Functional Imaging of The Brain

National Institute Of Neurological Disorders And Stroke

Investigators

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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. 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 three 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 completed an electrophysiological study in vivo that shows the potentiation in layer 4 propagates in direct proportion to the increase in TC potentiation throughout the cortical column and to S2, M1 and contralateral S1. No significant favoring of S2 over M1 was detected. Thus, there was no homeostatic downregulation after TC potentiation in the S1BF cortex or downstream areas. We were unable to detect any changes in cortical myelin with MRI due to this plasticity likely because myelin changes, if they occur, are small. Armed with the knowledge that the whole cortical pathway is upregulated we will inquire whether there are vascular changes to this heightened activity. We are testing if learning paradigms such as go-nogo licking task with whisker stimulation have effects on plasticity and whether learning during periods of active plasticity effect learning. Preliminary data is demonstrating both that plasticity can affect learning and learning can affect plasticity. We have developed a novel MRI gene expression reporter strategy using expression of ZIP14, which leads to MRI contrast due to manganese accumulation. Expression of ZIP14 is useful for anterograde and retrograde neural tracing studies which will make it a useful tool for plasticity studies. We have demonstrated that ZIP8 also works to enhance MRI contrast at least as well as ZIP14. Quantitative studies will be done to see if one is more efficient than the other. Over the next year we will determine if ZIP14 expression in neurons from thalamus that innervate cortex enables MRI to detect synaptic sprouting in vivo that electrophysiology predicts occurs with TC plasticity. This is work that occurs in coordination with our other Z01 entitled " MRI Contrast for Molecular and Cellular Imaging of the Brain". Aim 2: A number of years ago 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 have characterized the extent of host brain innervation and the effects of host age on the interactions between host and brain-like tissues growing in the CSF space. We see effective integration of these precursor cells in animals up to one year old and functional coupling to areas that the tissues project. It is also the case that the host can project to the tissue up to one year of age. There is functional coupling from host to tissue as well as tissue to host. This is remarkable considering that the textbook says long distance projections are complete at an early age. Host innervation is present in 1 year old rodents, but the extent is decreased. We are expanding the range of MRI we have done to help characterize these implants since they vary animal to animal as well as determine if we can recover function when transplanted into the somatosensory/motor cortex. A major hurdle is to get enough and proper projections and so we will work on the mechanism used by the host to innervate these ectopic tissues. We have focused work over the past couple of years on our project determining structural plasticity in the olfactory bulb due to odor restriction on MRI development to monitor single neural precursor migration into the brain. This is discussed in our groups other Z01 entitled MRI contrast for Molecular and Cellular Imaging of the Brain". We hope over the next year to determine how odor enrichment affects the migration patterns of these new neurons.