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 tranplanted 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 circulit and system level changes that occur in the rodent brain during plasticity and learning. Aim 1: Over the past few years we 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: those that have marker gene expression changes indicating plasticity and those that do not indicate gene expression changes associated plasticity. Over the next period we hope to characterize these separate populations and determine if there is heterogeniety in plasticity. If cells can be distinguished, we will ask if responses are altered as expected from the gene expression analysis. A study was completed in collaboration with Sengsoo Chueng and Hyesoo Lee that indicated that the plasticity we have discovered is associated with faster learning and improved retention in a whisker roughness task. This establishes a behavioral correlate of this plasticity. In our own lab we have established a simple whisker task based on detection of pole position in a head fixed apparatus that can translate to future imaging experiments. We are in the process of determining whether the whisker plasticity affects pole position detection. In addition to thalamocortical plasticity, we have demonstrated a synaptic basis for cellular takeover by the spared whiskers of the denervated whisker S1 barrel cortex via the corpus callosum input. This input can undergo LTP in the adult and the callosal inputs are strengthened on to layer 5 pyramidal neurons. This strengthening is so large that this synapse can no longer undergo LTP. This plasticity is very different depending on which area of the brain that the layer 5 neuron sends outputs. This is compelling evidence that this plasticity may have specific functional consequences. Our ability to do whisker task behavior will let us address the functional significance of this plasticity. This opens the question of whether outputs from the intact cortex has been affected and whether information to other areas such M1 and S2 is altered. We will combine fMRI, MRI neural tracing techniques and electrophysioloy to address this question over the next period. Aim 2: A few 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 are completing 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. We are also completing studies that show these tissues are functionally integrated into the host. Exciting results show these brain-like tissues can functionally couple to the olfactory system or the motor system of the host depending on where the tissue is grown. There is extensive reciprocal connections to frontal cortex and thalamic regions. The relevance of this functional coupling on behavior and the mechanism for how the host sends long distance projections into these tissues will be studied over the next period.