortex. Within the cerebral Although the volume of the corpusin humans, as well as a better interpretation cortex, the parietal lobe (situated at the callosum in the alcohol-exposed studyof findings from animal studies. This upper middle of the cerebrum) is reduced participants was not different from thatnew information will guide researchers by prenatal alcohol exposure, whereas in the control participants, the variabil­working with animals in their attempts the temporal and occipital lobes ity in the shape of the corpus callosumto target mechanisms and potential (located on the sides and back of the was much higher in the alcohol-exposedtherapeutic interventions for humans. brain, respectively) are not. These group. The authors suggest that varia­ anatomical data clearly show that alco- tions in corpus callosum size, volume, hol’s effect on the developing brain is and shape revealed by MRI can beMicrocephaly not uniform but varies depending on used as diagnostic criteria for FAS andMicrocephaly is defined as having a the brain region. Wass and colleagues related brain disorders. Thus, MRIsmall head relative to body size and is (2001) used ultrasound sonography to could be used to solicit more socialbased on the ratio of body weight to examine living fetuses exposed to alco­ support services, which often are lack­head circumference or height-to-head hol and found a reduction in the size ing for adolescents and adults affectedcircumference (not to be confused with of the frontal cortex, but not other cor­ by prenatal alcohol exposure.microencephaly, which refers to the size tices, of the cerebrum.of the brain). Early studies showed that Clark and colleagues (2000) usedmicrocephaly was related to alcohol use MRI to examine the brains of adults Autopsy Studiesthroughout pregnancy (Ernhart et al. who had been exposed to alcohol in Anatomical changes occurring at the1985; Rosett et al. 1983). Coles (1994) utero and were classified as nonre­ cellular level in humans can best bereported that children whose mothers tarded (as assessed by IQ score). They revealed with autopsy material. Althoughstopped drinking before the end of the found only one abnormal case, a thin­ only a very small number of brains aresecond trimester had larger head circum­ ning corpus callosum in the adult with available for this level of analysis, find­ferences on average than children whose the lowest IQ. (The corpus callosum is ing any microscopic changes in themothers continued to drink throughout a bundle of fibers through which the brain lends considerable support to thepregnancy. This finding suggests that a two cerebral hemispheres communicate.) claim that developmental alcohol expo­pregnant woman may be able to avoid Otherwise, the MRIs of all other study sure induces neuronal injury, whichadditional injury to her baby’s brain if participants were considered to be in ultimately may be responsible for theshe stops drinking before the third trimester. the normal range. Some of the partici­ behavioral and cognitive changesThese data are useful for counseling observed in children exposed to alcoholpregnant women about the benefits to 1 Heavy drinking is defined as 7 to 13.99 ounces (oz) prenatally.their unborn children of reducing or absolute alcohol per week or 14 to 27.9 standard drinks Clarren and associates (1978) found per week (approximately 12 oz beer, 5 oz wine, 1.25 ozceasing their alcohol consumption as liquor) in the NIH 1988 National Health Interview Survey changes in the structure of the autop­soon as their pregnancy is identified. (USDHHS 1988). sied brains of four children diagnosedVol. 27, No. 2, 2003 175
