Abstract
Compared to men, women disproportionally experience alcohol-related organ damage, including brain damage, and while men remain more likely to drink and to drink heavily, there is cause for concern because women are beginning to narrow the gender gap in alcohol use disorders. The hippocampus is a brain region that is particularly vulnerable to alcohol damage, due to cell loss and decreased neurogenesis. In the present study, we examined sex differences in hippocampal damage following binge alcohol. Consistent with our prior findings, we found a significant binge-induced decrement in dentate gyrus (DG) granule neurons in the female DG. However, in the present study, we found no significant decrement in granule neurons in the male DG. We show that the decrease in granule neurons in females is associated with both spatial navigation impairments and decreased expression of trophic support molecules. Finally, we show that post-binge exercise is associated with an increase in trophic support and repopulation of the granule neuron layer in the female hippocampus. We conclude that sex differences in alcohol-induced hippocampal damage are due in part to a paucity of trophic support and plasticity-related signaling in females.
Similar content being viewed by others
References
Agartz I, Momenan R, Rawlings RR, Kerich MJ, Hommer DW (1999) Hippocampal volume in patients with alcohol dependence. Arch Gen Psychiatry 56:356–363
Agartz I, Brag S, Franck J, Hammarberg A, Okugawa G, Svinhufvud K, Bergman H (2003) MR volumetry during acute alcohol withdrawal and abstinence: a descriptive study. Alcohol Alcohol 38:71–78
Alfonso-Loeches S, Pascual M, Guerri C (2013) Gender differences in alcohol-induced neurotoxicity and brain damage. Toxicology 311:27–34
Bannerman DM, Deacon RM, Offen S, Friswell J, Grubb M, Rawlins JN (2002) Double dissociation of function within the hippocampus: spatial memory and hyponeophagia. Behav Neurosci 116:884–901
Bannerman DM, Grubb M, Deacon RM, Yee BK, Feldon J, Rawlins JN (2003) Ventral hippocampal lesions affect anxiety but not spatial learning. Behav Brain Res 139:197–213
Beresford TP, Arciniegas DB, Alfers J, Clapp L, Martin B, Du Y, Liu D, Shen D, Davatzikos C (2006) Hippocampus volume loss due to chronic heavy drinking. Alcohol Clin Exp Res 30:1866–1870
Collins AC, Yeager TN, Lebsack ME, Panter SS (1975) Variations in alcohol metabolism: influence of sex and age. Pharmacol Biochem Behav 3:973–978
Collins MA, Corso TD, Neafsey EJ (1996) Neuronal degeneration in rat cerebrocortical and olfactory regions during subchronic “binge” intoxication with ethanol: possible explanation for olfactory deficits in alcoholics. Alcohol Clin Exp Res 20:284–292
Corso TD, Mostafa HM, Collins MA, Neafsey EJ (1998) Brain neuronal degeneration caused by episodic alcohol intoxication in rats: effects of nimodipine, 6,7-dinitro-quinoxaline-2,3-dione, and MK-801. Alcohol Clin Exp Res 22:217–224
Crews FT (2008) Alcohol-related neurodegeneration and recovery: mechanisms from animal models. Alcohol Res Health 31:377–388
Crews FT, Braun CJ (2003) Binge ethanol treatment causes greater brain damage in alcohol-preferring P rats than in alcohol-nonpreferring NP rats. Alcohol Clin Exp Res 27:1075–1082
Crews FT, Nixon K (2009) Mechanisms of neurodegeneration and regeneration in alcoholism. Alcohol Alcohol 44:115–127
Crews FT, Collins MA, Dlugos C, Littleton J, Wilkins L, Neafsey EJ, Pentney R, Snell LD, Tabakoff B, Zou J, Noronha A (2004) Alcohol-induced neurodegeneration: when, where and why? Alcohol Clin Exp Res 28:350–364
Crippens D, White ML, George MA, Jaworski JN, Brunner LJ, Lancaster FE, Gonzales RA (1999) Gender differences in blood levels, but not brain levels, of ethanol in rats. Alcohol Clin Exp Res 23:414–420
Davis MI (2008) Ethanol-BDNF interactions: still more questions than answers. Pharmacol Ther 118:36–57
