Investigation of Cognitive and Affective Deficits Post TBI Using Multimodal Flexible Neural Probes - PROJECT SUMMARY: Traumatic brain injury (TBI) is a global health crisis, and persistent cognitive-affective symptoms are common among TBI survivors. Methylphenidate (MPH), a dopamine (DA) transporter (DAT) inhibitor, has demonstrated improved outcomes with sex differences in the response. Our prior work suggests daily MPH treatment in rats with experimental TBI helps normalize electrically evoked striatal DA, but the effect on striatal basal DA level and the postsynaptic striatal medium spiny neurons (MSNs) has not been investigated. The other major striatal input, glutamatergic cortical neurons, can contribute to TBI-induced excitotoxicity. We hypothesize ongoing Glu-induced excitotoxicity post-TBI not only reduces tonic [DA] firing but also limits MSN outflow via MSN damage, consequently leading to DA transmission dysfunction and cognitive-affective deficits that are rescued by MPH. A detailed investigation of the striatum, including its inputs (DA/Glu) and output (MSN firing) is critical to understand TBI-induced striatal damage, behavior effects, MPH mechanisms and sex differ- ences to customize treatment for TBI patients. To enable such investigation, we will develop a multimodal mi- croelectrode array (MEA) to monitor the rat striatum for 3 wks after TBI and MPH, and correlate MSN neural activity, basal [DA] and [Glu] to molecular and behavioral assessments. Current state of art MEAs typically use one modality or assess one analyte, and suffer from chronic recording or sensing degradations due to biofouling, inflammatory tissue reaction, or sensor/electrode material degrada- tion. TBI exerts additional mechanical and biochemical challenges to the implanted device, and its effect on device function is unknown. By pairing novel square wave voltammetry with a poly(3,4-ethylenedioxythio- phene)/acid functionalized carbon nanotube (PEDOT/CNT) coating, we have achieved basal DA sensing in vivo for 3 wks. Meanwhile, an innovative nanoparticle technology shows promise in stabilizing Glu oxidase, allowing for selective functionalization of individual electrode sites for Glu sensing. Additionally, flexible substrates and antifouling coatings have independently shown benefits in the seamless tissue integration of MEAs. The goal of this project is to take advantage of these novel technologies to build a flexible MEA that can chronically interrogate striatal DA & Glu neurotransmission while recording striatal MSN firing, in order to advance our understanding of biological mechanisms underlying sex-specific cognitive-affective symptoms and treatment post-TBI. To accomplish this goal, we will 1) develop and optimize a flexible multimodal MEA for in vivo sensing of basal [DA] and [Glu], and neural recording in naïve rats, 2) investigate TBI effects on device performance, and 3) explore striatal mechanisms of cognitive-affective symptoms after TBI and MPH treatment using recorded striatal neural activity and basal [DA/Glu] paired with behavioral, molecular, and histological analyses to build a holistic mechanistic picture of the striatum post TBI and treatment.
