Neuroprotective Role of Parvalbumin Interneurons Following Ischemia in the Aged Brain PROJECT SUMMARY/ABSTRACT There is no cure for stroke. The lack of pharmacological treatments, restricted to acute clot-buster interventions aimed to restore blood flow to ischemic brain regions as soon as possible makes stroke the fifth leading cause of death and the leading cause of long-term adult disability in North America. Studies in animal models of stroke have thrown promising results, however interventions to prevent extended brain cell death have not translated yet into useful treatments for humans. Given that age is associated with worse functional outcome after stroke in both, humans and animals, a better understanding of the effects of normal aging in neuronal brain circuits will provide a foundation for the development of therapeutic interventions designed to protect the ischemic brain from further progression of the damage, regardless of the age on the patient. Our overall hypothesis is that inhibitory interneuron activity is a neuroprotective mechanism and an age-related reduction in the presence and/or activity of parvalbumin (PV) interneurons renders the aged brain more susceptible to ischemic damage. PV neurons are probably the most abundant inhibitory interneurons in the cortex and the inhibitory action that these cells exert on the principal cortical excitatory neurons could be utilized to prevent the massive release of glutamate by these neurons during stroke. Therefore, our goal is to elucidate the degree of vulnerability of PV interneurons with age and during brain ischemic conditions and whether these neurons could be used during the early stages of the ischemic cascade to attenuate the glutamate-induced excitoxicity characteristic of this brain injury. This will have the potential to open the door to new neuroprotective interventions aimed to minimize the severity of the stroke and improve functional outcome. We will test the following hypotheses: (a) PV interneuron density decreases with age and that these neurons are more susceptible to ischemia in the aged brain, which may account for poorer prognosis following stroke in the aged brain. In addition we will test the hypothesis that aging induces a selective alteration in the relative abundance of RNA species associated with inhibitory neurotransmission in PV neurons; (b) PV interneuron activity is reduced in the peri-infarct cortex and that the deficits in PV network activity after ischemia are exacerbated in the aged brain; (c) promoting PV activity early after MCAO will have a neuroprotective effect, preventing the loss of synaptic inputs of L5 pyramidal neurons, and will improve functional recovery in both young and aged mice. We will use transgenic mice for in vivo 2PE microscopy and optogenetics using conditional expression of viral vectors, behavioral tasks, and electrophysiological recordings. Specifically:
Aim 1 will determine the extent to which the number of PV interneurons in the peri-infarct cortex is affected by stroke and by age as well as the age-related changes in gene expression in these neurons that increases their susceptibility to aging and ischemia.
Aim 2 will characterize network inhibitory activity and PV interneuron excitability following stroke.
Aim 3 will promote synaptic plasticity and functional recovery after stroke using optogenetic stimulation of PV interneurons in the peri-infarct cortex following stroke. By using state of the art techniques and innovative experimental models, we will elucidate the effects of normal aging and ischemia on the integrity of inhibitory cortical circuits for the future development of therapeutic interventions designed to protect and improve functional outcome after stroke, especially in the aged brain.
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