# Genetic and physiological dissection of the circuit mechanisms in the striatum.

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $385,000

## Abstract

PROJECT ABSTRACT
With the ongoing opioid crisis, there is a tremendous need for an in-depth understanding of opioid
actions and the underlying mechanisms at the cellular and circuit levels. The striatum integrates
excitatory inputs from the interconnected cortex and thalamus to form a triangular circuit that mediates
critical brain functions, including motor control, affective pain, decision-making, and reward. Opioids
impose strong modulation of this circuit, but their specific actions, such as “where” and “how” they act,
are not fully understood. The overarching goal of our proposal is to comprehensively elucidate how
individual elements in the thalamo-cortico-striatal triangular circuit are modulated by distinct opioid
receptor agonists and how these modulations alter the function of the circuit.
The thalamo-cortico-striatal circuit is organized based on specific subregions within the cortex,
thalamus, and striatum. During the previous funding period, we established the first comprehensive
thalamo-cortico-striatal circuit wiring diagram, which allowed us to identify and delineate subregion-
specific connectivity. In our preliminary studies, we have identified the exact convergent sites of the
anterior cingulate cortex (ACC) and the mediodorsal (MD) thalamus, both of which play critical roles in
affective pain and reward, in the dorsomedial striatum (DMS). This MD-ACC-DMS circuit presumably
drives pain and reward-associated executive functions. Different subtypes of opioid receptors are
expressed in all three of these brain regions, making this circuit a likely substrate for opioids. However,
the precise actions of agonists in the context of specific opioid receptor types, cell types, and brain
subregions are poorly characterized in this circuit. In the current proposal, we will use cutting-edge tools
to dissect subregion-specific, cell type-specific, opioid receptor type-specific, and synapse-specific
modulation of the synapses in the MD-ACC-DMS circuit. Specifically, we will take advantage of our
unique research strengths, including the novel connectomic information we acquired during the
previous funding period, our novel imaging capability for directly visualizing subcellular cAMP/PKA
signaling downstream of opioid receptors in living tissue, and our establishment of novel brain slice
preparations for monitoring opioid modulation of multi-synaptic information propagation. Using these
approaches, we will identify the action sites (Aim 1), the underlying intracellular signaling mechanisms
(Aim 2), and the functional impacts (Aim 3) of distinct activated opioid receptors. Our proposed
experiments will result in an in-depth, mechanistic understanding of the actions of opioid receptors in
the MD-ACC-DMS circuit that may facilitate the development of strategies to more effectively address
the role of opioids in analgesia and addiction.

## Key facts

- **NIH application ID:** 10189709
- **Project number:** 5R01NS081071-08
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Tianyi Mao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2013-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189709

## Citation

> US National Institutes of Health, RePORTER application 10189709, Genetic and physiological dissection of the circuit mechanisms in the striatum. (5R01NS081071-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10189709. Licensed CC0.

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