Selective vulnerability of fronto-insular network in aging and Alzheimer's disease - PROJECT SUMMARY Alzheimer’s disease (AD) is a prevalent aging-related neurodegenerative disorder that causes severe cognitive decline, affecting memory and decision-making. While basic sensorimotor functions remain relatively preserved in its early stages, cognitive decline varies widely across individuals, suggesting that selective neural circuit dysfunction underlies this variability. The Frontal-Insular Network (FIN)—comprising the medial prefrontal cortex (mPFC) and anterior insular cortex (aIC)—plays a central role in integrating cognitive and affective processes essential for adaptive decision-making and behavioral flexibility. Hallmark AD pathologies, including beta- amyloid plaques and tau neurofibrillary tangles, accumulate preferentially in these higher-order association areas before spreading to primary sensorimotor regions. However, how this pathology interacts with the intrinsic features of the FIN, such as its dense dopaminergic (DA) innervation and low parvalbumin (PV) inhibitory neuron density, to drive age-dependent cognitive decline remains poorly understood. This project aims to investigate the selective vulnerability of the FIN in aging and AD by integrating in vivo structural, functional, and molecular analyses with behavioral assessments in mouse models. Aim 1 will determine age-related structural and functional changes in the FIN of wild-type mice by using two-photon imaging to track dendritic spine dynamics and DA terminal remodeling, along with fiber photometry to measure neural activity and DA release during cognitive flexibility tasks. Aim 2 will examine how AD-related genetic mutations (APP/PS1) accelerate FIN degeneration, using similar methodologies to compare APP/PS1 mice across disease progression stages with age-matched wild-type controls. Aim 3 will investigate cell-type-specific molecular dysregulation in the FIN using spatial transcriptomics and assess whether targeted neuromodulation (pharmacogenetics and optogenetics) can improve cognitive flexibility in APP/PS1 mice. This study is highly innovative, leveraging a multi-level approach to dissect the structural, functional, and molecular mechanisms of FIN vulnerability. Identifying circuit-specific deficits will provide critical insights into targeted interventions that could preserve cognitive function in AD, ultimately guiding therapeutic strategies for neurodegenerative diseases.
