# Corticostriatal and Corticoinsular Circuit Mechanisms Underlying Stress Effects on Effort-based Reward Processing

> **NIH NIH K99** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $120,825

## Abstract

Project Summary
The ability to effectively weigh costs and benefits for action selection is integral to survival. Many environmental
and internal factors influence the decision to pursue reward in the face of costs such as energy expenditure. This
type of decision making, referred to as “effort valuation” allows individuals to navigate circumstances in which
effort and reward contingencies change and to maximize the utility of actions. Effort valuation is often impaired
in individuals suffering from disorders of motivation including depression and schizophrenia, whereby they may
perceive the anticipated effort cost to outweigh the value of expected rewards. Disrupted signaling in the anterior
cingulate cortex (ACC) is known to impair effort valuation and bias individuals toward suboptimal behavioral
responses, however, the precise function of discrete ACC circuits in encoding reward- and effort-related
information and enabling this behavior remains unknown. We will integrate in vivo 2-photon calcium imaging
(Aim 1), and optogenetics (Aim 2) to delineate the roles of two projection-defined ACC subtypes - corticostriatal
and corticoinsular neurons – in encoding of task features including reward- and effort-predictive cues. Clinical
and preclinical evidence suggests that these subcortical structures (the nucleus accumbens and insular cortex)
are critically involved in driving goal-directed behavior and monitoring internal state, respectively, processes that
may support different aspects of effort valuation. To facilitate these experiments, we have developed and
validated an imaging-compatible effort valuation task which enables measurement of motivational (anticipatory)
and hedonic (consummatory) reward seeking behavior in low- and high-effort conditions. Using this task, we will
determine the effects of chronic psychosocial stress, a risk factor for depressive symptoms, on effortful reward
seeking and circuit function (Aim 3). Importantly, only a subset of individuals who experience stress develop
depression while many remain `resilient.' Uncovering the neurobiological bases for individual differences in
susceptibility to stress is important to understanding the etiology of psychiatric disorders. In the independent
phase, we will explore these differences through single-cell transcriptomic interrogation of corticostriatal and
corticoinsular neurons in stress-susceptible and resistant animals in the hope of uncovering novel molecular
pathway candidates to inform therapeutic targets. Training in circuit dissection and individual and population-
level neural activity data analysis will be provided by the primary mentor, Dr. Liston, and complemented by Drs.
Victor and Rajasethupathy with all available resources in their labs at Weill Cornell Medicine and Rockefeller
University. As co-mentor, Dr. Macosko (Harvard Medical School), will train the candidate in single-cell RNA-
sequencing methods with local support from Dr. Anrather. Dr. Nestler (Mt. Sinai)...

## Key facts

- **NIH application ID:** 10284664
- **Project number:** 1K99MH127291-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Puja Parekh
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $120,825
- **Award type:** 1
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10284664

## Citation

> US National Institutes of Health, RePORTER application 10284664, Corticostriatal and Corticoinsular Circuit Mechanisms Underlying Stress Effects on Effort-based Reward Processing (1K99MH127291-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10284664. Licensed CC0.

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