Gap detection deficits have recently emerged as a potential biomarker for early detection of Alzheimer's. Full validity and relevance of gap detection as a biomarker will require that we understand the underlying pathophysiology that it reflects. Despite substantial knowledge of the molecular and genetic mechanisms contributing to amyloid pathology, very little is known about how these molecular mechanisms affect the operation of neural circuits, and how this disrupts neural computation to ultimately produce behavioral deficits. We recently demonstrated early-onset gap detection deficits in the 5XFAD mouse model of Alzheimer's, opening the door for detailed neurobiological investigation of this biomarker. Work under the active award has produced key advances in our understanding of the neural computations and corresponding circuit mechanisms contributing to gap detection, providing a unique opportunity to understand how these mechanisms are disrupted by amyloid pathology. Our preliminary data reveal gap encoding deficits in auditory cortex, but also implicate subcortical auditory structures. It is therefore unclear where in the brain and when during disease progression that neuropathology produces behavioral gap detection deficits. Without this detailed understanding, gap detection will remain an unvalidated biomarker without a clear relationship to Alzheimer's pathology. The objective of this proposal is to determine where in the auditory system and when during disease progression amyloid pathology produces neuronal gap encoding deficits that impair behavioral gap detection by 5XFAD mice. Our central hypothesis is that gap detection deficits in 5XFAD mice result from cascading effects of progressive damage at multiple levels of the auditory system. By providing the complete picture of the molecular and neurophysiological disruptions over time and across the brain areas underlying a specific behavior, this work will lay the foundation for fundamental advances in the detailed mechanistic understanding of how amyloid pathology disrupts neural circuits and leads to behavioral deficits. Understanding the precise spatial and temporal relationships between neuropathology, gap encoding deficits, and behavioral impairment will deepen and extend the validity of gap detection as an early biomarker for Alzheimer's.
There is widespread consensus that early detection of Alzheimer's using non-invasive biomarkers is critical, because cognitive and memory deficits occur past the point of no return. Here we propose to validate gap detection deficits, a recently discovered early biomarker, by determining where in the auditory system and when during disease progression gap detection is disrupted in a mouse model of Alzheimer's disease. Detailed understanding of the circuit mechanisms underlying physiological and behavioral deficits will greatly enhance the power of gap detection as a biomarker for diagnosis and for developing potential therapeutic approaches.
| Keller, Clifford H; Kaylegian, Katherine; Wehr, Michael (2018) Gap encoding by parvalbumin-expressing interneurons in auditory cortex. J Neurophysiol 120:105-114 |
| Moore, Alexandra K; Weible, Aldis P; Balmer, Timothy S et al. (2018) Rapid Rebalancing of Excitation and Inhibition by Cortical Circuitry. Neuron 97:1341-1355.e6 |
