Military occupational exposure to blast overpressure from improvised explosive devices can lead to mild traumatic brain injury (blast-TBI), resulting in debilitating persistent post-concussive symptoms (PPCS) and psychological dysfunction, but diagnoses and treatment options are limited. Common PPCS complaints of Veterans with blast histories include both cognitive difficulties and physiological symptoms. Likewise, common psychological dysfunctions include impulse control disorders, substance abuse, post traumatic stress disorder, depression and anxiety, but the causal mechanisms remain unknown. Therefore, increases in preclinical research efforts using rodent models are required to provide much needed insight into the underlying mechanisms by which blast-TBI contributes to subsequent dysfunction. While rodent models of blast-TBI have largely focused on potential memory-related cognitive effects, no study to date has utilized rodent models to examine the effects of blast exposure on impulsivity or attention, which are common and recurring complaints of blast exposed Veterans and are highly implicated in psychological dysfunction among civilian populations. Likewise, the neuromodulator dopamine plays a critical role in reward processing and decision making, and in civilian populations, perturbations of phasic dopamine release have been implicated in a variety of psychological dysfunctions that are similar in nature to those seen following blast-TBI. Surprisingly, few studies to date have investigated a role for dopamine dysfunction following blast exposure. The current proposal seeks to fill these knowledge gaps and will combine a mouse model of blast-induced TBI, fast scan cyclic voltammetry (FSCV) to measure subsecond nucleus accumbens (NAc) phasic dopamine release, and behavioral measures of impulsivity and attention.
Aim one will examine the near and long-term consequences of single and repetitive blast exposure on the mesolimbic dopamine system using FSCV and electrical stimulation of discrete brain regions.
Aim two will examine the near and long-term consequences of single and repetitive blast exposure on measures of impulsivity and attention, and will determine a potential role for augmented phasic dopamine release following blast in these behaviors. In rodent models, maladaptive measures of impulsivity and attention have been linked to an increase in phasic NAc dopamine neurotransmission. Therefore, based on the large number of blast-TBI Veterans presenting with impulsivity and attention impairments and our preliminary data demonstrating a blast-induced increase in impulsivity related behaviors and stimulated phasic dopamine release, we hypothesize that blast exposure will result in increased NAc dopamine release that in turn drives maladaptive measures of impulsivity and attention. These experiments are intended to further our understanding of the behavioral and neurochemical mechanisms underlying blast-TBI dysfunction, and will be an important preclinical step in elucidating potential treatment targets and strategies. My overall goals of the CDA2 application are: (i) To create a translational research program to investigate the near and long term effects of blast-TBI on subsequent cognitive, psychological and dopaminergic dysfunction. (ii) To develop new skills and understanding of rodent models of blast-TBI, as well as the clinical issues facing Veterans with and without blast-TBI histories so that my research is both informed by and has the potential to inform future preclinical and clinical lines of research. (iii) To gain working knowledge and expertise in statistical techniques for use with advanced behavioral assays and large data sets. (iv) Lastly, by virtue of these goals, to clearly differentiate myself as an independent VA investigator who is both unique from my mentors and complementary to their efforts in helping Veterans with blast-TBI histories.
Blast related traumatic brain injury (blast-TBI) is the most common form of TBI in Operation Iraqi Freedom/Operation Enduring Freedom/Operation New Dawn (OIF/OEF/OND) Veterans, and has been called a ?signature injury? of these armed conflicts. While such blast overpressures (BOP) are often mild, repetitive blast exposures are common over the course of a military career and frequently results in persistent post- concussive symptoms and psychological dysfunction, leading to a significant negative impact on the Veterans' quality of life, but treatment options are limited. The aims of the current study are centered on determining a role for augmented dopamine release in blast-induced behavioral dysfunction using an established mouse model of blast-TBI. Knowledge gained will provide translational evidence for the behavioral phenotype and associated dopamine dynamics seen following blast-TBI, as well as provide the basis for which potential pharmacotherapy efficacies can be tested.
|Schindler, A G; Meabon, J S; Pagulayan, K F et al. (2017) Blast-related disinhibition and risk seeking in mice and combat Veterans: Potential role for dysfunctional phasic dopamine release. Neurobiol Dis 106:23-34|