The Gigantocellular Reticular Nucleus Plays a Significant Role in Locomotor Recovery after Incomplete Spinal Cord Injury.

Traditionally, the brainstem has been seen as hardwired and poorly capable of plastic adaptations following spinal cord injury (SCI). Data acquired over the past decades, however, suggest differently: following SCI in various animal models (lamprey, chick, rodents, nonhuman primates), different forms of spontaneous anatomic plasticity of reticulospinal projections, many of them originating from the gigantocellular reticular nucleus (NRG), have been observed. In line with these anatomic observations, animals and humans with incomplete SCI often show various degrees of spontaneous motor recovery of hindlimb/leg function. Here, we investigated the functional relevance of two different modes of reticulospinal fiber growth after cervical hemisection, local rewiring of axotomized projections at the lesion site versus compensatory outgrowth of spared axons, using projection-specific, adeno-associated virus-mediated chemogenetic neuronal silencing. Detailed assessment of joint movements and limb kinetics during overground locomotion in female adult rats showed that locally rewired as well as compensatory NRG fibers were responsible for different aspects of recovered forelimb and hindlimb functions (i.e., stability, strength, coordination, speed, or timing). During walking and swimming, both locally rewired as well as compensatory NRG plasticity were crucial for recovered function, while the contribution of locally rewired NRG plasticity to wading performance was limited. Our data demonstrate comprehensively that locally rewired as well as compensatory plasticity of reticulospinal axons functionally contribute to the observed spontaneous improvement of stepping performance after incomplete SCI and are at least partially causative to the observed recovery of function, which can also be observed in human patients with spinal hemisection lesions.SIGNIFICANCE STATEMENT Following unilateral hemisection of the spinal cord, reticulospinal projections are destroyed on the injured side, resulting in impaired locomotion. Over time, a high degree of recovery can be observed in lesioned animals, like in human hemicord patients. In the rat, recovery is accompanied by pronounced spontaneous plasticity of axotomized and spared reticulospinal axons. We demonstrate the causative relevance of locally rewired as well as compensatory reticulospinal plasticity for the recovery of locomotor functions following spinal hemisection, using chemogenetic tools to selectively silence newly formed connections in behaviorally recovered animals. Moving from a correlative to a causative understanding of the role of neuroanatomical plasticity for functional recovery is fundamental for successful translation of treatment approaches from experimental studies to the clinics.

Early reduced behavioral activity induced by large strokes affects the efficiency of enriched environment in rats.

The majority of stroke patients develop post-stroke fatigue, a symptom which impairs motivation and diminishes the success of rehabilitative interventions. We show that large cortical strokes acutely reduce activity levels in rats for 1-2 weeks as a physiological response paralleled by signs of systemic inflammation. Rats were exposed early (1-2 weeks) or late (3-4 weeks after stroke) to an individually monitored enriched environment to stimulate self-controlled high-intensity sensorimotor training. A group of animals received Anti-Nogo antibodies for the first two weeks after stroke, a neuronal growth promoting immunotherapy already in clinical trials. Early exposure to the enriched environment resulted in poor outcome: Training intensity was correlated to enhanced systemic inflammation and functional impairment. In contrast, animals starting intense sensorimotor training two weeks after stroke preceded by the immunotherapy revealed better recovery with functional outcome positively correlated to the training intensity and the extent of re-innervation of the stroke denervated cervical hemi-cord. Our results suggest stroke-induced fatigue as a biological purposeful reaction of the organism during neuronal remodeling, enabling new circuit formation which will then be stabilized or pruned in the subsequent rehabilitative training phase. However, intense training too early may lead to wrong connections and is thus less effective.

Layer-Specific Refinement of Sensory Coding in Developing Mouse Barrel Cortex.

Rodent rhythmic whisking behavior matures during a critical period around 2 weeks after birth. The functional adaptations of neocortical circuitry during this developmental period remain poorly understood. Here, we characterized stimulus-evoked neuronal activity across all layers of mouse barrel cortex before, during, and after the onset of whisking behavior. Employing multi-electrode recordings and 2-photon calcium imaging in anesthetized mice, we tested responses to rostro-caudal whisker deflections, axial "tapping" stimuli, and their combination from postnatal day 10 (P10) to P28. Within this period, whisker-evoked activity of neurons displayed a general decrease in layer 2/3 (L2/3) and L4, but increased in L5 and L6. Distinct alterations in neuronal response adaptation during the 2-s period of stimulation at ~5 Hz accompanied these changes. Moreover, single-unit analysis revealed that response selectivity in favor of either lateral deflection or axial tapping emerges in deeper layers within the critical period around P14. For superficial layers we confirmed this finding using calcium imaging of L2/3 neurons, which also exhibited emergence of response selectivity as well as progressive sparsification and decorrelation of evoked responses around P14. Our results demonstrate layer-specific development of sensory responsiveness and response selectivity in mouse somatosensory cortex coinciding with the onset of exploratory behavior.