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Fatty acid synthase as a factor required for exercise-induced cognitive enhancement and dentate gyrus cellular proliferation.

Chorna NE, Santos-Soto IJ, Carballeira NM, Morales JL, de la Nuez J, Cátala-Valentin A, Chornyy AP, Vázquez-Montes A, De Ortiz SP - PLoS ONE (2013)

Bottom Line: In experiments addressing the functional role of FASN in our experimental model, chronic intracerebroventricular (i.c.v.) microinfusions of C75, an irreversible FASN inhibitor, and significantly impaired exercise-mediated improvements in spatial learning and memory in the Barnes maze.Furthermore, pharmacologic blockade of FASN function with C75 resulted in a significant reduction, compared to vehicle treated controls, of the number of proliferative cells in the DG of running mice as measured by immunoreactive to Ki-67 in the SGZ.Taken together, our data suggest that FASN plays an important role in exercise-mediated cognitive enhancement, which might be associated to its role in modulating exercise-induced stimulation of neurogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Metabolomics Research Center, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico, United States of America ; Department of Biology, Functional Genomics Research Core, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico, United States of America.

ABSTRACT
Voluntary running is a robust inducer of adult hippocampal neurogenesis. Given that fatty acid synthase (FASN), the key enzyme for de novo fatty acid biosynthesis, is critically involved in proliferation of embryonic and adult neural stem cells, we hypothesized that FASN could mediate both exercise-induced cell proliferation in the subgranular zone (SGZ) of the dentate gyrus (DG) and enhancement of spatial learning and memory. In 20 week-old male mice, voluntary running-induced hippocampal-specific upregulation of FASN was accompanied also by hippocampal-specific accumulation of palmitate and stearate saturated fatty acids. In experiments addressing the functional role of FASN in our experimental model, chronic intracerebroventricular (i.c.v.) microinfusions of C75, an irreversible FASN inhibitor, and significantly impaired exercise-mediated improvements in spatial learning and memory in the Barnes maze. Unlike the vehicle-injected mice, the C75 group adopted a non-spatial serial escape strategy and displayed delayed escape latencies during acquisition and memory tests. Furthermore, pharmacologic blockade of FASN function with C75 resulted in a significant reduction, compared to vehicle treated controls, of the number of proliferative cells in the DG of running mice as measured by immunoreactive to Ki-67 in the SGZ. Taken together, our data suggest that FASN plays an important role in exercise-mediated cognitive enhancement, which might be associated to its role in modulating exercise-induced stimulation of neurogenesis.

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FASN inhibition in the forebrain affects escape latency and spatial discrimination in the Barnes maze.Graphed data depicting results obtained from acquisition training and LTM tests in the Barnes maze were given to Sedentary (punctuate line) and Running (solid line) mice injected with VHL (A), SH (B) or C75 (C). Each session during acquisition and LTM testing consisted of 4 training trials for which the latency in min to find the escape hole in the Barnes maze. Specific statistically significant differences between groups identified by Bonferroni post- testing specific are depicted (*P<0.05, **P<0.01, ***P<0.001). Results are presented as means ± SEM.
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pone-0077845-g005: FASN inhibition in the forebrain affects escape latency and spatial discrimination in the Barnes maze.Graphed data depicting results obtained from acquisition training and LTM tests in the Barnes maze were given to Sedentary (punctuate line) and Running (solid line) mice injected with VHL (A), SH (B) or C75 (C). Each session during acquisition and LTM testing consisted of 4 training trials for which the latency in min to find the escape hole in the Barnes maze. Specific statistically significant differences between groups identified by Bonferroni post- testing specific are depicted (*P<0.05, **P<0.01, ***P<0.001). Results are presented as means ± SEM.

Mentions: We next carried out specific analyses of the behavioral data in order to determine if animals in the different groups displayed differences in the usage of non-spatial (random), serial (thigmotaxic), or spatial searching strategies throughout acquisition and/or LTM testing. Results indicate that indeed animals in the various groups did display important differences with respect to the strategy used to search the maze during acquisition and LTM testing. Additionally, mice displayed a tendency to switch from random to either spatial or serial navigation strategies during acquisition. The VHL-S group (Fig. 5,A), showed a significant difference between the percent of mice using the different strategies on different days during acquisition and LTM testing (Two-Way RM ANOVA: Strategy - F(2,108) = 6.886, **P<0.005; Training Days - F(4,108) = 0.8978, P>0.05; Interaction - F(8,108) = 8.251 ***P<0.0001). Bonferroni post-testing indicated that on Day 1 of acquisition training (day 29 in the study; see Fig. 4) there was a higher percentage of VHL-S mice searching randomly in the maze, compared to low percentages searching either serially (***P<0.001) or spatially (***P<0.001). However, as acquisition proceeded toward LTM testing, the serial strategy became preferred compared to the random (***P<0.001) and spatial strategies (***P<0.001).


