Sex differences in hippocampal damage, cognitive impairment, and trophic factor expression in an animal model of an alcohol use disorder - PubMed (original) (raw)

Sex differences in hippocampal damage, cognitive impairment, and trophic factor expression in an animal model of an alcohol use disorder

Mark E Maynard et al. Brain Struct Funct. 2018 Jan.

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.

Keywords: Alcohol binge; Cognitive deficits; Neurodegeneration; Neurorestoration; Sex differences; Trophic support.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: The authors declare that they have no conflict of interest.

Figures

Figure 1

Figure 1. Sex-dependent effect of binge alcohol on the dentate gyrus

Binge alcohol significantly decreased the number of remaining granule neurons in the dentate gyrus of female rats, but not males. *p < 0.05 significantly different from control.

Figure 2

Figure 2. Binge alcohol decreased cell proliferation and increased cell death in the dentate gyrus

Cell proliferation was significantly decreased by binge alcohol in both sexes (A; arrowheads in panel a indicate Ki67+ cells). Cell death (B) was increased by binge alcohol in the dentate gyrus of both sexes (FJB+ cells indicated in panel b by arrowheads). Cell death in the dentate gyrus did not appear to be apoptotic in nature, as we found virtually no TUNEL+ cells in binged animals (C; left panel shows positive control with arrowhead pointing to TUNEL+ cell).

Figure 3

Figure 3. Sex-dependent effect of binge alcohol on spatial navigation

Panel A shows the timeline of behavioral analysis following binge alcohol. Binge alcohol had a significant, sex-dependent effect on acquisition of the spatial task. All groups ultimately learned the platform location, but binged males and females were initially slower to find it compared to same-sex controls (B). Binged males more rapidly achieved control performance, compared to binged females. The significant Sex x Diet interaction is apparent for both latency (C) and path length (D), with binged females being significantly different from all other groups. There was no difference between groups for swim speed (E). There were no differences between groups for reversal learning (F–H). *p < 0.05 significantly different from all other groups.

Figure 4

Figure 4. Sex differences in protein expression during binge exposure

Expression of proteins associated with trophic support was assessed after 24 (A) and 48 (B) hours of binge exposure, Binge alcohol caused a decrease in pCREB, BDNF and trkB at 24 hours in females, whereas males showed a decrease in pCREB only. Binged males showed an increase in IGFR at 24 hours, but binged females did not show this until 48 hours, at which point IGF-1 was downregulated in binged animals of both sexes. At 48 hours, binged males had normalized expression of pCREB, but binged females did not. *p < 0.05 significantly different from same sex control.

Figure 5

Figure 5. Sex differences in protein expression after binge exposure

Expression of proteins associated with trophic support was assessed 8 hours after the end of binge exposure. Binged females continue to show a decrease in pCREB and at this point CREB is decreased as well. They also show decreased BDNF as well as the trkB receptor and IGF-1. In contrast, binged males only show a decrease in BDNF. *p < 0.05 significantly different from same sex control.

Figure 6

Figure 6. Exercise-driven repair is associated with increased expression of plasticity-related proteins

The binge-induced decrement in remaining granule neurons in the dentate gyrus of the female hippocampus is detectable immediately following binge (Binge 0) as well as 4 weeks later (Binge 28) (A). However, if animals exercise for at least 2 weeks post-binge, the number of granule neurons is normalized (B). Panel C depicts the total distance covered by animals that ran for 1, 2 or 3 weeks, beginning after 7 days of abstinence. One week of post-binge exercise increased the expression of pCREB, BDNF and IGF-1 (D). *p < 0.05 significantly different from control; **p < 0.05 significantly different from sedentary.

Similar articles

Cited by

References

    1. Agartz I, Brag S, Franck J, Hammarberg A, Okugawa G, Svinhufvud K, Bergman H. MR volumetry during acute alcohol withdrawal and abstinence: a descriptive study. Alcohol and alcoholism. 2003;38:71–78. - PubMed
    1. Agartz I, Momenan R, Rawlings RR, Kerich MJ, Hommer DW. Hippocampal volume in patients with alcohol dependence. Archives of general psychiatry. 1999;56:356–363. - PubMed
    1. Alfonso-Loeches S, Pascual M, Guerri C. Gender differences in alcohol-induced neurotoxicity and brain damage. Toxicology. 2013;311:27–34. - PubMed
    1. Bannerman DM, Deacon RM, Offen S, Friswell J, Grubb M, Rawlins JN. Double dissociation of function within the hippocampus: spatial memory and hyponeophagia. Behavioral neuroscience. 2002;116:884–901. - PubMed
    1. Bannerman DM, Grubb M, Deacon RM, Yee BK, Feldon J, Rawlins JN. Ventral hippocampal lesions affect anxiety but not spatial learning. Behavioural brain research. 2003;139:197–213. - PubMed

MeSH terms

Substances

LinkOut - more resources