An exploration of neural network activity within the limb-associated somatosensory cortex of the healthy and stroke injured brain of mice
Creators: Bandet, Mischa V.
Publisher: name: University of Alberta Library
Year: 2022

<p>Altered somatosensation is a hallmark of incomplete recovery from stroke. Although the basic mechanisms of limb-associated somatosensation have been well studied in primates, comparatively little literature exists on the limb-associated somatosensory system of rodents. Rodent models are the primary animal models used to study post-stroke plasticity and cortical network function. Further study into the basic function of the limb-associated somatosensory system in the healthy and stroke injured brain of rodents may provide insight into therapeutic targets to improve recovery after stroke. </p>

<p>The somatosensory cortex of mice has often been a focus for studies measuring the effect of stroke on sensory-evoked cortical activation. Most of these studies have looked at widescale activity across the entire limb-associated somatosensory cortex as a marker of post-stroke plasticity and changes in cortical excitability. A limited number of studies have looked at changes in the activity of individual neurons post-stroke within the limb associated somatosensory cortex. However, these studies have not thoroughly defined why the particular stimulation parameters were chosen, if the somatosensory cortex of mice can reliably respond to the multi-modal features of the stimuli, and if the cortical representations of the stimuli would change based on different stimulus frequencies or durations. The goal of Chapter 2 of this thesis was to assess if the somatosensory cortex of mice can differentially represent distinct stimuli with unique patterns of activity, even if they have overlapping features, and provide fundamental insight into sensory-evoked response properties of the limb-associated somatosensory cortex that can be applied to future studies examining these same patterns after stroke. To do this, we utilized widefield flavoprotein autofluorescence imaging to map the somatosensory cortex of anesthetized C57BL/6 mice, then used in vivo two-photon Ca2+ imaging to define patterns of neuronal activation during mechanical square-wave stimulation of the contralateral forelimb or hindlimb at various frequencies from 3-300Hz. We discovered that the variation in cortical response to different square-wave stimuli can be represented by the population pattern of supra-threshold Ca2+ transients, the magnitude and temporal properties of the evoked activity, and the structure of the stimulus-evoked correlation between neurons.</p>

<p>After having studied the representation of artificial mechanical limb stimuli in the limb-associated somatosensory cortex of the uninjured brain, we shifted to a model in which we could repeatedly measure network activity of the limb-associated somatosensory cortex at the single neuron level over the course of recovery from focal forelimb stroke. We noted that despite substantial recent progress in mapping the trajectory of network plasticity resulting from focal ischemic stroke, questions remained about the state of neuronal excitability and activity within the peri-infarct cortex of mice. Mounting evidence pointed to a deficit in sensory-evoked cortical activation after stroke despite multiple markers of impaired inhibitory neurotransmission and a potential for epileptogenic hyperexcitability. However, most of these findings had come from anesthetized animals, acute tissue slices, or immunoassays on extracted tissue and may not reflect cortical activity dynamics in the intact, awake cortex after stroke. To provide further insight on this discrepancy, we used in vivo two-photon Ca2+ imaging of awake head-fixed mice in a floating homecage at baseline and weekly for 2 months to longitudinally examine patterns of neural activity, network functional connectivity, and neural assembly architecture within the peri-infarct and distal cortex. We combined these observations with behavioral testing on a tapered beam task, string pull task, and in monitoring animal movement within the mobile homecage during imaging to monitor behavioral recovery in concert with the weekly imaging sessions. In Chapter 3, we provided the first evidence of a significant deficit in neural network functional connectivity and assembly architecture concurrent with a trend towards reduced neuronal firing within the peri-infarct cortex 1 week after stroke. We could not detect these network deficits a short distance outside the peri-infarct cortex in the distal region. Finally, we demonstrated that deficits in peri-infarct neural function and network architecture occur concurrently with a transient behavioral deficit in the tapered beam task within the same timeframe.</p>