  • with FAS. The most prevalent findings control factors such as dose, timing, and recently have suggested that these alco-in these brains were incorrectly located pattern of alcohol exposure in animal hol-induced reductions in brain vol­(i.e., ectopic) neurons in the white mat­ studies. And because there are so few ume and neuronal loss may be attrib­ter, suggesting errors in the migration human autopsy cases, researchers have uted to alcohol-induced neurodegener­of neurons throughout the brain. In performed most neuroanatomical ation via programmed cell death (i.e.,one case there was a complete absence assessments, particularly at the cellular apoptosis).of the corpus callosum and anterior level, on animals. The following sectionscommissure, another fiber bundle that briefly summarize several hallmark find­connects regions of the brain. Ferrer ings related to neuroanatomical studies Neuronal Lossand Galofre (1987) found that the of the effects of developmental alcohol One of the most devastating and extremeshort, hair-like projections (i.e., den­ exposure in animals. consequences of developmental alcoholdritic spines) on fibers called dendrites, exposure is the loss of neurons, and thewhich extend from neurons to receive data documenting neuronal loss areinformation from other neurons, also Microencephaly derived mostly from animal studies.were affected. They reported that the Microencephaly, defined in animal sub­ Although selective programmed neu­brain from a 4-month-old infant with jects as having a small brain relative to ronal death is a normal aspect of CNSFAS showed a significant decrease in the body size, is a gross neuroanatomical development, excessive neuronal deathnumber of dendritic spines on nerve anomaly associated with heavy alcohol disrupts the development of normalcells projecting from the cortex to exposure during development. As neural networks and may lead to cog­other parts of the brain and spinal described above, such an anomaly in nitive and behavioral dysfunctions (incord. Another autopsy case, of a 2- humans is inferred by deficits in head both humans and animals). Distinctmonth-old infant born to a mother who circumference because we cannot regions and specific cell types appear tobinge drank during pregnancy (primar­ remove and weigh the human brain. be affected by alcohol-induced neuronalily during the first trimester), revealed However, in animals, the most common loss. Studies in rats have clearly demon­absent olfactory bulbs and tracts (which and traditional means of measuring strated that alcohol causes a reductionthe brain uses to sense odors); poorly microencephaly is brain weight. of cerebellar Purkinje cells, cells of thedeveloped optic tracts; fused anterior Numerous reports have shown that olfactory bulb, and pyramidal cells in abrain structures such as the septum, alcohol exposure during the brain growth part of the hippocampus known as thethalamus, and the head of the caudate spurt (a period of most intense brain CA1 region (Chen et al. 1998, 1999a;nucleus; fewer cells in the dentate gyrus, growth) in rats significantly reduces Livy et al. 2003). In other neuronalwhich is part of the hippocampus (an the weight of the forebrain, brain stem, populations, however, such as those inarea crucial for memory); and fewer and cerebellum (Maier et al. 1997). the ventrolateral nucleus of the thala­nerve cells in the cerebellum (which reg­ Importantly, in the microencephalic mus (an area important for voluntaryulates balance, posture, movement, and brain, not every brain region is affected movement) and the locus coeruleus (amuscle coordination) known as Purkinje equally. Using state-of-the-art three- group of nerve cells involved in arousalcells, and disorientation of these cells dimensional stereological techniques, and vigilance), alcohol does not cause(Coulter et al. 1993). Although these researchers can estimate the volume cell loss (Chen et al. 1999b; Livy et al.autopsy data are based on a small num­ (size) of various brain regions to 2001). This pattern of alcohol-inducedber of subjects, they seem to show that demonstrate microencephaly. Many of loss of neurons is important for twoprenatal alcohol exposure does have a these stereological studies have demon­ reasons: (1) it establishes a correlationdamaging effect on the structural organi­ strated that developmental alcohol expo­ between the severity of neuronal loss ofzation of the developing human brain. sure leads to reductions both in brain a specific neuronal population and the weight and volume in a rat model (Maier degree of behavioral deficits associated et al. 1997; Chen et al. 1998). It appears with such a