# Molecular and neural mechanisms associated with injury and recovery from traumatic brain injury

> **NIH VA IK2** · VA SAN DIEGO HEALTHCARE SYSTEM · 2023 · —

## Abstract

Optimal reward-guided behavior relies on intact connections between prefrontal cortex and striatum: circuitry
that is disrupted by frontal brain injury1,2. Sustaining a brain injury increases risk for developing depression,
anxiety, attention deficits, mood disorders and problems with impulse control3,4. The symptoms of frontal
traumatic brain injury (TBI) strongly resemble psychiatric disorders with regards to disruptions in reward-guided
behavior, and therefore may share common mechanisms driving behavioral impairments. Mechanisms may
include a combination of inflammatory, molecular, and cellular changes that are triggered by injury. Determining
which factors mediate persistent effects of behavior is necessary to understand chronic impacts of TBI and
develop treatments addressing the often debilitating symptoms enduring after injury. The proposed research will
examine how severe and mild frontal TBI impacts neural communication with its distributed striatal network to
influence reward-guided behavior. Identifying a neurophysiology signature associated with reward deficits would
provide a new target for brain-based treatment options. Neuromodulation, altering the electrical potentials of
the brain, may serve as a potential intervention to remediate behavioral deficits by restoring rhythmic brain
patterns and structural integrity of their underlying connections following injury. Preclinical testing in
translational animal models is critical to better understand the structural and functional mechanisms driving
behavioral impairments, and to test repetitive brain stimulation as a method to remediate effects of injury.
The first goal of this proposal is to quantify behavioral consequences of severe and mild frontal TBI made using
a controlled cortical impact (CCI) in rodents. TBI causes axonal shearing of white matter tracts and chronic
inflammation resulting in long-term changes to the brain’s microstructure. Abnormalities in corticostriatal
connectivity is being implicated in the onset of psychiatric-like symptoms, yet the relationship with TBI-induced
impairments remains unclear. As one of the most widely used injury models in animals, CCI produces focal
damage in rats that mirrors concussion, contusion, and hemorrhage in humans by driving an impactor directly
into the brain through a surgical opening in the skull30. The injury severity and location are controlled by the
experimenter and highly reproducible across animals. After injury, rats will perform a probabilistic reversal
learning task which requires reward-guided decision making, behavioral inhibition, flexible behavior, and
conditional discrimination: cognitive functions that all depend on intact prefrontal cortex. Reward-related
behavioral impairments on the reversal learning task will be related to microstructural changes.
To capture disturbances in the cortico-striatal network after TBI, brain activity will be recorded as rats run the
probabilistic reversal learning task. Neural activ...

## Key facts

- **NIH application ID:** 10693653
- **Project number:** 1IK2BX006125-01A1
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Miranda Francoeur Koloski
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10693653

## Citation

> US National Institutes of Health, RePORTER application 10693653, Molecular and neural mechanisms associated with injury and recovery from traumatic brain injury (1IK2BX006125-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10693653. Licensed CC0.

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