# Dissecting the role of the direct and indirect pathways in moment-to-moment action selection.

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2020 · $33,352

## Abstract

Brains transform sensory information into decisions and decisions into behaviors, which ultimately determine
fitness. Behavior can be broken down into a set of discrete chunks of movement, called actions. The basal
ganglia (BG) and in particular the input nucleus of the BG, the striatum, is critical for the proper sequencing and
selection of actions. At a cellular level, the striatum is comprised of spiny projection neurons (SPNs) that
constitute the direct pathway (dSPNs) and indirect pathway (iSPNs). Under the center-surround model of action
selection, dSPNs are thought to facilitate the expression of an action while iSPNs are thought to inhibit the
expression of other actions. However, it is not clear how each pathway contributes to action selection due to
methodological constraints in acquiring an objectively quantitative description of behavior. Our lab has recently
developed a pipeline, known as MoSeq, that acquires high-resolution behavioral data and uses an unsupervised
algorithm to model stereotyped pose dynamics (actions or “syllables”). Here I propose to combine this state-of-
the-art behavioral acquisition and detection technology with both cellular-resolution imaging and optogenetic
perturbation to study the population dynamics underlying action selection in the striatum. I hypothesize that
SPNs exhibit syllable-specific tuning, where dSPNs are tightly tuned to facilitate the expression of
related syllables, while iSPNs are more broadly tuned to suppress the simultaneous expression of other
syllables. I will dissect these two processes by recording and manipulating each SPN class during specific
syllable expression. In aim 1, I will perform cellular-resolution recordings of the direct or indirect pathway using
genetically encoded calcium indicators and miniaturized microendoscopy in the striatum. I will examine the
differential roles of the direct and indirect pathways in the context of behavioral tuning. My preliminary data
suggest that dSPNs are more sparsely tuned than iSPNs. In aim 2, I will functionally test the center-surround
model via direct and indirect pathway inhibition. I will use the inhibitory anion-conducting rhodopsin, ACR2. Using
a system capable of detecting syllable expression in real-time, I will perturb each pathway triggered upon the
expression of specific syllables to compare the same selection context across many trials. In summary, the
experiments proposed here will contribute to a mechanistic understanding of how the BG performs action
selection on a moment-to-moment timescale. This proposal is the first to test the predictions made by the center-
surround model and will advance our understanding of how the BG encodes actions.

## Key facts

- **NIH application ID:** 10026026
- **Project number:** 5F31NS113385-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Winthrop Gillis
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $33,352
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10026026

## Citation

> US National Institutes of Health, RePORTER application 10026026, Dissecting the role of the direct and indirect pathways in moment-to-moment action selection. (5F31NS113385-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10026026. Licensed CC0.

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