cell population, and (2) itAnimal Neuroanatomical that heavy alcohol exposure during the provides insight into the specific char­Studies brain growth spurt (early postnatal acteristics of neuronal populations that period in rats, and third trimester and are most vulnerable or most resistant toMost of the current information on early infancy in humans) leads to the alcohol-induced neuronal loss.how developmental exposure to alcohol most severe and pronounced microen­induces brain damage comes from animal cephaly compared with exposure duringstudies. Because of the obvious ethical other developmental stages. Surprisingly, Fewer Dendritic Spinesconstraints of performing certain proce­ in rats, even 1 day of alcohol exposure Proper CNS communication dependsdures on humans, the retrospective nature at a high dose (6.6 grams per kilogram on an adequate number of dendriticof the human data, and numerous con­ body weight) is sufficient to cause spines and dendritic branching, becausefounding variables, human studies cannot growth deficits in specific brain regions, dendrites are the sites of contact foraddress issues that can be addressed with such as the cerebellum (Goodlett et al. neurons. Animal studies, both in vivoanimal studies. Researchers are able to 1990). Olney and colleagues (2002) and in vitro, have demonstrated that176 Alcohol Research & Health
  • Alcohol and the Developing Braindevelopmental alcohol exposure nega­ cell, is crucial for proper adhesion, hippocampal mossy fibers (neurontively affects the structural integrity of migration, and differentiation of neurons extensions that terminate in mosslikethe dendrites and the number of den­ in the developing CNS. Therefore, dis­ branchings) was affected by develop­dritic spines in neurons located in the ruptions in the ECM can have severe mental alcohol exposure (West et al.substantia nigra (a group of nerve cells negative ramifications for developing 1981; West and Hodges-Savola 1983).involved in movement), the cortex, and neurons. One such disruption of the Prenatal alcohol exposure also maythe hippocampus (Tarelo-Acuna et al. ECM is evident in alcohol’s effects on significantly interrupt the development2000; Yanni and Lindsley 2000; Shetty the L1 cell adhesion molecule (L1CAM), of the cortical circuitry by interferinget al. 1993; Fabregues et al. 1985). For a cell surface protein that promotes with the proliferation and migration ofexample, Tarelo-Acuna and colleagues cell-to-cell binding. Charness and the cortical neurons. Miller (1986, 1993)(2000) showed that prenatal and post­ coworkers (1994) demonstrated that demonstrated that prenatal alcoholnatal alcohol exposure alters the pro­ alcohol inhibits the adhesive properties exposure delays the migration of neuronsportions of different spine shapes in the of L1CAM in cell cultures, preventing from the zone where they are producedlong (apical) dendrites of hippocampal neurons from properly adhering to each to their final destinations, and the rateCA1 pyramidal cells. other or to the ECM. Bearer and col­ of migration of these cortical neurons Changes in the dendritic morphology leagues (1999) reported that alcohol was decreased as well. Such errors inand reductions in dendritic spines in the inhibited L1CAM-mediated outgrowth proliferation and migration disrupthippocampus interfere with the optimal of the connective fibers from early post­ synchronized developmental events,transmission of the neural impulse. natal rat cerebellar neurons. Collectively, which results in ectopic clusters of cor­Relating these data to humans, it is pos­ these results suggest that developmental tical neurons and abnormal neuronalsible that these changes could contribute alcohol exposure may alter cellular circuitry. In sum, because of the criticalto the cognitive problems seen in children components, such as L1CAM, and that role of integrated neural circuits withinwith FAS, because the hippocampus is the consequences of a change in L1CAM the brain, it is obvious that abnormalitiesinvolved in learning and memory. function could be detrimental to brain in any component of a neuroanatomi­ development. cal circuit