Sinda Fekir - US grants

PROJECT SUMMARY Survival depends on forebrain computations that optimize behaviors to meet body needs. Vascular signals from the body, transmitted through the blood-brain barrier (BBB), are an essential pathway for conveying this information. However, the BBB stringently limits molecular traffic into the brain. This protection is essential to adaptive cognitive function, and failure of the BBB is a hallmark of many diseases, including vascular dementia and deterioration associated with Alzheimer?s Disease and depression. Here, I test the hypothesis that the brain resolves tension between the need to access critical information about body state and the need to keep the brain safe by dynamically regulating BBB permeability, increasing it only at key behavioral moments. Specifically, I predict that increased activity of Ventral Tegmental Area (VTA) neurons increases BBB permeability. As a second, independent motivation for increased brain access during periods of high behavioral relevance, computation at these times may require greater resources from the body. In support of this VTA-BBB Hypothesis, VTA neurons increase activity in response to a wide variety of behaviorally-relevant events. Further, VTA axons are well-positioned, as they are often in close apposition to forebrain vessels, and they release multiple neurotransmitters that drive key components of the neurovascular unit. Aim I of this proposal outlines the work I have accomplished using in vivo multiphoton calcium and vascular imaging, and full-field optogenetic stimulation. My Preliminary Data from these experiments support the hypothesis that VTA axon activity, endogenous and evoked, predicts increased BBB permeability in mouse primary somatosensory cortex (SI). Aim II provides details of experiments I will perform to complete this work, by testing the prediction, supported by my Preliminary Data, that VTA axons proximal to vessels (<10µm) drive faster and larger increases in BBB permeability than more distant axons. I will also test the related prediction that reward-predictive cues and reward events, known to activate neocortically-projecting VTA neurons, also drive increased BBB permeability. To test the first prediction, I will employ holographic optogenetic stimulation to drive specific subsets of VTA axons, grouped by their location relative to vessels. To test the second prediction, I will image mice trained to associate high amplitude vibrissal deflections with reward. This work will provide valuable new training in optical and behavioral techniques. I will further advance these skills, and my analytical abilities, by attending workshops and courses, and by one-on-one training and collaboration. Aim III describes the training I will obtain as a postdoctoral student, focused on more sophisticated, state-specific behavioral paradigms, and on learning molecular techniques to assay high-dimensional signals that indicate body states. Whether or not my data ultimately support the hypotheses described, the training provided in these Aims will ideally position me to build my future lab, focused on discovering new pathways through which body systems interact with the brain to create behavior.