Despite its limited regenerative capacity, the central nervous system (CNS) shares more repair mechanisms with peripheral tissues than previously recognized. Scar formation is a ubiquitous healing mechanism aimed at patching tissue defects via the generation of fibrous extracellular matrix (ECM). This process, orchestrated by stromal cells, can unfavorably affect the capacity of tissues to restore function. Vascular mural cells have been found to contribute to scarring after spinal cord injury. In the case of stroke, little is known about the responses of pericytes (PCs) and stromal cells. Here, we show that capillary PCs are rapidly lost after cerebral ischemia in both experimental and human stroke. Coincident with this loss is a massive proliferation of resident platelet-derived growth factor receptor beta (PDGFRb) þ and CD105 þ stromal cells, which originate from the neurovascular unit and deposit ECM in the ischemic mouse brain. The presence of PDGFRb þ stromal cells demarcates a fibrotic, contracted, and macrophage-laden lesion core from the rim of hypertrophic astroglia in both experimental and human stroke. We suggest that a previously unrecognized population of CNS-resident stromal cells drives a dynamic process of scarring after cerebral ischemia, which appears distinct from the glial scar and represents a novel target for regenerative stroke therapies.

The dorsal column nuclei complex (DCN-complex) includes the dorsal column nuclei (DCN, referring to the gracile and cuneate nuclei collectively), external cuneate, X, and Z nuclei, and the median accessory nucleus. The DCN are organized by both somatotopy and modality, and have a diverse range of afferent inputs and projection targets. The functional organization and connectivity of the DCN implicate them in a variety of sensorimotor functions, beyond their commonly accepted role in processing and transmitting somatosensory information to the thalamus, yet this is largely underappreciated in the literature. To consolidate insights into their sensorimotor functions, this review examines the morphology, organization, and connectivity of the DCN and their associated nuclei. First, we briefly discuss the receptors, afferent fibers, and pathways involved in conveying tactile and proprioceptive information to the DCN. Next, we review the modality and somatotopic arrangements of the remaining constituents of the DCN-complex. Finally, we examine and discuss the functional implications of the myriad of DCN-complex projection targets throughout the diencephalon, midbrain, and hindbrain, in addition to their modulatory inputs from the cortex. The organization and connectivity of the DCN-complex suggest that these nuclei should be considered a complex integration and distribution hub for sensorimotor information.

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The brainstem dorsal column nuclei (DCN) are essential to inform the brain of tactile and proprioceptive events experienced by the body. However, little is known about how ascending somatosensory information is represented in the DCN. Our objective was to investigate the usefulness of high-frequency (HF) and low-frequency (LF) DCN signal features (SFs) in predicting the nerve from which signals were evoked. We also aimed to explore the robustness of DCN SFs and map their relative information content across the brainstem surface. DCN surface potentials were recorded from urethane-anesthetized Wistar rats during sural and peroneal nerve electrical stimulation. Five salient SFs were extracted from each recording electrode of a seven-electrode array. We used a machine learning approach to quantify and rank information content contained within DCN surface-potential signals following peripheral nerve activation. Machine-learning of SF and electrode position combinations was quantified to determine a hierarchy of information importance for resolving the peripheral origin of nerve activation. A supervised back-propagation artificial neural network (ANN) could predict the nerve from which a response was evoked with up to 96.8 ± 0.8% accuracy. Guided by feature-learnability , we maintained high prediction accuracy after reducing ANN algorithm inputs from 35 (5 SFs from 7 electrodes) to 6 (4 SFs from one electrode and 2 SFs from a second electrode). When the number of input features were reduced, the best performing input combinations included HF and LF features. Feature-learnability also revealed that signals recorded from the same midline electrode can be accurately classified when evoked from bilateral nerve pairs, suggesting DCN surface activity asymmetry. Here we demonstrate a novel method for mapping the information content of signal patterns across the DCN surface and show that DCN SFs are robust across a population. Finally, we also show that the DCN is functionally asymmetrically organized, which challenges our current understanding of somatotopic symmetry across the midline at sub-cortical levels.

