Spatial Memory Impairment Is Associated with Hippocampal Insulin Signals in Ovariectomized Rats

Abstract

Estrogen influences memory formation and insulin sensitivity. Meanwhile, glucose utilization directly affects learning and memory, which are modulated by insulin signals. Therefore, this study investigated whether or not the effect of estrogen on memory is associated with the regulatory effect of this hormone on glucose metabolism. The relative expression of estrogen receptor β (ERβ) and glucose transporter type 4 (GLUT4) in the hippocampus of rats were evaluated by western blot. Insulin level was assessed by ELISA and quantitative RT-PCR, and spatial memory was tested by the Morris water maze. Glucose utilization in the hippocampus was measured by 2-NBDG uptake analysis. Results showed that ovariectomy impaired the spatial memory of rats. These impairments are similar as the female rats treated with the ERβ antagonist tamoxifen (TAM). Estrogen blockade by ovariectomy or TAM treatment obviously decreased glucose utilization. This phenomenon was accompanied by decreased insulin level and GLUT4 expression in the hippocampus. The female rats were neutralized with hippocampal insulin with insulin antibody, which also impaired memory and local glucose consumption. These results indicated that estrogen blockade impaired the spatial memory of the female rats. The mechanisms by which estrogen blockade impaired memory partially contributed to the decline in hippocampal insulin signals, which diminished glucose consumption.

Mice lacking the transcriptional regulator Bhlhe40 have enhanced neuronal excitability and impaired synaptic plasticity in the hippocampus

“…Hippocampi from seven WT and Seven Bhlhe40 KO 4–7 month old mice that had been behaviorally tested were homogenized in 100 μL M-PER buffer (Thermo Scientific cat#: 78501) with protease inhibitors (Roche; Cat#: 04693124001), centrifuged at 12,000 x g for 30 min at 4°C, then supernatant was collected [ 23 ]. Insulin levels were quantified by ELISA (EMD Millipore; Cat#: EZRMI-13K) according to the manufacturer’s protocol.…”

Insulin resistance and cognitive dysfunction

“…IR in the peripheral tissues facilitates IR in the brain by reducing brain insulin uptake and increasing levels of beta amyloid (Aβ) [40]. AD incidence in late diabetic patients is two times higher compared with normal elderly people [41], and thought to arise from islet β cell dysfunction that causes impaired insulin secretion and resistance, leading to nervous system damage and ultimately influencing cognitive function in patients [41].…”

Chronic restraint stress induces hippocampal memory deficits by impairing insulin signaling

“…Attenuated insulin production and IR activity result in learning and memory formation deficits [ 25 ], and deletion of brain IR leads to augmented anxiety, depressive-like behavior, and deficits in long-term memory [ 26 , 27 ]. Blockade of IR or downstream signaling molecules such as phosphatidylinositol-3-kinase (PI3K) impairs hippocampal memory function [ 28 , 29 ], whereas intrahippocampal insulin microinjection improves spatial memory [ 29 ].…”