resulting from developmen­ tal alcohol exposure would have severeDisrupted Mitochondrial consequences for CNS functions.Membrane Neural Circuitry ModificationsThe mitochondria are subcellular struc­ A complete, intact, and functionaltures that produce energy for the cell. neural circuitry requires proper connec­ Implications forChanges in the structural integrity of tions between regions of the brain. Prevention andthe mitochondrial membrane and its Developmental alcohol exposure has Interventionassociated proteins have been shown to been shown to cause aberrant wiringinitiate apoptosis or necrosis, two pos­ patterns or abnormalities in fiber bundles Recently, several studies have shownsible forms of cell death (Kroemer et al. in the developing brain. For instance, that complex motor training and phar­1997). Ramachandran (2001) demon­ the size of the corpus callosum, one of macological treatments are able tostrated that alcohol exposure in utero the largest fiber bundles in the brain, is prevent or ameliorate developmentalsignificantly elevates cytochrome c and significantly reduced following prenatal alcohol-induced alterations in specificapoptosis-inducing factor (AIF) levels alcohol exposure in rats (Zimmerberg anatomical structures. These studies arein mitochondria in the fetal rat brain. and Scalzi 1989). Further research has based on the assumption that restoringLight and colleagues (2002) showed shown that, in rats, in utero alcohol neuroanatomical integrity would resultthat 1 day of alcohol exposure (6.0 exposure alters the distribution of neurons in subsequent functional recovery.g/kg on postnatal day 4) leads to apop­ from cortical areas projecting through Therefore, identifying the structuraltotic Purkinje cells in early generated the corpus callosum into the somatosen­ alterations associated with prenatal alcoholcerebellar lobules. The observation of sory cortex, which receives tactile infor­ exposure and understanding the under­these apoptotic neurons coincides with mation from the body (Miller 1997). lying mechanisms of these changes arethe release of cytochrome c from the Recently, Elberger and associates found critical steps in developing both pre­mitochondria of the Purkinje cells. These that alcohol exposure during the period vention and intervention strategies.studies suggest that alcohol-induced equivalent to the second trimester inneuronal loss may occur via disruption rats resulted in an abnormal dendriticof mitochondria within those neurons. branching of corpus callosal projection Complex Motor Training neurons in the visual cortex (Qiang et Using a paradigm that involves complex al. 2002). These findings demonstrate motor training (see figure 1), KlintsovaChanges in Cell Adhesion Molecule that the interhemispheric connections and colleagues (2002) convincinglyProperties are affected by prenatal alcohol exposure. demonstrated structural reorganizationThe extracellular matrix (ECM), a fila­ Furthermore, early findings indicated in rat cerebellum following early postna­mentlike structure on the surface of the that the topographic organization of tal alcohol exposure. The most strikingVol. 27, No. 2, 2003 177
  • and profound aspect of these studies development. Recent data show that these peptides were reduced in mousewas that, although the complex motor melatonin, a known and effective antiox­ embryos which were exposed to alcoholskill training was initiated during adult­ idant, when given to neonatal rat pups prenatally (Spong et al. 2002). Morehood (180 days of age), it was able to simultaneously with alcohol, does not recently, these peptides have been shownsuccessfully stimulate the creation of prevent the early postnatal alcohol- to reverse alcohol-induced inhibitionnew connections between Purkinje cells induced Purkinje cell loss in either the of L1-mediated cell-to-cell adhesion inand the long connecting fibers (i.e., part of the cerebellum known as the vitro (Wilkemeyer et al. 2002). Despiteparallel fibers) of other neurons in animals cerebellar vermis or in lobule I (Edwards the promising findings that these peptidesthat were exposed to alcohol between et al. 2002). Taken