Fatty acid synthase as a factor required for exercise-induced cognitive enhancement and dentate gyrus cellular proliferation.

Chorna NE, Santos-Soto IJ, Carballeira NM, Morales JL, de la Nuez J, Cátala-Valentin A, Chornyy AP, Vázquez-Montes A, De Ortiz SP - PLoS ONE (2013)

FASN inhibition in the forebrain affects escape latency and spatial discrimination in the Barnes maze.Graphed data depicting results obtained from acquisition training and LTM tests in the Barnes maze were given to Sedentary (punctuate line) and Running (solid line) mice injected with VHL (A), SH (B) or C75 (C). Each session during acquisition and LTM testing consisted of 4 training trials for which the latency in min to find the escape hole in the Barnes maze. Specific statistically significant differences between groups identified by Bonferroni post- testing specific are depicted (*P<0.05, **P<0.01, ***P<0.001). Results are presented as means ± SEM.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3818398&req=5

pone-0077845-g005: FASN inhibition in the forebrain affects escape latency and spatial discrimination in the Barnes maze.Graphed data depicting results obtained from acquisition training and LTM tests in the Barnes maze were given to Sedentary (punctuate line) and Running (solid line) mice injected with VHL (A), SH (B) or C75 (C). Each session during acquisition and LTM testing consisted of 4 training trials for which the latency in min to find the escape hole in the Barnes maze. Specific statistically significant differences between groups identified by Bonferroni post- testing specific are depicted (*P<0.05, **P<0.01, ***P<0.001). Results are presented as means ± SEM.
Mentions: We next carried out specific analyses of the behavioral data in order to determine if animals in the different groups displayed differences in the usage of non-spatial (random), serial (thigmotaxic), or spatial searching strategies throughout acquisition and/or LTM testing. Results indicate that indeed animals in the various groups did display important differences with respect to the strategy used to search the maze during acquisition and LTM testing. Additionally, mice displayed a tendency to switch from random to either spatial or serial navigation strategies during acquisition. The VHL-S group (Fig. 5,A), showed a significant difference between the percent of mice using the different strategies on different days during acquisition and LTM testing (Two-Way RM ANOVA: Strategy - F(2,108) = 6.886, **P<0.005; Training Days - F(4,108) = 0.8978, P>0.05; Interaction - F(8,108) = 8.251 ***P<0.0001). Bonferroni post-testing indicated that on Day 1 of acquisition training (day 29 in the study; see Fig. 4) there was a higher percentage of VHL-S mice searching randomly in the maze, compared to low percentages searching either serially (***P<0.001) or spatially (***P<0.001). However, as acquisition proceeded toward LTM testing, the serial strategy became preferred compared to the random (***P<0.001) and spatial strategies (***P<0.001).

Bottom Line: In experiments addressing the functional role of FASN in our experimental model, chronic intracerebroventricular (i.c.v.) microinfusions of C75, an irreversible FASN inhibitor, and significantly impaired exercise-mediated improvements in spatial learning and memory in the Barnes maze.Furthermore, pharmacologic blockade of FASN function with C75 resulted in a significant reduction, compared to vehicle treated controls, of the number of proliferative cells in the DG of running mice as measured by immunoreactive to Ki-67 in the SGZ.Taken together, our data suggest that FASN plays an important role in exercise-mediated cognitive enhancement, which might be associated to its role in modulating exercise-induced stimulation of neurogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Metabolomics Research Center, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico, United States of America ; Department of Biology, Functional Genomics Research Core, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico, United States of America.

ABSTRACT
Voluntary running is a robust inducer of adult hippocampal neurogenesis. Given that fatty acid synthase (FASN), the key enzyme for de novo fatty acid biosynthesis, is critically involved in proliferation of embryonic and adult neural stem cells, we hypothesized that FASN could mediate both exercise-induced cell proliferation in the subgranular zone (SGZ) of the dentate gyrus (DG) and enhancement of spatial learning and memory. In 20 week-old male mice, voluntary running-induced hippocampal-specific upregulation of FASN was accompanied also by hippocampal-specific accumulation of palmitate and stearate saturated fatty acids. In experiments addressing the functional role of FASN in our experimental model, chronic intracerebroventricular (i.c.v.) microinfusions of C75, an irreversible FASN inhibitor, and significantly impaired exercise-mediated improvements in spatial learning and memory in the Barnes maze. Unlike the vehicle-injected mice, the C75 group adopted a non-spatial serial escape strategy and displayed delayed escape latencies during acquisition and memory tests. Furthermore, pharmacologic blockade of FASN function with C75 resulted in a significant reduction, compared to vehicle treated controls, of the number of proliferative cells in the DG of running mice as measured by immunoreactive to Ki-67 in the SGZ. Taken together, our data suggest that FASN plays an important role in exercise-mediated cognitive enhancement, which might be associated to its role in modulating exercise-induced stimulation of neurogenesis.

Show MeSH
Related in: MedlinePlus