Functional Imaging of The Brain

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

Specific aims have been redefined after an outstanding Board of Scientific Counselors review of the work in April 2021. The overall goal of this work remains to develop anatomical, functional, and molecular magnetic resonance imaging (MRI) techniques that allow non-invasive assessment of brain function and apply these tools to study plasticity, learning and integration of transplanted neural precursor cells in the rodent brain. MRI techniques are having a broad impact on understanding the brain. Anatomical based MRI has been very useful for distinguishing gray and white matter and detecting numerous brain disorders. Functional MRI techniques enable detection of regions of the brain that are active during a task. Molecular MRI is an emerging area, whose major goal is to image a large variety of processes in tissues. The goal of this project is to translate MRI developments in all these areas to study circuit and system level changes that occur in the rodent brain during plasticity and learning. Aim 1: We have established a rodent model that uses peripheral denervation to study brain plasticity in response to the injury. We have shown that denervation of the infraorbital nerve leads to large increases in barrel cortex responses along the spared whisker pathway as well as large ipsilateral cortical activity consistent with our previous work in the forepaw and hindpaw. Developments in fMRI (laminar specific fMRI) and manganese enhanced MRI for neural tracing by our group were able to predict a strengthening of thalamocortical input along the spared pathway which was verified in slice electrophysiology studies. Prior to this, it was widely believed that the thalamocortical input was not capable of strengthening after the critical period, but we have shown plasticity that mimics developmental plasticity can be reactivated. Preliminary single cell expression data indicates that there are four distinct populations of stellate cells: these cells have various extents of gene expression changes indicating plasticity and those that do not indicate gene expression changes associated plasticity. There were also changes in oligodendrocytes and endothelial cells. There is interest in potential myelin plasticity and whether the increased potentiation leads to increased vascular volume. Both of these can be measured by MRI and so the project is heading back to MRI to examine plasticity related to these changes. Over the past year we tested whether the plasticity affects behavior in a head fixed pole position task. No change in learning due to plasticity was observed. Over the next period we will test whether a roughness discrimination task is affected by the plasticity. Roughness detection is believed to require S1BC layer 4 processing so is a better task. All of the work to data has been on synaptic mechanisms underlying the systems level plasticity detected by MRI. We have begun electrophysiology in the anesthetized mouse during whisker stimulation to ask how the potentiation of thalamic inputs into layer 4 spread through the cortical column and to downstream areas in particular M1, S2 and S1 on the deprived side. Data so far indicates that the entire cortical column is potentiated although the ratio with respect to layer 4 is well maintained. During the next year we will determine if inputs to downstream areas are potentiated as well and equally distributed the same to all downstream areas or preference for some areas has occurred. We have synaptic evidence that in the deprived side, outputs were preferential to spared S1 as opposed to deprives side M1 and S2 indicating that the plasticity can have differential effects on outputs. The goal is to test this on the spared side BCS1 outputs. Aim 2: We discovered that cortical precursor cells can be grown in mature, brain tissue when implanted into the CSF. These tissues project to the host brain and the host brain projects to the tissue. We are completing and preparing for publication an exciting study that characterizes the extent of host brain innervation and the effects of age on the interactions between host and brain-like tissues growing in the CSF space. We see effective integration of these precursor cells in up to one year old animals. It is also the case that the host can project to the tissue up to one year of age. This is remarkable considering that the textbook says long distance projections are complete at an early age. We are completing studies that show these tissues are functionally integrated into the host. These brain-like tissues functionally couple to the olfactory system of the host. There is extensive reciprocal connections to frontal cortex and thalamic regions. Odor stimulation leads to responses in the tissue and we are testing if stimulation of the tissue leads to responses in OFC. The relevance of this functional coupling on behavior and the mechanism for how the host sends long distance projections into these tissues will begin to be studied over the next period.