together, these data prevent some aspects of fetal alcohol-postnatal days 4 and 9. Although the suggest that preserving the intact neural induced damage, their ability to preventnumber of Purkinje cells was unchanged structures depends on the type offollowing the complex motor training, damage to specific neural anatomical antioxidant used and possibly the tim­ structures has not been examined.the increased volume of the parame­ ing of antioxidant administration.dian lobule of the cerebellar cortex and Recent data suggest that administer­ Treatment with antioxidants beforethe increased number of parallel fiber ing MK–801, a compound that blocks alcohol exposure may be critical for thesynapses per Purkinje cell were sufficient antioxidant to be available in an amount receptors for the brain chemical gluta­anatomical changes to result in improved that would most effectively inhibit mate, during alcohol withdrawal reducesmotor skills. These findings have rele­ alcohol-induced generation of free the loss of hippocampal pyramidal cellsvant clinical significance and important radicals. Recently, two peptides derived in the CA1 region in a neonatal rattherapeutic implications. They suggest from growth factors that are associated model. However, the most profoundthat complex rehabilitative motor train­ with normal development (i.e., effect of this pharmacological treatmenting can improve motor performance NAPVSIPQ [NAP] and SALLRSIPA is its ability to reverse the behavioralof children, or even adults, with FAS. [SAL, also called ADNF–9]) have been impairment in a specific learning taskHowever, at present it is unclear whether shown to be effective in preventing pre­ that was induced by early postnatalrecovery or reorganization of neural natal alcohol-induced somatic and brain alcohol exposure (Thomas et al. 2002).connections is possible in regions other growth retardation in a mouse model These findings demonstrate that pre­than the cerebellum and motor cortex of serving the integrity of neural structures (Spong et al. 2001). In addition, support­the nervous system. Moreover, it remains ing evidence indicated that the levels of is important for upholding function.to be seen whether the improvement inmotor skills and anatomical alteration insynapses following complex motortraining is permanent.Pharmacological TreatmentsAntioxidant therapy has been reportedto be effective in reducing early post­natal alcohol-induced neurotoxicity inanimal studies. Heaton and colleagues(2000) showed that vitamin E protectsagainst early postnatal alcohol-inducedcerebellar Purkinje cell loss in lobule I,a lobule that is most sensitive to alco­hol during development. Although ithas not yet been documented, researchersspeculate that antioxidant treatment Figure 1 A rat undergoing complex motor training. This training consists of prod­would protect the functions of the ding the rat to traverse an elevated course with multiple obstacles andcerebellum from early postnatal alcohol challenges without falling off. Each rat runs the course five times per dayexposure because the antioxidant prevents for 12 days, and each run is timed. Over time, the rat will learn to traversethe formation of harmful free radicals. the course in less time without falling. Such motor training experiencesIn contrast to complex motor training, during adulthood stimulate connections between nerve cells in animals that received alcohol during the early postnatal period (i.e., during thewhich is an intervention, administering brain growth spurt). The resulting improved performance on the obstaclevitamin E during pregnancy is a pre­ course suggests a potential intervention that may attenuate the severity ofventive effort. Prevention in many ways developmental alcohol–induced brain injury.is more effective and economical thanintervention in attenuating the detrimen­ SOURCE: Photograph courtesy of Dr. Anna Klintsova, Binghamton University, Binghamton, New York.tal effects of alcohol exposure during178 Alcohol Research & Health
