Brain Insulin Administration Triggers Distinct Cognitive and Neurotrophic Responses in Young and Aged Rats.
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.
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
CB
Haas
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.
Eduardo
E
Kalinine
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.|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
ER
Zimmer
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.
Gisele
G
Hansel
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.
Andressa W
AW
Brochier
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
JP
Oses
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.
Luis V
LV
Portela
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. alexandrep.muller@gmail.com.
Alexandre P
AP
Muller
D000375:Aging / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007276:Injections, Intraventricular; D007328:Insulin / Q000008:administration & dosage* / Q000494:pharmacology*; D008297:Male; D009414:Nerve Growth Factors / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D065852:Spatial Memory / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; D007328:Insulin; D009414:Nerve Growth Factors; D020813:Receptor, trkB
BDNF; Brain; Hippocampus; Insulin; Neurogenesis; Spatial Memory