A fiber implant for long-term, deep-brain imaging and manipulation in mouse models of Alzheimer disease

About This Grant

PROJECT SUMMARY Neurological disorders, such as Alzheimer disease (AD) and Parkinson disease, chronically affect critical regions of the deep brain, including the hippocampus and substantia nigra. Long-term monitoring of disease progression and responses to interventions in mouse models, which have well-characterized timelines and are equipped with a variety of manipulation tools, holds significant promise for uncovering new mechanisms and therapeutic targets. However, existing technologies, including optical microscopy and microendoscopy, face major limitations related to invasiveness, biocompatibility, and long-term accessibility when studying the deep brain in mouse models. To address these challenges, we propose the development of a fiber implant for longitudinal, multifunctional, deep- brain interfacing in awake mice. This implant, with a small diameter and constructed from biocompatible materials, has the potential to address the limitations of existing approaches and enable longitudinal deep-brain monitoring with minimal impact on brain function over an extended period (>9 months). Our innovative design will integrate photoacoustic microscopy (PAM) and two-photon microscopy (TPM) for simultaneous functional and molecular imaging, along with microelectrode-based neural stimulation and microfluidics-based drug delivery for targeted brain manipulation: creating a comprehensive bidirectional interface. We will use this technology to test a set of hypotheses derived from our prior study: (1) hippocampal-dependent memory loss is a consequence of impaired blood oxygen supply in the hippocampus; (2) reduced blood oxygen supply is secondary to vascular amyloid pathology; and (3) restoring blood oxygen supply rescues memory loss. Testing these hypotheses relies on the advanced capabilities of the bidirectional fiber implant. Specifically, longitudinal monitoring is essential to unravel the temporal relationship between amyloid pathology, vascular dysfunction, and memory loss in AD. Access to the hippocampus is critical, as it is one of the first regions affected in AD and is directly linked to memory loss. The simultaneous use of PAM and TPM will allow for comprehensive assessments of both blood oxygen supply and vascular amyloid pathology. Microelectrode-based stimulation will facilitate the evaluation of the impairment in vascular functional hyperemia, while microfluidic drug delivery will enable localized application of a vasodilator to determine whether blood oxygen supply can be restored in the face of amyloid pathology, and, if so, how such restoration affects memory function in AD. Successful completion of this project will enhance our capacity for longitudinal studies of the deep brain in animal models and provide new insights into the mechanisms underlying memory impairment in AD, with significant implications for developing therapeutic strategies targeting vascular dysfunction and oxygen supply restoration.