RESUMO
Obesity is currently one of the most serious threats to human health in the western civilization. A growing body of evidence suggests that obesity is associated with cognitive dysfunction. Physical exercise not only improves fitness but it has also been shown in human and animal studies to increase hippocampus-dependent learning and memory. High-fat diet (HFD)-induced obesity and physical exercise both modulate adult hippocampal neurogenesis. Adult neurogenesis has been demonstrated to play a role in hippocampus-dependent learning and memory, particularly flexible memory expression. Here, we investigated the effects of twelve weeks of HFD vs. control diet (CD) and voluntary physical activity (wheel running; -R) vs. inactivity (sedentary; -S) on hippocampal neurogenesis and spatial learning and flexible memory function in female C57Bl/6 mice assessed in the Morris water maze. HFD was initiated either in adolescent mice combined with long-term concurrent exercise (preventive approach) or in young adult mice with 14days of subsequent exercise (therapeutic approach). HFD resulted in impaired flexible memory expression only when initiated in adolescent (HFD-S) but not in young adult mice, which was successfully prevented by concurrent exercise (HFD-R). Histological analysis revealed a reduction of immature neurons in the hippocampus of the memory-impaired HFD-S mice of the preventive approach. Long-term physical exercise also led to accelerated spatial learning during the acquisition period, which was accompanied by increased numbers of newborn mature neurons (HFD-R and CD-R). Short-term exercise of 14days in the therapeutic group was not effective in improving spatial learning or memory. We show that (1) alterations in learning and flexible memory expression are accompanied by changes in the number of neuronal cells at different maturation stages; (2) these neuronal cells are in turn differently affected by HFD; (3) adolescent mice are specifically susceptible to the negative effects of HFD. Thus, physical exercise, by modulating adult neurogenesis in the hippocampus, might represent a potential preventive approach for treating cognitive impairments associated with adolescent obesity.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Hipocampo/citologia , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/prevenção & controle , Neurogênese/fisiologia , Condicionamento Físico Animal/fisiologia , Fatores Etários , Animais , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Feminino , Transtornos da Memória/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Fatores de TempoRESUMO
The neurodegenerative disorder Parkinson's disease affects motor abilities as well as cognition. The gold standard therapy is L-Dopa, which mainly restores motor skills. Therefore, we require additional interventions to sustain cognitive functions in Parkinson's disease. The lifestyle intervention "physical activity" improves adult hippocampal neurogenesis and memory but so far, its impact has not been investigated in rodent models for Parkinson's disease previously treated with the standard therapy. We hereby asked whether physical activity serves as a pro-neurogenic and -cognitive stimulus in dopamine-depleted mice previously treated with L-Dopa. Therefore, we injected dopamine-depleted mice with L-Dopa/Benserazide followed either by exercise or by a sedentary lifestyle. We analysed adult hippocampal neurogenesis histologically and assessed spatial memory in the Morris water maze. Furthermore, we investigated the hippocampal and striatal monoaminergic cross-talk. Physical activity prevented memory decline and was linked to a slower dopamine turnover but did not enhance neurogenesis in dopamine-depleted mice previously treated with L-Dopa. In conclusion, physical activity did not develop its full pro-neurogenic potential in mice previously treated with L-Dopa but sustained spatial cognition in Parkinson's disease.
Assuntos
Antiparkinsonianos/farmacologia , Benserazida/farmacologia , Hipocampo/fisiopatologia , Levodopa/farmacologia , Intoxicação por MPTP/terapia , Memória/fisiologia , Atividade Motora/fisiologia , Animais , Antiparkinsonianos/efeitos adversos , Benserazida/efeitos adversos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Dopamina/metabolismo , Combinação de Medicamentos , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Levodopa/efeitos adversos , Intoxicação por MPTP/patologia , Intoxicação por MPTP/fisiopatologia , Intoxicação por MPTP/psicologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Distribuição Aleatória , Comportamento SedentárioRESUMO
Parkinson's disease (PD) is characterized by a continuous loss of dopaminergic neurons in the substantia nigra, which not only leads to characteristic motor symptoms but also to cognitive impairments. Physical exercise has been shown to improve hippocampus-dependent cognitive functions in PD patients. Animal studies have demonstrated the involvement of adult hippocampal neurogenesis in exercise-induced improvements of visuo-spatial learning and memory. Here, we investigated the direct impact of voluntary wheel running on hippocampal neurogenesis and spatial learning and memory in the Morris water maze (MWM) using the1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We also analyzed striatal and hippocampal dopamine transmission and mRNA expression levels of dopamine receptors. We show that MPTP-induced spatial learning deficits were alleviated by short-term physical exercise but not MPTP-induced spatial memory impairments in either exercise intervention group. Neural precursor proliferation was transiently altered in MPTP-treated mice, while the cell survival was increased by exercise. Dopamine was progressively depleted by MPTP and its turnover altered by exercise. In addition, gene expression of dopamine receptor D1/D5 was transiently upregulated following MPTP treatment but not affected by physical exercise. Our findings suggest that physical exercise benefits spatial learning but not memory performance in the MWM after MPTP-induced dopamine depletion by restoring precursor cell proliferation in the hippocampus and influencing dopamine transmission. This adds to the understanding of cognitive decline and mechanisms for potential improvements by physical exercise in PD patients.