NIH grant: Investigating optimization of monoamine signaling in traumatic brain injury-induced neurobehavioral phenotypes (1R03NS141082-01A1)

retained text

NIH grant 1R03NS141082-01A1: Investigating optimization of monoamine signaling in traumatic brain injury-induced neurobehavioral phenotypes
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Corina Oana Bondi. Award: $159000.
Start: 2026-08-07T00:00:00.
ABSTRACT
Traumatic brain injuries (TBIs) affect over 69 million patients annually worldwide, causing enduring and
debilitating cognitive and psychosocial impairments. Laboratory models typically focus on spatial learning,
declarative memory, and motor function tasks, rendering complex executive function and emotionality alterations
inadequately characterized to date. Specifically, cognitive flexibility, sustained/focused attention, behavioral
inhibition, and anxiety-like responding are markedly affected by TBI regardless of injury location. A growing
literature supports multi-neurotransmitter impairments influencing cognitive and emotional impairments following
brain trauma. Thus, the overarching aim of this R03 proposal resubmission is to implement, for the first time, a
multimodal approach to interrogate neurochemical and mechanistic questions surrounding the brain circuitry
responsible for such complex behavioral alterations following frontal lobe injury and normalizing performance
and monoamine signaling via chronic administration of the non-amphetamine cognitive enhancer, modafinil
(MOD, Provigil®). MOD has been increasingly considered as a therapy for mental fatigue, as well as to improve
motivation and memory. It has significantly lower propensity for abuse than amphetamines and its mechanism
of action is, at least in part, that of a dual dopamine (DA) and norepinephrine (NE) reuptake blocker, making it a
pharmacological tool of interest for assessing beneficial effects on neurobehaviors by simultaneously
augmenting these monoamines disrupted by trauma. The aims are designed to 1) evaluate interactions of
moderate frontal TBI on sustained attention and impulsivity (3-choice serial reaction time task), cognitive
flexibility (attentional set-shifting), and anxiety-like/coping responses (open field test, shock probe defensive
burying) and assess the efficacy of chronic MOD administration on restoring neurobehavioral function, and 2)
evaluate TBI-induced and drug-related changes in cortical monoamine release (i.e., in vivo microdialysis for DA
and NE) and markers of brain neurotransmitter life cycle [i.e., synthesis (tyrosine hydroxylase, dopamine beta-
hydroxylase), storage/release (vesicular monoamine transporter 2), reuptake (DA- and NE-transporters), and
degradation (catechol-O-methyltransferase, monoamine oxidase)] in regions critical for directly or indirectly
modulating complex attention and affect. Studies will be conducted in both male and normal cycling female rats,
an approach that is clinically relevant. Females represent up to 45% of the TBI cases, thus evaluating normal
cycling female rats parallels the real world, where injuries occur independent of menstrual cycles. Assessing
effects of frontal TBI on complex sustained attention and, importantly, measuring in vivo, steady state
catecholamine release in frontal cortex during performance on sensitive, high-order attentional tasks has never
been reported. The findings from this R03 Small Research Grant will advance our understanding of TBI-related
phenotypes and pathophysiological mechanisms for which therapeutic approaches may target relevant
catecholamines modulating neurobehavioral symptoms in the clinic.

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