Targeting Cholinergic Deficits with Retinoic Acid after TBI

点击翻译按钮获取中文摘要

ABSTRACT Cognitive deficits are a pervasive disability following traumatic brain injury (TBI). As of yet, there are no treatments to combat these sequelae. Alterations in neurochemical (neurotransmission) and white matter connectivity have been identified as two contributors to deficits in learning and memory behaviors after TBI. The neurotransmitter acetylcholine (ACh) is a crucial factor in regulation of cognitive function, specifically in learning and memory. Studies in experimental TBI have shown deficits in cholinergic function, and alterations in proteins involved with cholinergic neurotransmission. Recent studies have found that exogenous all-trans retinoic acid (ATRA), an active metabolite of vitamin A, can increase protein levels of choline acetyltransferase (ChAT), the vesicle ACh transporter (VAChT), and acetylcholinesterase (AChE). This leads us to posit that ATRA can be used as a potential therapeutic to improve cognitive behavior after experimental TBI. The primary goal of this project is to provide proof-of-concept evidence that ATRA can attenuate cholinergic deficits after TBI. Moreover, in support of this effect in the context of TBI, we provide preliminary data demonstrates that ATRA treatment can attenuates spatial memory retention deficits after experimental TBI. Cholinergic deficits may also be, at least partially, attributable to white matter damage. Neurons of the medial septum and the diagonal band of Broca innervate the hippocampus via the fimbria–fornix bundle. In experimental studies, damage to the fimbra/fornix produces cholinergic denervation in the hippocampus with concomitant deficits in cognition and ACh neurotransmission. Clinically, diffusion MRI tractography studies have found decreased fimbria/fornix integrity after TBI. Assessment of high-definition fiber tractography in preclinical TBI are well suited to understand global connectivity and represent a high translational outcome to evaluate ATRA therapy. The primary hypothesis of this project is to provide evidence that RA can attenuate cholinergic deficits after TBI. This hypothesis will be tested in two Aims to elucidate the effects of ATRA on the ACh system and assess the effect of RA on the integrity of axonal connectivity between cholinergic brain regions. Aim 1 will determine if ATRA treatment can attenuate cholinergic the loss of key cholinergic proteins important for ACh neurotransmission (AChE, ChaT) and (VAChT). To enhance the specificity of assessing ATRA’s effects on cholinergic function, a scopolamine challenge paradigm will be utilized. Scopolamine, a muscarinic receptor antagonist, is a memory disturbing agent. After experimental TBI, it has been reported that there is a reduction in the sensitivity of scopolamine to disrupt memory. In Aim 2, the effects of experimental TBI on cholinergic-associated white matter tracts, both with and without ATRA therapy, will be examined. If successful, this project will demonstrate for the first time the therapeutic utility of RA to attenuate cholinergic protein and white matter deficits after TBI.