Modulatory effects over cognition and synaptic plasticity of mice under non-pharmacological interventions: intermittent fasting and physical exercise.

Author(s)

João Victor Cabral Costa

• Document type: Master's Dissertation
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2017-05-31

Examining board members

Elisa Mitiko Kawamoto Iwashe; Hudson de Sousa Buck; Rosana Camarini; Tatiana Rosado Rosenstock

• Advisor: Elisa Mitiko Kawamoto Iwashe

Abstract

First characterized as a tumor suppressor, PTEN (phosphatase and tensin deleted on chromosome 10) has been a target studied in many projects related to processes involving cell proliferation, survival and migration, showing a potential modulatory role in controlling neurogenesis and synaptic plasticity. Environmental factors, such as intermittent fasting and physical exercise, can also modulate those processes, thus having the potential of being applied as neuroprotective interventions aiming to improve learning and memory deficits. PTEN absence in neurons cause anatomical and functional anomalies, culminating in increased synaptogenesis and LTP and LTD reduction. Considering the potential of intermittent fasting and physical exercise to exert a modulatory role over the PI3K/AKT pathway, the assessment of the influence of these interventions over the effects of PTEN neuronal deletion is of great interest, as it can help better elucidate the mechanisms of synaptic plasticity. This work aimed to functionally and biochemically assess the hippocampus and the cortex of adult mice with a conditioned neuronal deletion of PTEN (PtenloxP/+;Nse-Cre+), evaluating its effects under the influence of non-pharmacological interventions. Animals were submitted to an intermittent fasting or to a voluntary physical exercise protocol for 30 days, then assessed by behavioral (elevated plus maze, open field, novel object or object location recognition tests, Morris water maze, and passive avoidance) and biochemical (Western blotting, nitric oxide synthase activity, BDNF levels) assays. The neuronal PTEN deletion induced macrocephaly through an increase in cortical mass. Also, under the stimuli of non-pharmacological interventions intermittent fasting or physical exercise the deletion induced an anxiolytic effect on the elevated plus maze assay. On the other hand, the open field results were paradoxical. Interestingly, social isolation an intrinsic factor from the physical exercise protocol induced an increase in the anxiety behavior, independently of genotype or treatment. Results from the Morris water maze assay were not conclusive, however they pointed to a likely spatial memory deficit on animals with the PTEN deletion. Surprisingly, a deleterious effect of physical exercise was also observed an effect found on BDNF levels as well. At the passive avoidance test, the deficit from the HT group was effectively rescued by either intermittent fasting and physical exercise. The hippocampus did not show any significant biochemical alterations. However, the decreased PTEN expression was confirmed in the cortex, as well as the possible AKT activation, although any effect over the glutamatergic ionotropic receptor was found. The Cre recombinase expression profile was validated through the reporter lineage Nse-Cre+;tdTomato+. The study of PtenloxP/+;Nse-Cre+ lineage showed great potential of assessing PTEN effects on cognition and synaptic plasticity. However, a deeper standardization of parameters is recommended in order to better evaluate the observed effects. In addition, by expanding the study of this lineage through the application of other stimuli could constitute an interesting way of revealing these non-observed results. (AU)

• FAPESP's process: 14/18689-8 - Evaluation of the PTEN signaling effects over neurogenesis and cognition of mice under a physical exercise regimen
• Grantee: João Victor Cabral Costa
• Support Opportunities: Scholarships in Brazil - Master