Nagheme Thomas

Learning a novel motor skill is associated with well characterized structural and functional plasticity in the rodent motor cortex. Furthermore, neuroimaging studies of visuomotor learning in humans have suggested that structural plasticity can occur in white matter (WM), but the biological basis for such changes is unclear. We assessed the influence of motor skill learning on WM structure within sensorimotor cortex using both diffusion MRI fractional anisotropy (FA) and quantitative immunohistochemistry. Seventy-two adult (male) rats were randomly assigned to one of three conditions (skilled reaching, unskilled reaching, and caged control). After 11 d of training, postmortem diffusion MRI revealed significantly higher FA in the skilled reaching group compared with the control groups, specifically in the WM subjacent to the sensorimotor cortex contralateral to the trained limb. In addition, within the skilled reaching group, FA across widespread regions of WM in the contralateral hemisphere correlated significantly with learning rate. Immunohistological analysis conducted on a subset of 24 animals (eight per group) revealed significantly increased myelin staining in the WM underlying motor cortex in the hemisphere contralateral (but not ipsilateral) to the trained limb for the skilled learning group versus the control groups. Within the trained hemisphere (but not the untrained hemisphere), myelin staining density correlated significantly with learning rate. Our results suggest that learning a novel motor skill induces structural change in task-relevant WM pathways and that these changes may in part reflect learning-related increases in myelination.

The organization of forelimb representation areas of the monkey, cat, and rat motor cortices has been studied in depth, but its characterization in the mouse lags far behind. We used intracortical microstimulation (ICMS) and cytoarchitectonics to characterize the general organization of the C57BL/6 mouse motor cortex, and the forelimb representation in more detail. We found that the forelimb region spans a large area of frontal cortex, bordered primarily by vibrissa, neck, shoulder, and hindlimb representations. It included a large caudal forelimb area, dominated by digit representation, and a small rostral forelimb area, containing elbow and wrist representations. When the entire motor cortex was mapped, the forelimb was found to be the largest movement representation, followed by head and hindlimb representations. The ICMS-defined motor cortex spanned cytoarchitecturally identified lateral agranular cortex (AGl) and also extended into medial agranular cortex. Forelimb and hindlimb representations extended into granular cortex in a region that also had cytoarchitectural characteristics of AGl, consistent with the primary motor-somatosensory overlap zone (OL) characterized in rats. Thus, the mouse motor cortex has homologies with the rat in having 2 forelimb representations and an OL but is distinct in the predominance of digit representations.

Immune checkpoint inhibitors (ICIs) extend survival in many patients with cancer but are ineffective in patients without pre-existing immunity1–9. Although personalized mRNA cancer vaccines sensitize tumours to ICIs by directing immune attacks against preselected antigens, personalized vaccines are limited by complex and time-intensive manufacturing processes10–14. Here we show that mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to ICIs. In preclinical models, SARS-CoV-2 mRNA vaccines led to a substantial increase in type I interferon, enabling innate immune cells to prime CD8+ T cells that target tumour-associated antigens. Concomitant ICI treatment is required for maximal efficacy in immunologically cold tumours, which respond by increasing PD-L1 expression. Similar correlates of vaccination response are found in humans, including increases in type I interferon, myeloid–lymphoid activation in healthy volunteers and PD-L1 expression on tumours. Moreover, receipt of SARS-CoV-2 mRNA vaccines within 100 days of initiating ICI is associated with significantly improved median and three-year overall survival in multiple large retrospective cohorts. This benefit is similar among patients with immunologically cold tumours. Together, these results demonstrate that clinically available mRNA vaccines targeting non-tumour-related antigens are potent immune modulators capable of sensitizing tumours to ICIs. mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to immune checkpoint inhibitors.

Rehabilitation-dependent motor recovery after cerebral ischemia is associated with functional reorganization of residual cortical tissue. Recovery is thought to occur when remaining circuitry surrounding the lesion is "retrained" to assume some of the lost function. This reorganization is in turn supported by synaptic plasticity within cortical circuitry and manipulations that promote plasticity may enhance recovery. Activation of the cAMP/CREB pathway is a key step for experience-dependent neural plasticity. Here we examined the effects of the prototypical phosphodiesterase inhibitor 4 (PDE4) rolipram and a novel PDE inhibitor (HT-0712), known to enhance cAMP/CREB signaling and cognitive function, on restoration of motor skill and cortical function after focal cerebral ischemia. Adult male rats were trained on a skilled reaching task to establish a baseline level of motor performance. Intracortical microstimulation was then used to derive high-resolution maps of forelimb movement representations within the caudal forelimb area of motor cortex contralateral to the trained paw. A focal ischemic infarct was created within approximately 30% of the caudal forelimb area. The effects of administering either rolipram or the novel PDE4 inhibitor HT-0712 during rehabilitation on motor recovery and restoration of movement representations within residual motor cortex were examined. Both compounds significantly enhanced motor recovery and induced an expansion of distal movement representations that extended beyond residual motor cortex. The expansion beyond the initial residual cortex was not observed in vehicle injected controls. Furthermore, the motor recovery seen in the HT-0712 animals was dose dependent. Our results suggest that PDE4 inhibitors during motor rehabilitation facilitate behavioral recovery and cortical reorganization after ischemic insult to levels significantly greater than that observed with rehabilitation alone.