# Circuit mechanisms underlying temporal processing in auditory cortex

> **NIH NIH R01** · UNIVERSITY OF OREGON · 2020 · $365,551

## Abstract

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.

## Key facts

- **NIH application ID:** 10123554
- **Project number:** 3R01DC015828-04S1
- **Recipient organization:** UNIVERSITY OF OREGON
- **Principal Investigator:** Michael Wehr
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $365,551
- **Award type:** 3
- **Project period:** 2020-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123554

## Citation

> US National Institutes of Health, RePORTER application 10123554, Circuit mechanisms underlying temporal processing in auditory cortex (3R01DC015828-04S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10123554. Licensed CC0.

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