Project Summary Alzheimer’s disease (AD), the most common dementia, currently affects ~6.7 million individuals in the U.S. alone and is expected to grow to 13 million by the year 2050. A major component of its devastation is the progressive loss of the patient’s ability to form memories. Treatments for rescuing memory function in AD patients do not exist, due in part to insufficient research performed to characterize the activity of memory-supporting neural circuits compromised by the disease. The effort to develop memory-restorative therapeutics that intervene in neural circuits requires investigation of which circuit-level functions are impacted during pathophysiological progression, and how they relate to memory performance. Neurons in the entorhinal cortex (EC) act as a gateway for sensory inputs feeding into the hippocampus. This EC-hippocampus circuit is critical for memory formation and retrieval. Inside the EC, the lateral entorhinal cortex (LEC) is a primary site of atrophy and activity loss in the early phases of AD. Despite its significance to AD pathophysiology, it remains unclear what type of activity is lost in the LEC of AD patients or animal models. Our laboratory’s pioneering previous research has developed exciting preliminary results that suggest a path forward. We have found in healthy rats that LEC neurons develop reward-associated spike representations during associative learning. Recently, using optogenetic circuit analyses, we found in healthy wild type (WT) mice that (i) LEC layer 2a neurons categorize rewarded vs. unrewarded sensory cues when mice are performing associative learning, and (ii) this categorization activity is facilitated by dopamine inputs from the ventral tegmental area (VTA) to the LEC. Our overall hypothesis is that dysfunction of LEC neuronal activity for memory encoding causes associative memory impairment in APP knock- in mice. To test this hypothesis, we will (Aim 1) determine cell types that show activity dysfunction in the LEC, (Aim 2) determine if dysfunction of LEC dopamine causes associative memory impairment, and (Aim 3) determine if LEC 20-40Hz oscillation deficit underlies associative memory impairment. The project is expected to yield advances toward the development of therapeutics to rescue memory function in the LEC.