Traumatic brain injury and aging: targeting the cholinergic system for deficits in sustained attention and executive function

点击翻译按钮获取中文摘要

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 α7 receptors play important roles in attention, working memory, reward, as well as in neuroprotective and anti-inflammatory pathways. Positive allosteric modulators (PAMs) of α7 nAChRs are novel and promising therapeutic tools that can potentiate α7 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 α7 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, α7 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.