# A dendritic mechanism for cholinergic neuromodulation of cortical function

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2020 · $347,813

## Abstract

Acetylcholine (ACh) exerts diverse and powerful effects on animal behavior and underlying cortical neural
dynamics. However, identifying the cellular and circuit substrates mediating these processes has proved
challenging due to the many targets of ACh action and the lack of specific tools. ACh is thought to act on local
cortical circuit components, specifically interneurons, to indirectly influence pyramidal neuron dynamics. We
hypothesize that direct cholinergic neuromodulation of pyramidal neurons dendrites is an important new locus
for the effects of ACh on cortical dynamics and behavior. By leveraging a new genetically targeted
pharmacological tool with unprecedented specificity, we will causally test the contribution of AChR-dependent
dendritic mechanisms to a cortical sensorimotor computation.!Our preliminary evidence shows that muscarinic
acetylcholine receptors (mAChRs) potently modulate the excitability of distal apical trunk dendrites in layer 5
cortical pyramidal neurons (L5 PNs). These dendrites exhibit an active supralinear mechanism that can drive
high frequency somatic spiking during coincident “bottom-up” and “top-down” cortical input. L5 PN trunk
dendrites are therefore well positioned to implement a canonical cortical computation for combining multiple
inputs. In the mouse barrel cortex, bottom-up sensory information is combined with top-down motor input via
this subcellular coincidence detection mechanism to produce a whisker object localization signal. We will use
this system to test a novel role for ACh in cortical function by characterizing the effect of mAChR activation on
L5 PN dendritic integration (Aim 1) and identifying its ion channel mechanism (Aim 2). We will then employ a
novel genetically-targeted pharmacology strategy with unprecedented specificity to causally test the
contributions of mAChR-dependent dendritic mechanisms to a cortical sensorimotor computation during
behavior (Aim 3). These experiments will establish a new pathway linking a single neuromodulator – and its ion
channel target(s) in a genetically defined L5 PN cell type – to cellular processing, circuit computation, and
behavior, providing critical insight into how ACh modulates brain function. !

## Key facts

- **NIH application ID:** 9898496
- **Project number:** 5R01NS106031-03
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Mark Thomas Harnett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,813
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898496

## Citation

> US National Institutes of Health, RePORTER application 9898496, A dendritic mechanism for cholinergic neuromodulation of cortical function (5R01NS106031-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898496. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*