# Systematic Testing of the VTA-BBB Hypothesis

> **NIH NIH F99** · BROWN UNIVERSITY · 2022 · $47,752

## Abstract

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 hyp...

## Key facts

- **NIH application ID:** 10478922
- **Project number:** 5F99NS125823-02
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Sinda Fekir
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $47,752
- **Award type:** 5
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10478922

## Citation

> US National Institutes of Health, RePORTER application 10478922, Systematic Testing of the VTA-BBB Hypothesis (5F99NS125823-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10478922. Licensed CC0.

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