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Brain Insulin Administration Triggers Distinct Cognitive and Neurotrophic Responses in Young and Aged Rats

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Abstract

Aging is a major risk factor for cognitive deficits and neurodegenerative disorders, and impaired brain insulin receptor (IR) signaling is mechanistically linked to these abnormalities. The main goal of this study was to investigate whether brain insulin infusions improve spatial memory in aged and young rats. Aged (24 months) and young (4 months) male Wistar rats were intracerebroventricularly injected with insulin (20 mU) or vehicle for five consecutive days. The animals were then assessed for spatial memory using a Morris water maze. Insulin increased memory performance in young rats, but not in aged rats. Thus, we searched for cellular and molecular mechanisms that might account for this distinct memory response. In contrast with our expectation, insulin treatment increased the proliferative activity in aged rats, but not in young rats, implying that neurogenesis-related effects do not explain the lack of insulin effects on memory in aged rats. Furthermore, the expression levels of the IR and downstream signaling proteins such as GSK3-β, mTOR, and presynaptic protein synaptophysin were increased in aged rats in response to insulin. Interestingly, insulin treatment increased the expression of the brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) receptors in the hippocampus of young rats, but not of aged rats. Our data therefore indicate that aged rats can have normal IR downstream protein expression but failed to mount a BDNF response after challenge in a spatial memory test. In contrast, young rats showed insulin-mediated TrkB/BDNF response, which paralleled with improved memory performance.

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Acknowledgments

We thank Prof. Dr. Harm Kampinga Laboratory of Cell Biology from University of Groningen, The Netherlands for his generous scientific contributions to this work. This work was supported by grants from CNPq (Grant No. 401645/2012-6), FAPERGS, and CAPES.

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Authors and Affiliations

  1. Departamento de Bioquímica, ICBS, UFRGS. Programa de Pós Graduação em Ciências Biológicas-Bioquímica, Rua Ramiro Barcelos, 2600 anexo, CEP 90035-003, Porto Alegre, Rio Grande do Sul, Brazil

    Clarissa B. Haas, Eduardo Kalinine, Eduardo R. Zimmer, Gisele Hansel, Andressa W. Brochier & Luis V. Portela

  2. Programa de Pós-Graduação em Saúde & Comportamento Centro de Ciências da Vida e da Saúde, Universidade Católica de Pelotas, Rua Almirante Barroso, 1202 sala G109, CEP: 96010-280, Pelotas, RS, Brazil

    Jean P. Oses

  3. Unidade de Ciências da Saúde, Laboratório de Bioquímica e Fisiologia do Exercício Universidade do Extremo Sul Catarinense-UNESC, Av. Universitária, 1105 - Bairro Universitário, CEP: 88806-000, Criciúma, Santa Catarina, Brazil

    Alexandre P. Muller

  4. Instituto do Cérebro do Rio Grande do Sul (InsCer ), PUCRS, A. Ipiranga, 6690, prédio 63 – Bairro, Jardim Botânico, CEP 90610.000, Porto Alegre, Rio Grande do Sul, Brazil

    Eduardo R. Zimmer

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  1. Clarissa B. Haas
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Correspondence to Alexandre P. Muller.

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The animal care followed the official governmental guidelines in compliance with the Federation of Brazilian Societies for Experimental Biology and was approved by the Ethics Committee 22535 of the Federal University of Rio Grande do Sul (UFRGS), Brazil.

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Haas, C.B., Kalinine, E., Zimmer, E.R. et al. Brain Insulin Administration Triggers Distinct Cognitive and Neurotrophic Responses in Young and Aged Rats. Mol Neurobiol 53, 5807–5817 (2016). https://doi.org/10.1007/s12035-015-9494-6

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  • DOI: https://doi.org/10.1007/s12035-015-9494-6

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