Alzheimer’s disease (AD) is the sixth leading cause of death in the general population and develops at a 60% higher rate in the Veteran Population. Traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are associated with the development of amyloid and tau pathology and increase the rate of cognitive decline, ultimately resulting in significant morbidity to veterans and their families. Altered plasticity and neurotransmitter pathways are strongly implicated in cognitive dysfunction associated with Alzheimer’s disease since they compromise the integrity of neuronal circuits. Understanding the mechanisms of plasticity dysfunction will allow us to identify specific checkpoints that can be targeted in the future to restore function, potentially ameliorating Alzheimer’s cognitive sequelae. Outstanding questions include: 1) what cell-specific transcriptomic abnormalities reflect plasticity pathway pathophysiology in Alzheimer’s disease, 2) what is the topographic relation between the location of b-amyloid deposits and the manifestation of transcriptomic and functional (neuronal response properties) abnormalities in different cell types, 3) how does the transcriptomic and functional profile of circuit dysfunction deteriorates during disease progression? To probe the capacity of cortical circuits for plasticity we use a well-validated implicit visual learning paradigm (stimulus-selective response potentiation or SRP) introduced by M Bear. Implicit learning developed phylogenetically earlier than conscious learning, is ubiquitous in the neocortex and plays a fundamental role in re-shaping cortical circuits to meet changing environmental demands. It is a true memory phenomenon that shares core molecular features with LTP, requires sleep for consolidation and has a behavioral correlate. Working in the visual cortex confers a strong advantage for dissecting circuit mechanisms of plasticity dysfunction in AD, since excellent control of the input allows a precise quantification of how neuronal properties change with learning in a particularly well-studied neocortical circuit. We will use chronic in vivo 2-photon imaging to measure neuronal responses before and after SRP as a function of distance from b-amyloid deposits at different stages of disease progression, in the 5xFAD mouse model of AD. Two-photon measurements will be complemented with the recently developed high-throughput multiplexed error- robust fluorescence in situ hybridization (MERFISH) imaging, to dissect how mRNA expression profiles change in different types of neurons and glia as a function of distance from b-amyloid foci. Aligning in vivo imaging with cell- specific MERFISH images obtained in vitro from the same tissue, will link abnormal neuronal responses and plasticity profiles to transcriptomic signatures obtained from the same neurons. An added benefit of this is that it can potentially extend our observations to the earliest period of malfunction, preceding amyloid plaq...