Understanding Neural Bases for Neuropsychiatric Impairments in Alzheimer's Disease Models

Project Summary Neuropsychiatric symptoms (NPS) represent a significant but frequently overlooked facet of Alzheimer’s disease (AD). These symptoms, which encompass non-cognitive disturbances like apathy, depression, anxiety, agitation, and aggressiveness, are prevalent in patients with AD and related dementias and can potentially affect the trajectory of AD progression. While AD-NPS impose major challenges on the well-being of patients and burdens on caregivers, our understanding of their origins, interconnections and neural mechanisms in relation to pathophysiology remains limited. This proposed research seeks to understand the neural foundations of NPS-related behavioral abnormalities in mouse AD models. As a starting point, we will focus on behaviors related to apathy, and test our central hypothesis that pathological and molecular/cellular changes in the anterior cingulate cortex (ACC) are accompanied with altered excitation/inhibition (E/I) balance which leads to behavioral impairments, while rebalancing the E/I may ameliorate apathy-like deficits in two mouse AD models. By combining a suite of cutting-edge approaches, we will integrate multimodality data from behavior assessments to spatial transcriptomics, anatomy, pathology, and neural function of the brain. In Specific Aim 1, we will explore cortical pathological and molecular/cellular/transcriptional changes associated with the progression of NPS-like behavioral impairments. In Specific Aim 2, we will determine how cortical neuronal functional changes contribute to apathy-like deficits in AD. The proposed study aims to generate new mechanistic understandings of neuropsychiatric impairments in AD, which may help to develop novel strategies for patient care and therapeutic approaches to mitigate adverse impacts of NPS in AD management.