# Functional and anatomical characterization of the striosomal system

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2024 · $387,750

## Abstract

The striatum is critically important to health and well-being, and to our ability to adapt behaviorally to our
environment. As the great input-output center of the basal ganglia, the striatum receives projections from all
parts of the neocortex including mood-related areas connecting to specialized striatal zones called striosomes,
and sensorimotor areas projecting to action control circuits, involving mainly the other compartment, the matrix.
Crucially, the striatum is the main target of the tract input carrying dopamine (DA) from the substantia nigra pars
compacta (SNc), which degenerates in Parkinson’s disease. Striosomes project back to the SNc, so as to form
the nigro-striato-nigral loop famed in the clinic. The DA SNc cells not only modulate movement initiation, but also
mood, vigor, learning and decision-making. The ‘return’ striatonigral tract mainly arises in striosomes. Thus
striosomes are strategically wired to directly influence these DA neurons. Due to formidable technical hurdles,
the functions of this critical part of the nigro-striato-nigral loop remain unclear. Yet, there are clues about the
functions. Previous studies suggest that striosomes could process mood-related cortical information and send
the resultant neural signals to DA neurons in SNc. Models suggest, among others, that striosomes could serve
as critics in actor-critic reinforcement learning models. However, critically lacking is the understanding of the
relationship between the striosome-matrix axis—striosomes (S) receiving limbic, and the surrounding matrix (M)
receiving sensorimotor/associative cortical inputs—and the D1-D2 axis of the striatum—composed of direct (D1)
movement-promoting striatal projection neurons (dSPNs) and indirect (D2) movement-suppressing iSPNs, due
to the lack of experimental tools to dissociate the two axes. We have overcome some of the technical hurdles
and propose to address these issues guided by our overarching hypotheses, that the cortico-striosomal circuit
gates the state transitions of brain networks underlying mood, motivation, or vigor of action; that this circuit
modulates learning processes through its powerful connections with DA-containing SNc neurons; and that
striosome-dopamine circuits can adjust functional balance across distinct SPN subtypes with identities
multiplexed across S-M compartments and D1-D2 pathways. We will use intersect methods in mice to dissect
individual SPN subtypes according to their D1-D2 and S-M identities, DA sensors to measure DA release under
the control of the striatonigral path, and chemogenetics to manipulate each component of the nigro-striato-nigral
circuit so as to assess its causal role in behavior. Thus, we are fully equipped, standing on our groundworks that
found that cost-benefit, approach-avoidance conflict recruit the cortico-striosomal circuit, that identified by
snRNA-seq differential gene-expression patterns of individual SPN subtypes, and that have developed strategies
for simultane...

## Key facts

- **NIH application ID:** 10834876
- **Project number:** 5R01MH060379-23
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Ann M Graybiel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $387,750
- **Award type:** 5
- **Project period:** 2000-08-03 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10834876

## Citation

> US National Institutes of Health, RePORTER application 10834876, Functional and anatomical characterization of the striosomal system (5R01MH060379-23). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10834876. Licensed CC0.

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