Plasticizing the Cortex to Enhance Stroke Recovery

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ABSTRACT Stroke is the leading cause of long-term disability, affecting almost 800,000 patients per year in the US. Most stroke survivors have some degree of spontaneous recovery, but this recovery is unpredictable and in many cases incomplete. Successful recovery requires plasticity at the synaptic and cellular level to collectively “rewire” damaged brain networks, in a process called remapping. On a global scale, plasticity in brain networks can be observed in the restoration of functional connectivity (fc) between repaired circuits and distant brain networks. Fc likely contributes to recovery of more complex. However, little is known about the mechanisms underlying network plasticity in remapping and fc. The overarching goal of this proposal is to understand mechanisms of plasticity in brain networks after stroke. Enhancing these mechanisms of repair may be key to designing therapies to improve recovery and attenuate disability after stroke. Many of the processes underlying plasticity in the injured brain mirror those that occur in the developing brain. Most saliently demonstrated in the visual cortex (V1) during development, binocular vision leads to balanced segregation of eye inputs into ocular dominance (OD) columns in V1. Monocular deprivation (MD, suturing one eye shut) during development leads the OD columns of the spared eye to competitively take over the OD columns of the deprived eye, similar to remapping after stroke. This plasticity dissipates in adulthood due to the maturation of inhibitory parvalbumin interneurons (PV-INs) in V1. PV-INs are the most prevalent inhibitory neurons in the brain, and act as ‘brakes’ to close critical periods of developmental plasticity, cementing in place mature spatial/temporal patterns of brain activity. However, recent studies have shown that juvenile-like OD plasticity can be restored in adult mice by selectively reducing firing rates in PV-INs, or by weakening the strength of excitatory synapses onto PV-INs (thus weakening their feed-forward inhibitory activity). PV-INs have been further implicated in restricting plasticity in the hippocampus, striatum, prefrontal cortex, and auditory cortex. Given the prevalence of PV-INs throughout the brain, these findings invite the exciting possibility that PV-INs are “gate-keepers” of neuronal plasticity, and potential targets for therapeutic intervention in the injured brain. The central hypothesis of this grant is that activity in PV-INs regulates network plasticity during sensory deprivation and after stroke. We will employ cutting edge non-invasive optical neuroimaging of cortical calcium dynamics in mice to probe changes in local sensory maps and global fc, in combination with viral gene transfer targeted to PV-INs, to understand the role of activity (Aim 1) and synaptic inputs onto PV-INs (Aim 2) in mediating deprivation-induced cortical plasticity and recovery from stroke. Aim 1: To determine if modulating PV-IN activity can enhance cortical plasticity during whisker sensory deprivation and recovery after ischemic injury. Aim 2: To determine the mechanistic role of excitatory synapses onto PV-INs in regulating cortical plasticity during whisker sensory deprivation and recovery after ischemic injury. Aim 3: To identify the translatome of plasticity in PV and Pyramidal neurons during whisker deprivation and after ischemic injury.