Traumatic brain injury (TBI) impacts 2.8 million individuals in the US each year, with older adults over 65 years being at greater risk. Survivors exhibit long-lasting cognitive impairments and psychopathologies, such as anxiety, and are more susceptible for Alzheimer's disease and related dementias, such as frontotemporal degeneration. TBI models have typically not focused on complex attentional impairments, which are common in most TBIs, such as deficits of sustained attention, goal-directed behavior, and cognitive flexibility. The cholinergic system is an important modulator of cognition, with nicotinic receptors (nACHRs) found throughout the brain. The ?7 receptors play important roles in attention, working memory, reward, as well as in neuroprotective and anti-inflammatory pathways. Positive allosteric modulators (PAMs) of ?7 nAChRs are novel and promising therapeutic tools that can potentiate ?7 currents in the presence of endogenous acetylcholine, display high receptor selectivity, and may provide neuroprotective effects. Type I PAMs enhance agonist-evoked peak currents without delaying desensitization and do not reactivate desensitized receptors. Therefore, this New/Early Stage Investigator R01 application aims to a) assess cognitive-behavioral and anxiety-like dimensions sensitive to both TBI and aging, b-c) evaluate potential benefits of subacute (7 days) and chronic (4 weeks) administration of NS 1738, a Type I PAM, alone or in combination with abbreviated environmental enrichment (EE), a preclinical rehabilitation model, on attentional dysfunction after TBI in young adult and aged rats, as well as d) address mechanistic questions regarding altered cholinergic neurotransmission responsible for such behavioral deficits by investigating proteomic and neurotransmitter regulation markers in relevant brain regions. Specifically, the aims are designed to 1) evaluate interactions of moderate parietal TBI and aging on sustained attention (3- choice serial reaction time task), cognitive flexibility (attentional set-shifting test), and anxiety-like responses (elevated plus-maze test), 2) assess age-dependent effects of the combined approach of NS 1738 treatment and abbreviated EE (4hrs daily) to restore neurobehavioral function, as well as test receptor selectivity by blocking ?7 nAChRs with methyllycaconitine, 3) quantitate proteomic profiling using mass spectrometry to identify key biomarkers (tissue and serum) correlating with neurobiological responses to aging, brain trauma, and treatment paradigms, and 4) measure brain markers of cholinergic transmission (e.g., choline acetyltransferase, acetylcholinesterase, vesicular cholinergic transporter, ?7 nAChRs), as they correlate with neurobehavior. Studies will employ both male and normal cycling female rats, as women represent up to 45% of TBIs, with injuries occurring independent of menstrual cycles. Integrating animal models of higher-order attention after TBI, as well as assessing pharmacotherapy- and rehabilitation-related cholinergic and proteomic regulation in relevant cortical regions is pivotal to developing treatment approaches relevant to the clinic.
Traumatic brain injuries (TBIs) affect 2.8 million individuals each year in the United States and often cause long-lasting cognitive and mood alterations, with the greatest external cause for TBI being falls, especially in older adults over 65 years of age. Given that behavioral tests performed to date after experimental brain trauma have primarily focused on motor and spatial learning deficits and not on commonly-reported complex attention impairments, this R01 application aims to characterize alterations in sustained attention, behavioral flexibility, and anxiety-like responses after experimental TBI in both young adult and aged rats, as well as to address mechanistic questions regarding altered cholinergic neurotransmission responsible for such behavioral impairments by restoring behavioral performance and acetylcholine brain marker levels with NS 1738 - a positive allosteric modulator of alpha-7-nicotinic acetylcholine receptors ? alone or in a combination with enriched environment housing as a preclinical model of neurorehabilitation. Integrating animal models of higher-order cognitive processing in the behavioral battery after TBI is paramount to finding clinically-relevant therapeutic targets, and therefore the proposed studies will be carried out in males and females, an approach which may prove valuable for translation from bench to bedside and advanced rehabilitation research.
