Longitudinal functional imaging of VIP interneurons reveals sup-population specific effects of stroke that are rescued with chemogenetic therapy

Abstract

Stroke profoundly disrupts cortical excitability which impedes recovery, but how it affects the function of specific inhibitory interneurons, or subpopulations therein, is poorly understood. Interneurons expressing vasoactive intestinal peptide (VIP) represent an intriguing stroke target because they can regulate cortical excitability through disinhibition. Here we chemogenetically augmented VIP interneuron excitability in a murine model of photothrombotic stroke and show that it enhances somatosensory responses and improves recovery of paw function. Using longitudinal calcium imaging, we discovered that stroke primarily disrupts the fidelity (fraction of responsive trials) and predictability of sensory responses within a subset of highly active VIP neurons. Partial recovery of responses occurred largely within these active neurons and was not accompanied by the recruitment of minimally active neurons. Importantly, chemogenetic stimulation preserved sensory response fidelity and predictability in highly active neurons. These findings provide a new depth of understanding into how stroke and prospective therapies (chemogenetics), can influence subpopulations of inhibitory interneurons.

Clozapine-Induced Chemogenetic Neuromodulation Rescues Post-Stroke Deficits After Chronic Capsular Infarct

“…Clozapine is also an FDA-approved drug and is currently prescribed to treat drug-resistant schizophrenia [36]. Therefore, despite recent reports of chemogenetic perturbation of inhibitory or glutamatergic neurons with CNO in rodents [37,38], our results provide a road-map for overcoming the major hurdles in translating chemogenetic neuromodulation to human patients. When a new treatment strategy is applied to manage stroke disorders, it is critical to have a sensitive and specific biomarker to predict the outcome and progress of that treatment.…”

Optical opening of the blood brain barrier for targeted and ultra-sparse viral infection of cells in the mouse cortex

“…While there are many possible applications for this method, we highlight one example 357 focused on cortical plasticity following stroke. Our lab and several others have used longitudinal 358 2-photon imaging through a cranial window to describe structural and functional changes to 359 cortical circuits in the days and weeks that follow an ischemic stroke in the forelimb somatosensory 360 cortex [20][21] . An obvious, yet until now very difficult experiment, would be to functionally identify 361 the part of the forelimb cortex that emerges weeks after stroke (so called "re-organized" or "re-362 emergent" cortical representation), and use AAVs to image and/or map their connections.…”

“…Moreover, we can restrict AAV delivered opto-or chemo-genetic actuators to neurons in these surviving regions, so that we can precisely manipulate their function/activity and potential role in stroke recovery, with simple, imprecise light sources (eg. Surface LEDs) or systemic administration of chemogenetic ligands 20,21 . The spatial resolution of this method is also advantageous for investigating finely organised topological maps, such as targeting functional subdomains within a single whisker barrel 22 , or retinotopic/feature-specific microdomains in the visual cortex 23,24 .…”

“…All mice imaged in the present study had a craniectomy based cranial window implanted over the right hemisphere. As previously described [20][21] , two to four month old mice were anesthetized with isoflurane (2% for induction and 1 -1.3% for maintenance) mixed in medical air (flow rate: 0.7L/mL) and then fitted into a custom head fixing plate for surgery. Body temperature was maintained at 37°C with a feedback based heating system.…”

Global disinhibition and corticospinal plasticity for drastic recovery after spinal cord injury

“…3), which supported the cortical origin of excitability. Recent studies suggest that vasoactive intestinal peptide (VIP) interneurons mediate disinhibition in the neocortical circuits and their activation promotes recovery after stroke ( 22 ). Considering its global and nonspecific properties, it is likely to be related to subcortical divergent projection systems such as cholinergic ( 23 ), monoaminergic ( 24 ) or serotonergic ( 25 ) neurons, all of which modulate the GABAergic interneurons in the cortex including the VIP interneurons.…”