Hippocampal-specific insulin resistance elicits behavioral despair and hippocampal dendritic atrophy

Abstract

Insulin resistance is a major contributor to the neuroplasticity deficits observed in patients with metabolic disorders. However, the relative contribution of peripheral versus central insulin resistance in the development of neuroplasticity deficits remains equivocal. To distinguish between peripheral and central insulin resistance, we developed a lentiviral vector containing an antisense sequence selective for the insulin receptor (LV-IRAS). We previously demonstrated that intra-hippocampal injection of this vector impairs synaptic transmission and hippocampal-dependent learning and memory in the absence of peripheral insulin resistance. In view of the increased risk for the development of neuropsychiatric disorders in patients with insulin resistance, the current study examined depressive and anxiety-like behaviors, as well as hippocampal structural plasticity in rats with hippocampal-specific insulin resistance. Following hippocampal administration of either the LV-control virus or the LV-IRAS, anhedonia was evaluated by the sucrose preference test, despair behavior was assessed in the forced swim test, and anxiety-like behaviors were determined in the elevated plus maze. Hippocampal neuron morphology was studied by Golgi-Cox staining. Rats with hippocampal insulin resistance exhibited anxiety-like behaviors and behavioral despair without differences in anhedonia, suggesting that some but not all components of depressive-like behaviors were affected. Morphologically, hippocampal-specific insulin resistance elicited atrophy of the basal dendrites of CA3 pyramidal neurons and dentate gyrus granule neurons, and also reduced the expression of immature dentate gyrus granule neurons. In conclusion, hippocampal-specific insulin resistance elicits structural deficits that are accompanied by behavioral despair and anxiety-like behaviors, identifying hippocampal insulin resistance as a key factor in depressive illness.

Characterization of Hippocampal Synaptic Plasticity in Orchidectomized Insulin-resistant Rats

“…Also, the glucose levels for the orchidectomized and utamide group increased signi cantly compared to the control group (Fig. 4), this can be as a result of conservation of more glucose since orchidectomy has halted the process of reproduction which uses a signi cant amount of glucose, also the serum testosterone levels decreased in the orchidectomized group and utamide group, since the organ responsible for testosterone has been removed, it will cause a reduction in its production thereby reducing the amount present in the blood stream and insulin levels in orchidectomized-insulin resistant rats, and to estimate the degree of insulin resistance, the rats also showed impaired hippocampal synaptic plasticity, this is in comparison to study carried out by (Lin, 2021;Reagan, 2021) to show that insulin resistance impairs hippocampal synaptic plasticity, in the study, the rats were fed diet high in saturated fats and simple sugars and their water was supplemented with high fructose corn syrup, the diet was seen to increase fasting blood glucose levels and serum cholesterol and triglyceride levels, it was also found out that the diet impaired hippocampus-dependent learning, synaptic plasticity and dendritic spines density. The serum nitric oxide levels across the different groups (Fig.…”

SELENOM Knockout Induces Synaptic Deficits and Cognitive Dysfunction by Influencing Brain Glucose Metabolism

“…Insulin signaling plays a key role in the development and maintenance of neuroplasticity, which begins early in development. , Insulin promotes synapse formation and synaptic transmission in the brain. The literature suggests that SELENOM knockout also causes an increase in insulin levels …”

Interactions of alcohol and combination antiretroviral (cART) drug in diabetic male Sprague Dawley rats: Hippocampal perturbations and toxicosis

“…But the upregulation of insulin receptors in the DAL and DAA groups, and significantly lower NFBG levels in these groups compared to DB is consistent with earlier reports of mitigated glycaemic control and insulin sensitivity with alcohol use in diabetes [2] , [38] . These observations of impaired hippocampal insulin receptors are an indication of possible toxicosis and are often hallmarks of dysfunction in hippocampal cognition, behavioural despair, and anxiety-like behaviours [9] , [64] , [56] .…”