The immune response contributes to ongoing secondary tissue destruction following spinal cord injury (SCI). Although infiltrating neutrophils and monocytes have been well studied in this process, T-cells have received less attention. The objective of this study was to assess locomotor recovery and tissue morphology after SCI in athymic (nude) rats, in which T-cell numbers are reduced. Results in athymic rats were compared with heterozygote littermates with normal T-cell profiles and with Sprague-Dawley rats from previous studies in our lab. Following transection of rat spinal cords at T10, we assessed the animals' locomotor recovery on a weekly basis for up to 11 weeks, using the Basso-Beattie-Bresnahan locomotor rating scale. Nude rats showed better locomotor recovery than did heterozygote or Sprague-Dawley rats, achieving scores of 5.6 +/- 0.8 versus 1.0 +/- 0.0, respectively (p = 0.002), at 4 weeks postinjury. The improved recovery of nude rats persisted for the 11-week postinjury assessment period, and was consistent with improved spinal reflexes rather than with recovery of descending motor pathways. Anatomical evaluation at 11 weeks indicated no difference in nude versus heterozygote rats in the size or distribution of cavities caudal to the transection site, but secondary damage was more severe rostral to the transection site in heterozygote rats. In neither group did cavities extend beyond 4 mm caudal to the transection site, and were therefore not directly responsible for the functional differences between the two groups. Cellular expression of the microglia/macrophage antigen ectodysplasin A (ED1) was reduced in nude rats as compared to heterozygotes, but no difference was observed in expression levels of 5-hydroxytryptamine, the 200-kDa neurofilament, or glial fibrillary acidic protein. The findings of the study show that a reduction in T-cell numbers significantly improves locomotor recovery after spinal cord transection, indicating a deleterious role for these immune cells in neural repair after trauma.

BackgroundThe development of hypersensitivity following spinal cord injury can result in incurable persistent neuropathic pain. Our objective was to examine the effect of red light therapy on the development of hypersensitivity and sensorimotor function, as well as on microglia/macrophage subpopulations following spinal cord injury.MethodsWistar rats were treated (or sham treated) daily for 30 min with an LED red (670 nm) light source (35 mW/cm2), transcutaneously applied to the dorsal surface, following a mild T10 hemicontusion injury (or sham injury). The development of hypersensitivity was assessed and sensorimotor function established using locomotor recovery and electrophysiology of dorsal column pathways. Immunohistochemistry and TUNEL were performed to examine cellular changes in the spinal cord.ResultsWe demonstrate that red light penetrates through the entire rat spinal cord and significantly reduces signs of hypersensitivity following a mild T10 hemicontusion spinal cord injury. This is accompanied with improved dorsal column pathway functional integrity and locomotor recovery. The functional improvements were preceded by a significant reduction of dying (TUNEL+) cells and activated microglia/macrophages (ED1+) in the spinal cord. The remaining activated microglia/macrophages were predominantly of the anti-inflammatory/wound-healing subpopulation (Arginase1+ED1+) which were expressed early, and up to sevenfold greater than that found in sham-treated animals.ConclusionsThese findings demonstrate that a simple yet inexpensive treatment regime of red light reduces the development of hypersensitivity along with sensorimotor improvements following spinal cord injury and may therefore offer new hope for a currently treatment-resistant pain condition.

The brainstem dorsal column nuclei (DCN) play a role in early processing of somatosensory information arising from a variety of functionally distinct peripheral structures, before being transmitted to the cortex via the thalamus. To improve our understanding of how sensory information is represented by the DCN, we characterised and mapped low- (<200 Hz) and high-frequency (550-3300 Hz) components of nerve-evoked DCN surface potentials. DCN surface potentials were evoked by electrical stimulation of the left and right nerves innervating cutaneous structures (sural nerve), or a mix of cutaneous and deep structures (peroneal nerve), in 8-week-old urethane-anaesthetised male Wistar rats. Peroneal nerve-evoked DCN responses demonstrated low-frequency events with significantly longer durations, more high-frequency events and larger magnitudes compared to responses evoked from sural nerve stimulation. Hotspots of low- and high-frequency DCN activity were found ipsilateral to stimulated nerves but were not symmetrically organised. In conclusion, we find that sensory inputs from peripheral nerves evoke unique and characteristic DCN activity patterns that are highly reproducible both within and across animals.

Microinjections of low doses (in the femtomolar or low picomolar range) of angiotensin II (Ang II) into the nucleus tractus solitarii (NTS) evoke depressor responses. In this study we have mapped in the rat the precise location of the subregion within the NTS at which Ang II evokes significant sympathoinhibitory and depressor responses. Microinjections of 1 pmol of Ang II evoked large decreases (>or=20% of baseline) in renal sympathetic nerve activity (RSNA), from a highly restricted region in the medial NTS, at or very close to the level 0.2 mm caudal to the obex. Microinjections of the same dose of Ang II into the commissural or lateral NTS at the same rostrocaudal level, or into the medial and lateral NTS at the level of the obex evoked significantly smaller sympathoinhibitory responses, while microinjections into more rostral or caudal levels of the NTS evoked significant sympathoinhibitory responses even less frequently. In most cases (71%), the sympathoinhibitory responses were accompanied by depressor responses, the magnitudes of which were also greater within the medial NTS at the level 0.2 mm caudal to obex, as compared to the surrounding subregions. The results demonstrate that the cardiovascular effects of Ang II in the NTS are highly site-specific. Taken together with previous studies, the results also indicate that the neurons in the NTS that mediate the Ang II-evoked sympathoinhibition are a discrete subgroup of the population of sympathoinhibitory neurons within the nucleus.