147 Medial Septal Nucleus Theta Stimulation Improves Spatial Working Memory and Increases Hippocampal Neurovascular Activity in a Mouse Model of Alzheimers Disease (5xFAD)

Abstract

INTRODUCTION: Alzheimer’s disease (AD) remains among the most prolific neurodegenerative disorders. The pathogenesis is the result, in part, of aberrant cerebral circuitry; in particular, the mesolimbic-septohippocampal circuit and its associated medial septal nucleus (MSN). Interestingly, the administration of theta stimulation via deep brain stimulation (DBS) to the MSN has been demonstrated to increase hippocampal theta oscillations, which are critical to the role of the hippocampus in learning and memory. Recently, functional ultrasound imaging (fUSI) has emerged as a method of evaluating large-scale neural activity with both high spatiotemporal resolution (∼100 μm3) and sensitivity to slow blood flow (∼1 mm/s). fUSI allows for the in-vivo analyses of neurovascular changes secondary to our theta-burst neuromodulatory intervention. METHODS: 12 male 5xFAD mice were partitioned into two groups, one received theta-burst stimulation targeting the MSN (n = 4) and the other acted as controls (n = 8). Following stimulation, spatial working memory was assessed via the Barnes maze task. An additional 44 C57BL/6 mice were partitioned into three groups: one receiving theta (7.7 Hz) stimulation to the MSN (n = 16), one receiving gamma stimulation to the MSN (100 Hz, n = 14), and the remaining group acting as the control (n = 14). RESULTS: The MSN theta stimulation group of 5xFAD mice demonstrated decreased latency compared to controls (p = 0.003). CBF volumes in the hippocampus were relatively increased in the theta-burst group when compared to both control and gamma stimulation groups. CONCLUSIONS: Our results demonstrate significant improvement in cognitive performance secondary to MSN theta-burst stimulation. Additionally, these changes were mirrored by CBF volume increases in the hippocampus in a frequency-dependent manner. These findings provide evidence for the therapeutic role of theta MSN stimulation in the treatment of AD and furthers fUSI’s role in evaluating in-vivo CBF.