  • Alcohol and the Developing Brain Further evidence for the effectiveness been a significant contribution to the Noninvasive MRI studies in childrenof certain pharmacological treatments fetal alcohol field. Animal studies have exposed to alcohol in utero have beeninvolves the ability of the eight-carbon been important in the following ways: much more instructive than autopsylong-chain alcohol known as 1-octanol studies. They allow neuroanatomicalto attenuate alcohol-induced damage. • They have demonstrated that alco­ deficits to be correlated with functionalRecent data show that a low dose of 1­ hol exposure during development, deficits. MRI, fMRI, PET, and otheroctanol interacts with the L1CAM to even without polydrug use or neuroimaging techniques offer theblock an alcohol-induced mechanism undernourishment, can induce potential to help direct future researchof abnormal physical development in a significant structural changes to into pharmacological intervention andmouse embryo model (Wilkemeyer et the developing brain. treatment strategies with fetalal. 2000; Chen et al. 2001). As shown alcohol–exposed patients.in figure 2, it appears that l-octanol • They have demonstrated that vari­ Taken together, human and animalsignificantly reduces the severity of ous regions of the developing brain neuroanatomical studies have providedalcohol’s effects. Although it is unclear are not uniformly vulnerable, and both an experimental foundation for awhether treatment with 1-octanol in vivo that the brain is not equally vulner­ better understanding of the behavioralwould be just as effective as in vitro, able throughout its developmental impairments associated with heavy mater­or whether 1-octanol protects against period. Demonstrating so-called nal drinking, and an important meansalcohol-induced brain damage, this regional and temporal vulnerabil­ of evaluating potential neuroprotectivetreatment holds promise for developing ity, as well as other potential risk and therapeutic interventions. ■pharmacological agents to prevent alcohol- factors, has helped researchers toinduced injury during development. In understand the considerable vari­sum, these anatomical studies of devel­ ability observed in children prena­ Referencesopmental alcohol effects provide oppor­ tally exposed to alcohol. tunities to assess the effectiveness of ARCHIBALD, S.L.; FENNEMA-NOTESTINE, C.; GAMST,prevention and intervention methods. • The quantifiable nature of specific A.; ET AL. Brain dysmorphology in individuals with neuroanatomical anomalies offers severe prenatal alcohol exposure. Developmental Medicine & Child Neurology 43:148–154, 2001. a direct measure for future studiesConclusion to use in assessing the efficacy of BEARER, C.F.; SWICK, A.R.; O’RIORDAN, M.A.; putative neuroprotective agents. AND CHENG, G. Ethanol inhibits L1-mediated neu­Identifying specific neuroanatomical rite outgrowth in postnatal rat cerebellar granule cells. Journal of Biological Chemistry 274:13264–anomalies as adverse effects of heavy alco­ Similarly, important advances also 13270, 1999.hol exposure during development has have been made in human studies. BOOKSTEIN, F.L.; SAMPSON, P.D.; CONNOR, P.D.; AND STREISSGUTH, A.P. Midline corpus callosum is a neuroanatomical focus of fetal alcohol damage. Anatomical Record 269:162–174, 2002a. BOOKSTEIN, F.L.; STREISSGUTH, A.P.; SAMPSON, P.D.; ET AL. Corpus callosum shape and neuropsy­ chological deficits in adult males with heavy fetal alcohol exposure. NeuroImage 15:233–251, 2002b. CHARNESS, M.E.; SAFRAN, R.M.; AND PERIDES, G. Ethanol inhibits neural cell-cell adhesion. Journal of Biological Chemistry 269:9304–9309, 1994. CHEN, S.Y.; WILKEMEYER, M.F.; SULIK, K.K.; AND CHARNESS, M.E. Octanol antagonism of ethanol teratogenesis. FASEB Journal 15:1649–1651, 2001. CHEN, W.J.A.; PARNELL, S.E.; AND WEST, J.R. Neonatal alcohol and nicotine exposure limits brain growth and depletes cerebellar Purkinje cells. Figure 2 Representative mouse embryos from three experimental treatments. Alcohol 15:33–41, 1998. Left: Control embryo. Middle: Embryo exposed to alcohol (100 mM) CHEN, W.J.A.; PARNELL, S.E.; AND WEST, J.R. The in culture for 6 hours. Right: Embryo exposed to alcohol (100 mM) effects of alcohol and nicotine on developing olfac­ and a low dose of the long-chain alcohol l-octanol (3 µM) in culture. tory bulb: Loss of mitral cells and alteration in neuro­ It appears that l-octanol treatment significantly reduced the severity transmitter levels. Alcoholism: Clinical and of alcohol’s effects on the development of the embryo. Experimental Research 23:18–25, 1999a. CHEN, W.J.A.; PARNELL, S.E.; AND WEST, J.R. SOURCE: Adapted from Chen et al. 2001, with permission. Early postnatal alcohol exposure produced long- term deficits in brain weight, but not the numberVol. 27, No. 2, 2003 179
