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

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.

Dietary saturated fat and monounsaturated fat have reversible effects on brain function and the secretion of pro-inflammatory cytokines in young women

“…The brain protein level of BDNF was also lower, when measured after 6 months of diet 26 . BDNF signals partially via the insulin receptor substrate-1, phosphatidylinositol 3-kinase, and Akt pathway, similar to insulin 27 , but there also is evidence that intracerebroventricular infusion of insulin increased BDNF protein level in the hippocampus of young (4 months) but not older (24 months) rats 28 and that insulin signaling is required for normal BDNF transport and hippocampal synaptogenesis 29 .…”

Insulin-like growth factor 2 rescues aging-related memory loss in rats

“…In fact, to our knowledge, the effect of insulin as a memory enhancer has been reported to be controversial (Clayson 1971; Schwarzberg et al 1989; Kopf and Baratti 1996, 1999; Kopf et al 1998; Moosavi et al 2006). Moreover although insulin produces changes in proliferation of new cells and synaptic molecular pathways in aged animals, it enhances memory only in young but not aged populations, suggesting that it may protect against neuronal loss, but may not reliably improve memory performance in aging (Haas et al 2015). IGF-1, to our knowledge, has not yet been found effective in enhancing memory in healthy conditions (Stern et al 2014).…”

Inter‐relation between brain‐derived neurotrophic factor and antioxidant enzymes in bipolar disorder

“…Insulin signaling has also been shown to impact BDNF and antioxidant enzyme production. Animal studies have reported that central insulin signaling stimulates the expression of BDNF in hippocampal neurons, whereas brain insulin receptor dysfunction has been associated with decreased levels of BDNF . In addition, streptozotocin‐induced diabetes mellitus in rats leads to decreased synthesis of GPx and SOD, an effect that is reversed by the administration of insulin .…”