de la Monte SM, Kril JJ (2014) Human alcohol-related neuropathology. Acta Neuropathol 127:71–90
D’Hooge R, De Deyn PP (2001) Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev 36:60–90
Dwyer-Lindgren L, Flaxman AD, Ng M, Hansen GM, Murray CJ, Mokdad AH (2015) Drinking patterns in US counties from 2002 to 2012. Am J Public Health 105:1120–1127
Ehrlich DE, Josselyn SA (2016) Plasticity-related genes in brain development and amygdala-dependent learning. Genes Brain Behav 15:125–143
Erickson CK (1984) Ethanol clearance in nine inbred rat strains. Alcohol Clin Exp Res 8:491–494
Erol A, Karpyak VM (2015) Sex and gender-related differences in alcohol use and its consequences: contemporary knowledge and future research considerations. Drug Alcohol Depend 156:1–13
Fujioka T, Fujioka A, Duman RS (2004) Activation of cAMP signaling facilitates the morphological maturation of newborn neurons in adult hippocampus. J Neurosci 24:319–328
Giesen ES, Deimel H, Bloch W (2015) Clinical exercise interventions in alcohol use disorders: a systematic review. J Subst Abuse Treat 52:1–9
Gillette-Guyonnet S, Vellas B (2008) Caloric restriction and brain function. Curr Opin Clin Nutr Metab Care 11:686–692
Gomez-Pinilla F, Dao L, So V (1997) Physical exercise induces FGF-2 and its mRNA in the hippocampus. Brain Res 764:1–8
Griesbach GS, Gomez-Pinilla F, Hovda DA (2004) The upregulation of plasticity-related proteins following TBI is disrupted with acute voluntary exercise. Brain Res 1016:154–162
Gundersen HJ, Jensen EB, Kieu K, Nielsen J (1999) The efficiency of systematic sampling in stereology—reconsidered. J Microsc 193:199–211
Hamelink C, Hampson A, Wink DA, Eiden LE, Eskay RL (2005) Comparison of cannabidiol, antioxidants, and diuretics in reversing binge ethanol-induced neurotoxicity. J Pharmacol Exp Ther 314:780–788
Harker KT, Whishaw IQ (2002) Place and matching-to-place spatial learning affected by rat inbreeding (Dark-Agouti, Fischer 344) and albinism (Wistar, Sprague-Dawley) but not domestication (wild rat vs. Long–Evans, Fischer-Norway). Behav Brain Res 134:467–477
Herrera DG, Yague AG, Johnsen-Soriano S, Bosch-Morell F, Collado-Morente L, Muriach M, Romero FJ, Garcia-Verdugo JM (2003) Selective impairment of hippocampal neurogenesis by chronic alcoholism: protective effects of an antioxidant. Proc Natl Acad Sci USA 100:7919–7924
Holmila M, Raitasalo K (2005) Gender differences in drinking: why do they still exist? Addiction 100:1763–1769
Hommer D, Momenan R, Kaiser E, Rawlings R (2001) Evidence for a gender-related effect of alcoholism on brain volumes. Am J Psychiatry 158:198–204
Humm JL, Kozlowski DA, James DC, Gotts JE, Schallert T (1998) Use-dependent exacerbation of brain damage occurs during an early post-lesion vulnerable period. Brain Res 783:286–292
Hunt WA (1993) Are binge drinkers more at risk of developing brain damage? Alcohol 10:559–561
Kelso ML, Liput DJ, Eaves DW, Nixon K (2011) Upregulated vimentin suggests new areas of neurodegeneration in a model of an alcohol use disorder. Neuroscience 197:381–393
Knapp DJ, Crews FT (1999) Induction of cyclooxygenase-2 in brain during acute and chronic ethanol treatment and ethanol withdrawal. Alcohol Clin Exp Res 23:633–643
Kyrylkova K, Kyryachenko S, Leid M, Kioussi C (2012) Detection of apoptosis by TUNEL assay. Methods Mol Biol 887:41–47
Leasure JL, Jones M (2008) Forced and voluntary exercise differentially affect brain and behavior. Neuroscience 156:456–465
Leasure JL, Nixon K (2010) Exercise neuroprotection in a rat model of binge alcohol consumption. Alcohol Clin Exp Res 34:404–414
Llorens-Martin M, Torres-Aleman I, Trejo JL (2008) Growth factors as mediators of exercise actions on the brain. NeuroMol Med 10:99–107
Loncarevic-Vasiljkovic N, Pesic V, Todorovic S, Popic J, Smiljanic K, Milanovic D, Ruzdijic S, Kanazir S (2012) Caloric restriction suppresses microglial activation and prevents neuroapoptosis following cortical injury in rats. PLoS One 7:e37215
