Extracellular matrix regulation of neuronal structure, function, and plasticity

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Over the next five years, my research group will investigate how the tissue matrix that surrounds the cells of the brain regulate its activity. We will focus on extracellular matrix components called perineuronal nets (PNNs) to determine their influence on the activity of local neuronal networks in regions of the cortex important for cognitive behaviours (thought processes, attention, memory) and sensory perception. Notably, PNNs regulate the ability of the brain to appropriately wire itself during development. Recent work from our lab suggests that PNNs are reduced in cortex that is repairing itself after a focal injury, suggesting a reduction of PNNs may help the brain rewire. However, PNNs also protect neurons from damage and postmortem studies have shown that they are reduced in the cortex of individuals with schizophrenia. We have recently demonstrated that a loss of PNNs occurs in the cortex of rats in a model of schizophrenia. Moreover, we have directly shown that digestions of PNNs in the cortex leads to cognitive impairment. As such, there is a clear relationship between PNN integrity and the function of the cortex, but little is known about how changes in PNNs affect the activity of neurons. Interestingly, the majority of PNNs in the cortex are associated with “inhibitory” neurons important for reducing brain excitability. *** Here, advanced tools that allow us to optically record or control with light the activity of neurons will be used to define how neuronal activity across different cortical regions varies with PNN integrity during normal development, in animals with digested PNNs, in models of PNN loss during development (prenatal infection or pharmacological inhibition of PNN formation), or in models of brain injury. Repeated imaging using “two-photon microscopy” will be used to attain high resolution, real-time recordings of neuronal signaling in intact brains of awake and anaesthetized mice. Using genetically encoded indicators of brain activity, the activity of inhibitory neurons will be differentiated from other classes of neurons in the same areas. Spontaneous activity will be recorded in awake, behaving (running, grooming, resting) animals to permit analysis of regional activity and separation of individual neuronal firing patterns in different neurons. Sensory-evoked brain activation will be induced using auditory or somatosensory stimuli. *** The experiments proposed here will use advanced imaging tools to define how the presence or absence of PNNs at different ages of development or after injury as an adult regulates spontaneous and evoked activity in inhibitory and excitatory neurons in the cortex. A better understanding of the function of PNNs in modulating brain excitability will provide insight into their importance during neurodevelopment, their role in mental illness, and their contribution to recovery from brain injury.