# Multimodal analysis of primate infragranular pyramidal neurons and their modulation

> **NIH NIH R01** · ALLEN INSTITUTE · 2022 · $585,921

## Abstract

The long-term goal of this project is to determine the consequences of cell-type specific expression of
ion channel and neuromodulator receptor genes on primate neocortical function. The human brain is
composed of an astonishing number of cell types. Molecular profiling suggests that upwards of ~75 unique
neuronal cell types reside in a given neocortical area, and that each area has exclusive types. How do
differences in gene expression translate into a neuron’s phenotypic identity? Solving this problem is crucial
because several emerging lines of evidence suggest that human brain disorders may have cell type-specific etiologies, wherein different classes of neurons make distinct contributions to the pathophysiology
of the disease.
 We propose to examine in human and nonhuman primates how mRNA expression in two broad
categories of neocortical infragranular pyramidal neurons translates into their unique physiology,
morphology and response to neuromodulation. Employing a state-of-the-art patch clamping
technique, Patch-seq, we can genetically identify physiologically probed neurons from human and non-human primate neocortex. We test hypotheses about how specific ion channels and neuromodulator
receptors shape the unique input-output properties of these neurons. We also utilize viral tools to
prospectively label neurons, in particular the layer 5 (L5) extratelenephalic (ET)-projecting neurons (which
send axonal projections to subcerebral regions). Several types of L5 ET neurons are not found in the
rodent brain (e.g., Betz cells of motor cortex).
 Three factors make this proposal especially relevant for human health and disease. First, L5 ET
neurons represent the sole direct output of the neocortex to many subcerebral structures and are
implicated in several neurological disorders including Alzheimer’s disease and amyotrophic lateral sclerosis
(ALS). Second, we will be directly working in non-human primate and human brain slices rather than the
traditional rodent models. The latter point is especially pertinent given recent published findings of major
differences in murine and human pyramidal neuron physiology. Experiments with monkey tissue will
provide direct access to long-range axonal projection targets in vivo (which isn’t feasible for human brain
slices), as well as the ability to study brain areas rarely available in the human from surgical specimens
(e.g., primary motor cortex). Finally, this proposal lays the foundational knowledge necessary for eventual
development of cell type-specific genetic and pharmacological treatment of disease.

## Key facts

- **NIH application ID:** 10457490
- **Project number:** 5R01NS123959-02
- **Recipient organization:** ALLEN INSTITUTE
- **Principal Investigator:** NIKOLAI C DEMBROW
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $585,921
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457490

## Citation

> US National Institutes of Health, RePORTER application 10457490, Multimodal analysis of primate infragranular pyramidal neurons and their modulation (5R01NS123959-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10457490. Licensed CC0.

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