# Prefrontal Microcircuits Underlying Cognitive Flexibility (K99 Administrative Supplement)

> **NIH NIH K99** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $103,098

## Abstract

Project Summary
 The ability to flexibly adapt to changing circumstance is critical for navigating through the world. In
order to effectively use cues from the environment to inform choices and guide decisions, irrelevant cues
must be effectively ignored, and often an appropriate response in one situation becomes inappropriate in
another. This type of behavior, referred to as set-shifting, represents a form of cognitive flexibility. Chronic
stress can impair the ability to set-shift and may be related to the impairments in set-shifting that accompany
psychiatric disorders such as schizophrenia or depression. An extensive body of research in humans and in
translational animal models has established a critical role for the prefrontal cortex (PFC) in maintaining
cognitive flexibility. However, the precise anatomical and information processing characteristics of the neural
circuits within the PFC that enable this behavior remain unknown.
 Through three distinct aims, we propose to leverage powerful imaging techniques to survey the
activity of specific populations of prefrontal neurons in a mouse performing a set-shifting task. In Aim 1, we
will use advanced computational methods to identify neural populations encoding distinct task features and
map their functional connectivity, revealing subnetworks of neurons specialized for encoding particular
features of the environment and of the animal's behavior. In Aim 2, we will build upon these findings by
examining the task-related coding properties of projection-specific neuronal populations in mice undergoing
chronic stress in order to examine the effect of stress on behaviorally relevant information coding. In Aim 3,
which will be completed during the Independent Phase of the funding period, we will extend our investigation
of the effects of stress on prefrontal activity by using high-speed imaging to examine the effects of stress on
rapid, network-level state. Together, these aims will advance our understanding of the role of the prefrontal
cortex in supporting behavior related to cognitive flexibility and of the circuit-level mechanisms by which
stress may impair cognitive flexibility in psychiatric illness-related cognitive deficits.
 By addressing these questions and carrying out the proposed work, the candidate will build both
technical and professional skills that will provide a solid foundation for a future career as an independent
researcher. The co-mentors, Drs. Liston and Fusi, will supervise the candidate in formal aspects of the
experimental methods and the computational biology through regular meetings (see Training Plan) and also
advise and support the candidate in the process of securing a faculty position, setting up an independent lab,
and securing initial funding. The Advisory Panel, which consists of Drs. Nestler, Paninski and Grosenick, who
have extensive experience with the methods outlined in the Research Strategy, will provide consultation on
both the conduct and interpretation of...

## Key facts

- **NIH application ID:** 10226523
- **Project number:** 3K99MH117271-02S1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Timothy Spellman
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $103,098
- **Award type:** 3
- **Project period:** 2020-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226523

## Citation

> US National Institutes of Health, RePORTER application 10226523, Prefrontal Microcircuits Underlying Cognitive Flexibility (K99 Administrative Supplement) (3K99MH117271-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10226523. Licensed CC0.

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