# Thalamic reticular nucleus regulation of behavioral flexibility through modulation of a thalamocortical circuit

> **NIH NIH F32** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $70,494

## Abstract

PROJECT ABSTRACT
Behavioral flexibility, as modeled by reversal learning, is critical to achieving desired outcomes in the face of an
ever-changing environment, but is impaired across numerous neuropsychiatric conditions. Damage to the
lateral orbitofrontal cortex (LOFC) or mediodorsal thalamus (MD) produce similar reversal learning
impairments, suggesting the two regions interact to promote optimal behavior. While it is unknown how
information exchange occurs between these regions to support behavioral flexibility, one region that may
regulate communication between LOFC and MD is the thalamic reticular nucleus (TRN). TRN is the main
source of inhibitory input to the thalamus, has roles in sleep and sensory selection, and affects thalamic output
based on integration of feedforward information from the cortex and feedback information from the thalamus.
While TRN’s anatomical and functional interactions with sensory thalamus are well-characterized, it is
unknown how TRN interacts with associative thalamic nuclei and their cortical targets. This lack of information
limits our understanding of how the brain processes higher order cognition across thalamic and cortical
structures. This project will 1) characterize the effects of TRN manipulation on MD and LOFC activity, 2)
identify the effects of TRN inhibition on behavioral flexibility and cell-type specific LOFC activity, and 3)
determine whether TRN integrates prefrontal cortex (PFC) inputs to MD. The impact of optogenetic stimulation
of TRN on coordinated MD and LOFC neural activity will be assessed in Aim 1a using fiber photometry. In
addition, the impact of optogenetic inhibition of TRN on activity in a) LOFC excitatory neurons and b) LOFC
neurons receiving projections from MD will be examined using a trans-synaptic, dual-color fiber photometry
approach (Aim 1b). To assess the impact of TRN on behavioral flexibility and cell-type specific LOFC activity,
TRN will be optogenetically inhibited during reversal learning (Aim 2a), and cell-type specific LOFC activity
(Aim 2b) will be quantified using an immunohistochemical approach. Finally, I will examine the overlap of
different PFC inputs to TRN→MD projecting neurons to determine whether associative-projecting TRN has the
anatomical organization to permit PFC integration (Aim 3). This research will uncover novel insight into TRN’s
interactions with associative thalamic structures and their cortical targets, as well as determine whether TRN is
necessary for behavioral flexibility. The overall results of this proposal will identify innovative ways in which the
brain performs long range coordination of neuronal activity to support associative learning.

## Key facts

- **NIH application ID:** 10349071
- **Project number:** 1F32NS124755-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Hayley Fisher
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $70,494
- **Award type:** 1
- **Project period:** 2021-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10349071

## Citation

> US National Institutes of Health, RePORTER application 10349071, Thalamic reticular nucleus regulation of behavioral flexibility through modulation of a thalamocortical circuit (1F32NS124755-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10349071. Licensed CC0.

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