Sensory deprivation after focal ischemia in mice accelerates brain remapping and improves functional recovery through Arc-dependent synaptic plasticity

Abstract

Recovery after stroke, a major cause of adult disability, is often unpredictable and incomplete. Behavioral recovery is associated with functional reorganization (remapping) in perilesional regions, suggesting that promoting this process might be an effective strategy to enhance recovery. However, the molecular mechanisms underlying remapping after brain injury and the consequences of its modulation are poorly understood. Focal sensory loss or deprivation has been shown to induce remapping in the corresponding brain areas through activity-regulated cytoskeleton-associated protein (Arc)-mediated synaptic plasticity. We show that targeted sensory deprivation via whisker trimming in mice after induction of ischemic stroke in the somatosensory cortex representing forepaw accelerates remapping into the whisker barrel cortex and improves sensorimotor recovery. These improvements persisted even after focal sensory deprivation ended (whiskers allowed to regrow). Mice deficient in , a gene critical for activity-dependent synaptic plasticity, failed to remap or recover sensorimotor function. These results indicate that post-stroke remapping occurs through-mediated synaptic plasticity and is required for behavioral recovery. Furthermore, our findings suggest that enhancing perilesional cortical plasticity via focal sensory deprivation improves recovery after ischemic stroke in mice.

Peripheral sensory stimulation elicits global slow waves by recruiting somatosensory cortex bilaterally

“…Photothrombosis. Photothrombosis was performed as previously described (71). This protocol induces focal, well-circumscribed, and highly reproducible lesions (72).…”

“…Individual data points represent individual mice. Sample size and specific time points were selected on the basis of previous studies examining network connectivity changes in mice (34,41,71). Prism 8 software was used to perform statistical testing.…”

Plasticity after cortical stroke involves potentiating responses of pre-existing circuits but not functional remapping to new circuits

“…In mice, macroscopic brain imaging studies have similarly shown a range of alterations in cortical activity maps after stroke (Brown et al, 2009;Harrison et al, 2013;Jablonka et al, 2010;Kraft et al, 2018;Mohajerani et al, 2011), but whether those were associated with functional recovery has not been established. In a landmark in vivo calcium imaging study often cited as the best evidence for remapping after stroke, some neurons in peri-infarct cortex were more broadly tuned after stroke compared to neurons in control mice without a stroke (Winship et al, 2008).…”

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

“…Indeed, longitudinal imaging studies in barrel cortex suggested that inactive neurons are recruited during spared whisker map plasticity 60 . Previous stroke studies from our lab and others have found that mesoscopic sensory and motor maps can shift or displace after stroke 36,[62][63][64] , which implies there might be re-mapping of function at a cellular level. Although Winship and Murphy (2008) convincingly showed that forelimb selective neurons could become responsive to another limb after stroke, it was unknown that if same neurons could become more or less responsive to the same limb over time.…”