A hippocampal-lateral posterior thalamic nucleus neural circuit mediates cognitive impairment and metabolic dysfunction in male mice with type 2 diabetes.

OBJECTIVES: Type 2 diabetes mellitus (T2DM) is a multisystem disorder characterized by metabolic dysregulation and cognitive decline. While hippocampal dysfunction is a recognized feature of cognitive impairment, upstream neural circuits that couple peripheral metabolic signals to central cognition remain poorly defined. This study aimed to determine whether the lateral posterior thalamic nucleus-hippocampal glutamatergic (LP-HPCGlu) circuit mediates the intersection of metabolic and cognitive deficits in T2DM. METHODS: A T2DM mouse model was established using a high-fat diet (HFD) and low-dose streptozotocin (STZ). Viral tracing and chemogenetic tools were employed to map and manipulate the LP-HPCGlu neural circuit. Cognitive performance was assessed by object recognition, Y-maze, and Morris water maze tests, while metabolic profiling and molecular analyses focused on synaptic plasticity markers and IRS1/AKT/ERK signaling. RESULTS: T2DM mice exhibited persistent hyperglycemia, insulin resistance, hippocampal dendritic spine loss, and significant cognitive deficits. Viral tracing confirmed direct glutamatergic LP-HPC projections. Chemogenetic activation of the LP-HPCGlu pathway rescued both cognitive performance and glucose-lipid homeostasis, whereas inhibition induced T2DM-like phenotypes in healthy mice. Mechanistically, activation normalized IRS1/AKT/ERK signaling and restored synapsin I, PSD95, and BDNF expression. CONCLUSIONS: The LP-HPCGlu circuit contributes to metabolic and cognitive phenotypes in T2DM. Within the present design, activation of this circuit improved cognitive and metabolic outcomes in T2DM mice, whereas inhibition induced corresponding impairments in healthy mice, supporting its potential as a circuit-level intervention target.