The proposed research will test the novel hypothesis that enhanced blood supply to a local brain region impacts neural processing. A key feature of neural circuits is their flexibility, their ability to respond differently (for example, to a sensory stimulus) depending on context. This flexibility allows organisms in general and humans in particular to perform crucial tasks for survival, such as shifting attention. This flexibility is also crucial to brain health: Failures in normal mechanisms of neural dynamics - in the normal ability to shift sensitivity - have been implicated in diseases ranging from epilepsy to schizophrenia.
In this project the PIs will test the prediction that changes in blood supply to cortical sensory neurons can modulate their responses to sensory inputs. To test this hypothesis, they will integrate four techniques, bringing together expertise from two laboratories: whole animal electrophysiological and imaging studies to define the effect of changes in blood flow on neural activity and electrophysiological and imaging studies in brain slices to begin to investigate the mechanisms underlying this phenomenon. A key feature of the proposed research is development of a novel means of bidirectional blood flow regulation, the viral transfection of light-activated channels into smooth muscle. By constricting or relaxing smooth muscles using directed light, they will expand or contract local cerebral arterioles, regulating blood supply. This method provides an approach independent of the potential confounds of pharmacological intervention.
A second key feature of the proposed research is a summer research initiative for Queens College students at MIT. This program will provide a unique opportunity for Queens College students to experience the MIT environment, systematic training in research proposal development, execution of this plan, training in research ethics, and writing a summary for publication.
The brain is typically regarding as computing information with neurons. Recently, however, evidence has suggested that other networks in the brain, such as astrocytes, may play a direct role in information processing. In this research, we are testing the hypothesis that the vasculature--an elaborated, highly precise and dynamic network in the brain--could contribute to not only 'feeding' the brain, but also to its computations. Specifically, we are teting the idea that vascular dynamics, such as the local increase in blood flow associated with activity, may modulate the nearby neurons, thereby changing how they traffic signals. The intellectual merit and broader impact of answering this question is high: If alternative networks in the brain also help process signals, then we need to revise one of the most basic tenets held about brain function (that neurons compute and all other networks support). With regard to health, the import is also high: In diseases such as Alzheimer's, the deficits are attributed to neural problems. However, there are well know changes in the vasculature in Alzheimer's, and if this network plays a role in information processing, then memeory loss and other symptoms could be attributed to this source. If so, then treating the vessels could represent a novel therapeutic approach. In this work, we have made several advances: 1. We have refined a method for selectively controlling blood vessels in the brain, a drug that does not direcly impact neurons or astrocytes. Using this drug, we can then directly test what happens when the blood vessels dilate, without fear of contaminating our data. 2. Using this approach, we have imaged the brain and found evidence that astroctyes, the most prominent cell type in the brain and recently implicated in information processing, are impacted by inducing blood vessels. Dilation can increase the calcium in these cells, a key step in changing how they function. 3. Using neurophysiology, we have found that neurons also are impacted on short and longer time scales when a dilation is induced. The current data suggest an increase in cell excitability when local blood flow or volume are increased. These data, while preliminary, provide direct support for the hemo-neural hypothesis.