  • of neurons in the locus coeruleus. Brain Research: tive stereological study of synaptic plasticity in SHETTY, A.K.; BURROWS, R.C.; AND PHILLIPS, D.E.Developmental Brain Research 118:33–38, 1999b. female rat cerebellum. Brain Research 937:83–93, 2002. Alterations in neuronal development in the sub­ stantia nigra pars compacta following in uteroCLARK, C.M.; LI, D.; CONRY, J.; ET AL. Structural KROEMER, G.; ZAMZAMI, N.; AND SUSIN, S.A. ethanol exposure: Immunohistochemical and Golgiand functional brain integrity of fetal alcohol syn­ Mitochondrial control of apoptosis. Immunology studies. Neuroscience 52:311–322, 1993.drome in nonretarded cases. Pediatrics 105:1069– Today 18:44–51, 1997.1099, 2000. SPONG, C.Y.; ABEBE, D.T.; GOZES, I.; ET AL. LIGHT, K.E.; BELCHER, S.M.; AND PIERCE, D.R.CLARREN, S.K.; ALVORD, E.C.; SUMI, M.; ET AL. Time course and manner of Purkinje neuron death Prevention of fetal demise and growth restriction inBrain malformations related to prenatal exposure to following a single ethanol exposure on postnatal a mouse model of fetal alcohol syndrome. Journalethanol. Journal of Pediatrics 92:64–67, 1978. day 4 in the developing rat. Neuroscience 114:327– of Pharmacology and Experimental Therapeutics 297: 337, 2002. 774–779, 2001.COLES, C. Critical periods for prenatal alcohol expo­sure: Evidence from animal and human studies. LIVY, D.J.; MAIER, S.E.; AND WEST, J.R. Fetal alco­ SPONG, C.Y.; AUTH, J.; VINK, J.; ET AL. VasoactiveAlcohol Health & Research World 18:22–29, 1994. hol exposure and temporal vulnerability: Effects of intestinal peptide mRNA and immunoreactivity are binge-like alcohol exposure on the ventrolateral decreased in fetal alcohol syndrome model. RegulatoryCOULTER, C.L.; LEECH, R.W.; SCHAEFER, G.B.; ET nucleus of the thalamus. Alcoholism: Clinical and Peptides 108:143–147, 2002.AL.Midline cerebral dysgenesis, dysfunction of the Experimental Research 25:774–780, 2001.hypothalamic-pituitary axis and fetal alcohol effects. TARELO-ACUNA, L.; OLVERA-CORTES, E.; ANDArchives of Neurology 50:771–775, 1993. LIVY, D.J.; MILLER, E.K.; MAIER, S.E.; AND WEST, GONZALEZ-BURGOS, I. Prenatal and postnatal J.R. Fetal alcohol exposure and temporal vulnera- exposure to ethanol induces changes in the shape ofEDWARDS, R.B.; MANZANA, E.J.P.; AND CHEN, bility: Effects of binge-like alcohol exposure on the the dendritic spines from hippocampal CA1 pyra­W.J.A. Melatonin (an antioxidant) does not ame- developing rat hippocampus. Neurotoxicology and midal neurons of the rat. Neuroscience Letters 286:liorate alcohol-induced Purkinje cell loss in the Teratology 25:447–458, 2003.developing cerebellum. Alcoholism: Clinical and 13–16, 2000.Experimental Research 26:1003–1009, 2002. MAIER, S.E.; CHEN, W.J.A.; MILLER, J.A.; AND THOMAS, J.D.; FLEMING, S.L.; AND RILEY, E.P. WEST, J.R. Fetal alcohol exposure and temporal Administration of low doses of MK-801 duringERNHART, C.B.; WOLF, A.W.; LINN, P.L.; ET AL. vulnerability regional differences in alcohol-inducedAlcohol-related birth defects: Syndromal anomalies, ethanol withdrawal in the developing rat pup attenu­ microencephaly as a function of the timing ofintrauterine growth retardation, and neonatal ates alcohol’s teratogenic effects. Alcoholism: Clinical binge-like alcohol exposure during rat brain devel­behavioral assessment. Alcoholism: Clinical and and Experimental Research 26:1307–1313, 2002. opment. Alcoholism: Clinical and ExperimentalExperimental Research 9:447–453, 1985. Research 21:1418–1428, 1997. U.S. Department of Health and Human ServicesFABREGUES, I.; FERRER, I.; GAIRI, J.M.; ET AL. MILLER, M.W. Effects of alcohol on the generation (USDHHS), National Center for Health StatisticsEffects of prenatal exposure to ethanol on the mat­ and migration of cerebral cortical neurons. Science (NCHS). 