Lonze BE, Ginty DD (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron 35:605–623
Majchrowicz E (1975) Induction of physical dependence upon ethanol and the associated behavioral changes in rats. Psychopharmacologia 43:245–254
Mancinelli R, Binetti R, Ceccanti M (2007) Woman, alcohol and environment: emerging risks for health. Neurosci Biobehav Rev 31:246–253
Mann K, Ackermann K, Croissant B, Mundle G, Nakovics H, Diehl A (2005) Neuroimaging of gender differences in alcohol dependence: are women more vulnerable? Alcohol Clin Exp Res 29:896–901
Mantamadiotis T, Lemberger T, Bleckmann SC, Kern H, Kretz O, Martin Villalba A, Tronche F, Kellendonk C, Gau D, Kapfhammer J, Otto C, Schmid W, Schutz G (2002) Disruption of CREB function in brain leads to neurodegeneration. Nat Genet 31:47–54
Maynard ME, Leasure JL (2013) Exercise enhances hippocampal recovery following binge ethanol exposure. PLoS One 8:e76644
Middaugh LD, Frackelton WF, Boggan WO, Onofrio A, Shepherd CL (1992) Gender differences in the effects of ethanol on C57BL/6 mice. Alcohol 9:257–260
Moonat S, Starkman BG, Sakharkar A, Pandey SC (2010) Neuroscience of alcoholism: molecular and cellular mechanisms. Cell Mol Life Sci CMLS 67:73–88
Morris SA, Eaves DW, Smith AR, Nixon K (2010) Alcohol inhibition of neurogenesis: a mechanism of hippocampal neurodegeneration in an adolescent alcohol abuse model. Hippocampus 20:596–607
Munive V, Santi A, Torres-Aleman I (2016) A concerted action of estradiol and insulin like growth factor I underlies sex differences in mood regulation by exercise. Sci Rep 6:25969
Nakagawa S, Kim JE, Lee R, Chen J, Fujioka T, Malberg J, Tsuji S, Duman RS (2002) Localization of phosphorylated cAMP response element-binding protein in immature neurons of adult hippocampus. J Neurosci 22:9868–9876
Nixon K (2006) Alcohol and adult neurogenesis: roles in neurodegeneration and recovery in chronic alcoholism. Hippocampus 16:287–295
Nixon K, Crews FT (2002) Binge ethanol exposure decreases neurogenesis in adult rat hippocampus. J Neurochem 83:1087–1093
Obernier JA, Bouldin TW, Crews FT (2002a) Binge ethanol exposure in adult rats causes necrotic cell death. Alcohol Clin Exp Res 26:547–557
Obernier JA, White AM, Swartzwelder HS, Crews FT (2002b) Cognitive deficits and CNS damage after a 4-day binge ethanol exposure in rats. Pharmacol Biochem Behav 72:521–532
Paxinos G, Watson C (2009) The rat brain in stereotaxic coordinates. Elsevier Academic, London
Penland S, Hoplight B, Obernier J, Crews FT (2001) Effects of nicotine on ethanol dependence and brain damage. Alcohol 24:45–54
Pfefferbaum A, Lim KO, Zipursky RB, Mathalon DH, Rosenbloom MJ, Lane B, Ha CN, Sullivan EV (1992) Brain gray and white matter volume loss accelerates with aging in chronic alcoholics: a quantitative MRI study. Alcohol Clin Exp Res 16:1078–1089
Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33
Rivier C (1993) Female rats release more corticosterone than males in response to alcohol: influence of circulating sex steroids and possible consequences for blood alcohol levels. Alcohol Clin Exp Res 17:854–859
Rola R, Raber J, Rizk A, Otsuka S, VandenBerg SR, Morhardt DR, Fike JR (2004) Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp Neurol 188:316–330
Schmued LC, Hopkins KJ (2000) Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res 874:123–130
Schweinsburg BC, Alhassoon OM, Taylor MJ, Gonzalez R, Videen JS, Brown GG, Patterson TL, Grant I (2003) Effects of alcoholism and gender on brain metabolism. Am J Psychiatry 160:1180–1183
Seitz HK, Xu Y, Simanowski UA, Osswald B (1992) Effect of age and gender on in vivo ethanol elimination, hepatic alcohol dehydrogenase activity, and NAD+ availability in F344 rats. Res Exp Med (Berl) 192:205–212
Sharrett-Field L, Butler TR, Reynolds AR, Berry JN, Prendergast MA (2013) Sex differences in neuroadaptation to alcohol and withdrawal neurotoxicity. Pflugers Arch 465:643–654
