Altered theta rhythm and hippocampal-cortical interactions underlie working memory deficits in a hyperglycemia risk factor model of Alzheimer’s disease

Abstract

Diabetes mellitus is a metabolic disease associated with dysregulated glucose and insulin levels and an increased risk of developing Alzheimer’s disease (AD) later in life. It is thought that chronic hyperglycemia leads to neuroinflammation and tau hyperphosphorylation in the hippocampus leading to cognitive decline, but effects on hippocampal network activity are unknown. A sustained hyperglycemic state was induced in otherwise healthy animals and subjects were then tested on a spatial delayed alternation task while recording from the hippocampus and anterior cingulate cortex (ACC). Hyperglycemic animals performed worse on long delay trials and had multiple electrophysiological differences throughout the task. We found increased delta power and decreased theta power in the hippocampus, which led to altered theta/delta ratios at the end of the delay period. Cross frequency coupling was significantly higher in multiple bands and delay period hippocampus-ACC theta coherence was elevated, revealing hypersynchrony. The highest coherence values appeared long delays on error trials for STZ animals, the opposite of what was observed in controls, where lower delay period coherence was associated with errors. Consistent with previous investigations, we found increases in phosphorylated tau in STZ animals’ hippocampus and cortex, which might account for the observed oscillatory and cognitive changes.

RETRACTED: Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases

“…Disturbance in glucose homeostasis, lipid metabolism, mitochondrial dysfunction and endoplasmic reticulum stress are linked to mental deterioration parallel to neuronal dysfunctions in AD and PD [58,59]. Numerous investigations have been performed to reveal the effect of diabetes on the brain by using animals with decreased insulin production and persistent hyperglycaemia [60][61][62][63]. The most widely studied model is developed by the infusion of STZ, which leads to beta cell death and causes neurotoxicity, triggering memory deficits associated with impaired synaptic plasticity and altered brain metabolism [64,65].…”

Extreme conditions affect neuronal oscillations of cerebral cortices in humans in the China Space Station and on Earth

“…Notably, glucose regulates brain function, especially memory, and astrocytic lactate production is also essential for memory 42 . Biomolecules 43 inside the brain or cortex might particularly account for the association between observed neuronal oscillatory and cognitive changes 44 . Regarding research on psychological situations, space psychology, a focused frontier field in human sciences, was established with the launch of Yuri Gagarin on April 12, 1961 45 , and living in a confined and isolated environment impacts mood and cognition 4 .…”

Association between Blood Glucose Control and Subjective Cognitive Decline in Korean Patients with Diabetes Aged over 50 Years

“…Owing to the interaction between accumulated AGEs and the receptors for AGEs, beta-amyloid in the blood migrates to the brain tissue through the blood–brain barrier, thereby lowering beta-amyloid metabolism and causing Alzheimer’s disease [ 29 , 30 ]. Moreover, signaling between the hippocampus, which functions to store and retrieve information according to external environments, and the anterior cingulate cortex increases excessively when chronic hyperglycemia persists, resulting in decreased adaptability due to neural network hypersynchronization, which increases the risk of Alzheimer’s disease [ 31 ]. Furthermore, insulin receptors exist in the hippocampus, and increased glucose metabolism in the brain owing to insulin is involved in learning and memory, improves communication between neurons, and increases brain blood flow, thus directly protecting against dementia through beta-amyloid and tau protein cleaning [ 32 ].…”