1988 National Health Interview Survey.uration of the pyramidal neurons in the cerebral 233:1308–1311, 1986. Hyattsville, MD: NCHS, 1988.cortex of the guinea-pig: A quantitative Golgi study.Neuropathology and Applied Neurobiology 11:291– MILLER, M.W. Migration of cortical neurons is altered WASS, T.S.; PERSUTTE, W.H.; AND HOBBINS, J.C.298, 1985. by gestational exposure to ethanol. Alcoholism: Clinical The impact of prenatal alcohol exposure on frontal and Experimental Research 17:304–314, 1993. cortex development in utero. American Journal ofFERRER, I., AND GALOFRE, E. Dendritic spine Obstetrics and Gynecology 185:737–742, 2001.anomalies in fetal alcohol syndrome. Neuropediatrics MILLER, M.W. Effects of prenatal exposure to ethanol18:161–163, 1987. on callosal projection neurons in rat somatosensory WEST, J.R., AND HODGES-SAVOLA, C.A. Permanent cortex. Brain Research 766:121–128, 1997. hippocampal mossy fiber hyperdevelopment follow­GOODLETT, C.R.; MARCUSSEN, B.L.; AND WEST, ing prenatal ethanol exposure. NeurobehavioralJ.R. A single day of alcohol exposure during the brain OLNEY, J.W.; TENKOVA, T.; DIKRANIAN, K.; ET AL. Toxicology and Teratology 5:139–150, 1983.growth spurt induces brain weight restriction and Ethanol-induced apoptotic neurodegeneration incerebellar Purkinje cell loss. Alcohol 7:107–114, 1990. the developing C57BL/6 mouse brain. WEST, J.R.; HODGES, C.A.; AND BLACK, A.C., JR. Developmental Brain Research. 133:115–126, 2002. Prenatal ethanol exposure alters the organization ofHANNIGAN, J.H.; MARTIER, S.S.; CHUGANI, H.T.;AND SOKOL, R.J. Brain metabolism in children QIANG, M.; WANG, M.W.; AND ELBERGER, A.J. hippocampal mossy fibers. Science 211:957–959, 1981.with fetal alcohol syndrome (FAS): A positron Second trimester prenatal alcohol exposure alters WILKEMEYER, M.F.; SEBASTIAN, A.B.; SMITH, S.A.;emission tomography study. Alcoholism: Clinical development of rat corpus callosum. Neurotoxicology ET AL. Antagonists of alcohol inhibition of celland Experimental Research 19:53A, 1995. and Teratology 24:719–732, 2002. adhesion. Proceedings of the National Academy ofHEATON, M.B.; MITCHELL, J.J.; and PAIVA, M. RAMACHANDRAN, V.; PEREZ, A.; CHEN, J.; ET AL. Sciences of the U.S.A. 97:3690–3695, 2000.Amelioration of ethanol-induced neurotoxicity in In utero ethanol exposure causes mitochondrial WILKEMEYER, M.F.; MENKARI, C.E.; SPONG, C.Y.;the neonatal rat central nervous system by antioxi­ dysfunction, which can result in apoptotic cell AND CHARNESS, M.E. Peptide antagonists of ethanoldant therapy. Alcoholism: Clinical and Experimental death in fetal brain: A potential role for 4-hydroxy-Research 24:512–518, 2000. nonenal. Alcoholism: Clinical and Experimental inhibition of L1-mediated cell-cell adhesion. Journal Research 25:862–871, 2001. of Pharmacology and Experimental Therapeutics 303:HENDERSON, J.M.; WATSON, S.; HALLIDAY, G.M.; 110–116, 2002.ET AL. Relationships between various behavioural ROEBUCK, T.M.; MATTSON, S.N.; AND RILEY, E.P.abnormalities and nigrostriatal dopamine depletion A review of the neuroanatomical findings in chil­ YANNI, P.A., AND LINDSLEY, T.A. Ethanol inhibitsin the unilateral 6-OHDA-lesioned rat. dren with fetal alcohol syndrome or prenatal expo­ pyramidal neuron cultures. Developmental BrainBehavioural Brain Research 139:105–113, 2003. sure to alcohol. Alcoholism: Clinical and Experimental Research 120:233–243, 2000. Research 22:339–344, 1998.KLINTSOVA, A.Y.; SCAMRA, C.; HOFFMAN, M.; ET ZIMMERBERG, B., AND SCALZI, L.V. CommissuralAL.Therapeutic effects of complex motor training ROSETT, H.L.; WEINER, L.; LEE, A.; ET AL. Patterns size in neonatal rats: Effects of sex and prenatalon motor performance deficits induced by neonatal of alcohol consumption and fetal development. alcohol exposure. International Journal of Developmentalbinge-like alcohol exposure in rats: II. A quantita­ Obstetrics and Gynecology 61:539–546, 1983. Neuroscience 7:81–86, 1989.180 Alcohol Research & Health