Traumatic brain injury (TBI) affects 2 million individuals in the United States each year, ranging from mild concussions to severe trauma or death. TBI survivors endure long-lasting cognitive impairments associated with frontal lobe damage, as well as psychpathological consequences. TBI models in the laboratory have been associated for decades with declines in long-term learning and memory, although the types of behavioral tests performed to date have not focused on the complex attention impairments related to frontal lobe injury or dysfunction, which are common in most TBIs. Specifically, higher-order cognitive processes such as cognitive flexibility and behavioral inhibition are markedly affected by TBI and are essential to directing and focusing cognitive activity on specific stimuli or using environmental feedback to ?unlearn? a previously valid set of rules, switch gears and filter unwanted distractions, respectively. The overarching aim of this proposal is to assess clinically-relevant cognitive-behavioral dimensions sensitive to frontal lobe TBI, and to begin to address mechanistic questions regarding altered neurotransmission responsible for such behavioral deficits by restoring cognitive performance with chronic treatment of milnacipran, a novel, dual serotonin-norepinephrine reuptake inhibitor. Specifically, the aims are designed to 1) employ a multimodal approach to determine higher-order cognitive flexibility capabilities after moderate TBI to the frontal lobe by using two different, yet well-validated attentional set-shifting tasks, the operant and digging paradigms, which have not been utilized after experimental brain trauma, 2) assess the efficacy of a promising, novel dual serotonin-norepinephrine reuptake inhibitor with antidepressant and nootropic properties, milnacipran, and 3) evaluate TBI-induced changes in brain markers of monoamine synthesis (tyrosine hydroxylase, dopamine ?- hydroxylase, tryptophan hydroxylase), storage/release (vesicular monoamine transporter 2), and reuptake (norepinephrine- and serotonin- transporters) in discrete brain regions critical for directly or indirectly modulating cognitive flexibility and executive function. The proposed studies will be carried out in both male and normal cycling female rats, an approach that is clinically relevant. Specifically, females represent up to 45% of the TBI cases with injuries occuring independent of estrous stage and therefore evaluating normal cycling females parallels the real world. Integrating animal models of higher-order cognition in the standard neurotrauma battery of behavior after frontal TBI, exploring novel therapeutic targets, as well as assessing monoamine regulation in cortical regions not well studied after TBI is paramount to developing therapeutic and rehabilitative approaches more relevant to the clinic. This two-year R21 exploratory/developmental research grant will generate preliminary data that will serve as proof-of-concept for a NIH R01 individual grant application, allowing future work to also further evaluate potential pharmacological and rehabilitative therapies for TBI-induced cognitive dysfunction.
Traumatic brain injury (TBI) causes long-lasting cognitive impairments, as well as psychopathological consequences, but the behavioral tests performed to date after experimental TBI have primarily focused on motor and spatial learning deficits and not on the complex attention impairments related to the frontal lobe, which are common in most brain injuries. This R21 application aims to explore deficits of complex, higher- order, cognitive processes after frontal lobe experimental TBI, such as cognitive flexibility and behavioral inhibition, and to begin to address mechanistic questions regarding altered neurotransmission responsible for such behavioral impairments by restoring cognitive performance with chronic treatment of milnacipran, a novel, dual serotonin-norepinephrine reuptake inhibitor. Integrating animal models of higher-order cognitive processing in the standard neurotrauma behavioral battery after TBI is paramount to investigate complex cognitive problems and finding novel therapeutic targets more relevant to the clinic, and therefore these proposed exploratory/developmental studies will be carried out in males and females, an approach which may prove extremely valuable for successful translation from bench to bedside and advanced rehabilitation research.
