Project Summary Alzheimer’s disease (AD), the most common dementia, currently affects ~6 million individuals in the U.S. and is expected to triple by 2050. A devastating hallmark symptom is the progressive loss of the ability to form memories. Treatments for rescuing memory function in AD patients are nonexistent, due in part to insufficient research characterizing the activity of neural memory circuits affected by AD. Developing memory-restoring therapeutics that modulate specific neural circuits demands investigation of which circuit-level functions are impacted, when during pathophysiological progression they show impairment, 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. 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. The proposed studies center on two Specific Aims: (Aim 1) Determine the time course of memory cell impairment in APP-KI mice; and (Aim 2) Test whether reactivation of LEC dopamine inputs restores associative memory formation. This study is expected to identify neuronal dysfunction of the LEC in AD. The project is expected to yield advances towards developing therapeutics to rescue memory function via neuromodulation in the lateral entorhinal cortex.