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.
Highlights
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
In the current study, we found that animals administered a lowdose STZ protocol, that induced prolonged hyperglycemia in otherwise healthy animals, had unique alterations in hippocampal and cortical network activity
We report three main findings: (1) hyperglycemic animals exhibited identifiable patterns of network changes in both anterior cingulate cortex (ACC) and hippocampus; (2) hypersynchrony within and between areas was observed in the hyperglycemic animals as compared to controls; (3) during delay periods prior to error trials, cortico-hippocampal communication moved in opposite directions for control and hyperglycemic animals
Summary
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. DM and AD share multiple neuropathologies in the hippocampus, including impaired neurogenesis[20,21,22], dendritic atrophy[23], tau hyperphosphorylation, and increased neuroinflammation[10] All these results were identified in the streptozotocin (STZ) model[10]. Murtishaw et al.[10] employed an intermittent low-dose STZ model that mimics progressive and sustained hyperglycemia seen in late-stage DM2 known as “pancreatic exhaustion,” in an otherwise healthy animal In this model, learning and memory impairments were present, reiterating conclusions from previous studies that sustained hyperglycemia, and not sickness, induces cognitive impairments. This model renders pathological changes in the brain consistent with observations in AD model systems, including increased tau phosphorylation and sustained immune response (chronic neuroinflammation). The overlap of AD-related changes in the hyperglycemia model merits further investigations to determine whether changes in network-level function in the STZ model mirror changes observed in AD-specific models
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