Smith WB, Weisner C (2000) Women and alcohol problems: a critical analysis of the literature and unanswered questions. Alcohol Clin Exp Res 24:1320–1321
Somkuwar SS, Fannon MJ, Staples MC, Zamora-Martinez ER, Navarro AI, Kim A, Quigley JA, Edwards S, Mandyam CD (2016) Alcohol dependence-induced regulation of the proliferation and survival of adult brain progenitors is associated with altered BDNF-TrkB signaling. Brain Struct Funct 221:4319–4335
Stevenson JR, Schroeder JP, Nixon K, Besheer J, Crews FT, Hodge CW (2009) Abstinence following alcohol drinking produces depression-like behavior and reduced hippocampal neurogenesis in mice. Neuropsychopharmacology 34:1209–1222
Stoutenberg M, Rethorst CD, Lawson O, Read JP (2016) Exercise training—a beneficial intervention in the treatment of alcohol use disorders? Drug Alcohol Depend 160:2–11
Sullivan EV, Marsh L, Mathalon DH, Lim KO, Pfefferbaum A (1995) Anterior hippocampal volume deficits in nonamnesic, aging chronic alcoholics. Alcohol Clin Exp Res 19:110–122
Sullivan EV, Rosenbloom MJ, Pfefferbaum A (2000) Pattern of motor and cognitive deficits in detoxified alcoholic men. Alcohol Clin Exp Res 24:611–621
Tateno M, Ukai W, Yamamoto M, Hashimoto E, Ikeda H, Saito T (2005) The effect of ethanol on cell fate determination of neural stem cells. Alcohol Clin Exp Res 29:225s–229s
Tomsovic M (1974) “Binge” and continuous drinkers. Characteristics and treatment follow-up. Q J Stud Alcohol 35:558–564
van Praag H, Christie BR, Sejnowski TJ, Gage FH (1999a) Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci USA 96:13427–13431
van Praag H, Kempermann G, Gage FH (1999b) Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 2:266–270
Vaynman S, Gomez-Pinilla F (2005) License to run: exercise impacts functional plasticity in the intact and injured central nervous system by using neurotrophins. Neurorehabil Neural Repair 19:283–295
Vaynman S, Ying Z, Gomez-Pinilla F (2004a) Exercise induces BDNF and synapsin I to specific hippocampal subfields. J Neurosci Res 76:356–362
Vaynman S, Ying Z, Gomez-Pinilla F (2004b) Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 20:2580–2590
Vaynman SS, Ying Z, Yin D, Gomez-Pinilla F (2006) Exercise differentially regulates synaptic proteins associated to the function of BDNF. Brain Res 1070:124–130
Walter H, Dvorak A, Gutierrez K, Zitterl W, Lesch OM (2005) Gender differences: does alcohol affect females more than males? Neuropsychopharmacol Hung 7:78–82
Wilhelm CJ, Hashimoto JG, Roberts ML, Bloom SH, Beard DK, Wiren KM (2015) Females uniquely vulnerable to alcohol-induced neurotoxicity show altered glucocorticoid signaling. Brain Res 1601:102–116
Wilhelm CJ, Hashimoto JG, Roberts ML, Bloom SH, Andrew MR, Wiren KM (2016) Astrocyte dysfunction induced by alcohol in females but not males. Brain Pathol 26:433–451
Wilsnack SC, Wilsnack RW, Kantor LW (2013) Focus on: women and the costs of alcohol use. Alcohol Res 35:219–228
Zou J, Crews F (2006) CREB and NF-kappaB transcription factors regulate sensitivity to excitotoxic and oxidative stress induced neuronal cell death. Cell Mol Neurobiol 26:385–405
Acknowledgements
This study was supported by National Institute on Alcohol Abuse and Alcoholism R21 AA 021260. We thank Dr. Shaefali Rodgers for a critical reading of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
This study was supported by National Institute on Alcohol Abuse and Alcoholism R21 AA 021260.
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Maynard, M.E., Barton, E.A., Robinson, C.R. et al. Sex differences in hippocampal damage, cognitive impairment, and trophic factor expression in an animal model of an alcohol use disorder. Brain Struct Funct 223, 195–210 (2018). https://doi.org/10.1007/s00429-017-1482-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00429-017-1482-3