Paternal preconception donepezil exposure enhances learning in offspring – PubMed Black Hawk Supplements

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CONCLUSIONS: These findings indicate that prolonged paternal exposure to donepezil may enhance the learning and memory abilities of offspring, possibly by targeting nonneural, extracellular regions. Further research is required to fully elucidate any potential transgenerational effects.
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Paternal preconception donepezil exposure enhances learning in offspring - PubMed

Paternal preconception donepezil exposure enhances learning in offspring

Guangyuan Fan et al. Behav Brain Funct. .

Abstract

Background: Recent research has indicated that parental use of central nervous system-targeting medications during periconceptional periods may affect offspring across various developmental and behavioral domains. The present study sought to investigate the potential influence of paternal use of donepezil, a specific reversible central acetylcholinesterase inhibitor that activates the cholinergic system to promote cognition, on offspring.

Results: In this study, male rats were bred after 21 days of oral donepezil administration at a dose of 4 mg/kg to generate F1 offspring. Both male and female F₁ offspring displayed enhanced performance in learning and short-term memory tests, including novel object recognition, Y maze, and operant learning. Transcriptomic analysis revealed notable alterations in genes associated with the extracellular matrix in the hippocampal tissue of the F1 generation. Integration with genes related to intelligence identified potential core genes that may be involved in the observed behavioral enhancements.

Conclusions: These findings indicate that prolonged paternal exposure to donepezil may enhance the learning and memory abilities of offspring, possibly by targeting nonneural, extracellular regions. Further research is required to fully elucidate any potential transgenerational effects.

Keywords: Cross-generational inheritance; Donepezil; Short-term memory.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1

Chronic donepezil exposure improved learning and memory in adult male rats. (a) Schematic for donepezil administration, tests, and mating. (b) Body weights of Veh- and Done-treated male rats between day 0 and day 21. (c-f) Schematics (c) and results of open field test. The total distance traveled (d), distance traveled in the central area (e), time spent in the central area (f) of male rats exposed to chronic donepezil treatment are shown. (g-h) Schematics (g) and results of elevated plus maze. Time spent exploring the open arm (h) of male rats exposed to chronic donepezil treatment are shown. (i-k) Schematics (i) and results of novel object recognition. The total time spent exploring objects during the test phase (j), discrimination index (k) of male rats exposed to chronic donepezil treatment are shown. (l-n) Schematics (l) and results of operant conditioning in a Skinner box. Learning rate of operant behavior (m), incorrect lever times (n) of male rats exposed to chronic donepezil treatment are shown. The data are shown as the mean ± s.e.m. The numbers within each column represent the number of animals tested

Fig. 2
Fig. 2

Litter size and body weight of F1 and F2 offspring. (a) Schematic of the generation of F1 and F2 offspring. (b) Number of pups per litter sired by Veh and Done F0. (c) Body weights of Veh-F1 and Done-F1 offspring between 2 and 8 weeks. (d) Number of pups per litter sired by Veh and Done F1. (e) Body weights of Veh-F2 and Done-F2 offspring between 2 and 8 weeks. The data are shown as the mean ± s.e.m. The numbers within each column represent the number of animals tested

Fig. 3
Fig. 3

Chronic maternal donepezil exposure may improve learning and memory in F1 offspring. (a-c) Results of open field test. The total distance traveled (a), distance traveled in the central area (b), time spent in the central area (c) of F1 offspring are shown. (d) Elevated plus maze test of F1 offspring, the time spent exploring the open arm was shown. (e-f) Schematics (e) and results of sucrose preference test. The ratio of sucrose to water consumption (f) of F1 offspring are shown. (g-h) Results of novel object recognition test. The total time spent exploring objects during the test phase (g), discrimination index (h) of F1 offspring is shown. (i-k) Schematics (i) and results of Y maze test. The time spent exploring the novel arm (j), entries to novel arm(k) of F1 offspring are shown. (l-m) Results of operant conditioning. Learning rate (l), incorrect lever times (m) of F1 offspring operant behavior are shown. The data are shown as the mean ± s.e.m. The numbers within each column represent the number of animals tested. Filled circles, data from each male; open circles, data from each female

Fig. 4
Fig. 4

Chronic paternal donepezil exposure had no significant impact on learning and memory in F2 offspring. (a-c) Results of open field test. The total distance traveled (a), distance traveled in the central area (b), time spent in the central area (c) of F2 offspring are shown. (d) Elevated plus maze test of F2 offspring, the time spent exploring the open arm was shown. (e) Sucrose preference test of F2 offspring, the ratio of sucrose to water consumption was shown. (f-g) Results of novel object recognition test. The total time spent exploring objects during the test phase (f), and discrimination index (g) of F2 offspring is shown. (h-i) Results of Y maze test. The time spent exploring the novel arm (h), entries to novel arm (i) of F2 offspring are shown. (j-k) Results of operant conditioning. Learning rate (j), incorrect lever times (k) of F2 offspring operant behavior are shown. The data are shown as the mean ± s.e.m. The numbers within each column represent the number of animals tested. Filled circles, data from each male; open circles, data from each female

Fig. 5
Fig. 5

Impact of paternal metformin exposure on the hippocampal transcriptome of the F1 generation. (a) Heatmap showing significant differences in the hippocampal transcriptome between Done-F1 and Veh-F1. Done-F1, females, n = 5; males, n = 5; Veh-F1, females, n = 4; males, n = 3. (b) Gene Ontology functional enrichment analysis. Significant functional annotations of differentially expressed genes vs. the background (read counts ≥ 10). Left, biological process enrichment; right, cellular component enrichment. (c) Top file cell type annotations of significantly differentially expressed genes using Cell Marker 2.0. (d) Disease type annotations of significantly differentially expressed genes using DisGeNET, along with gene set enrichment analysis results. (e) Number of intelligence- and cognition-related genes among the significantly differentially expressed genes from the UK Biobank whole-genome association study. There were 44 out of 1110 intelligence-related genes and 106 out of 4998 cognition-related genes. (f) Network clustering of significantly differentially expressed genes related to cognition and intelligence using ClueGO. Different colors represent signaling pathway clusters annotated by different Wiki pathways. (g) Quantitive real-time PCR validation on the expression of RhoA, Rac1, Mmp14, Micb, Cdh20, and Cdh6 in hippocampal tissue of F1 generation. Done-F1, females, n = 4; males, n = 4; Veh-F1, females, n = 4; males, n = 4. The data are shown as the mean ± s.e.m. Filled circles, data from each male; open circles, data from each female

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Paternal preconception donepezil exposure enhances learning in offspring – PubMed