Human mesenchymal stromal cell transplantation modulates neuroinflammatory milieu in a mouse model of amyotrophic lateral sclerosis.

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs), after intraparenchymal, intrathecal and endovenous administration, have been previously tested for cell therapy in amyotrophic lateral sclerosis in the SOD1 (superoxide dismutase 1) mouse. However, every administration route has specific pros and cons. METHODS: We administrated human MSCs (hMSCs) in the cisterna lumbaris, which is easily accessible and could be used in outpatient surgery, in the SOD1 G93A mouse, at the earliest onset of symptoms. Control animals received saline injections. Motor behavior was checked starting from 2 months of age until the mice were killed. Animals were killed 2 weeks after transplantation; lumbar motoneurons were stereologically counted, astrocytes and microglia were analyzed and quantified after immunohistochemistry and cytokine expression was assayed by means of real-time polymerase chain reaction. RESULTS: We provide evidence that this route of administration can exert strongly positive effects. Motoneuron death and motor decay were delayed, astrogliosis was reduced and microglial activation was modulated. In addition, hMSC transplantation prevented the downregulation of the anti-inflammatory interleukin-10, as well as that of vascular endothelial growth factor observed in saline-treated transgenic mice compared with wild type, and resulted in a dramatic increase in the expression of the anti-inflammatory interleukin-13. CONCLUSIONS: Our results suggest that hMSCs, when intracisternally administered, can exert their paracrine potential, influencing the inflammatory response of the host.

Reconsidering Luria's speech mediation: Verbalization and haptic picture identification in children with congenital total blindness.

Current accounts of behavioral and neurocognitive correlates of plasticity in blindness are just beginning to incorporate the role of speech and verbal production. We assessed Vygotsky/Luria's speech mediation hypothesis, according to which speech activity can become a mediating tool for perception of complex stimuli, specifically, for encoding tactual/haptic spatial patterns which convey pictorial information (haptic pictures). We compared verbalization in congenitally totally blind (CTB) and age-matched sighted but visually impaired (VI) children during a haptic picture naming task which included two repeated, test-retest, identifications. The children were instructed to explore 10 haptic schematic pictures of objects (e.g., cup) and body parts (e.g., face) and provide (without experimenter's feedback) their typical name. Children's explorations and verbalizations were videorecorded and transcribed into audio segments. Using the Computerized Analysis of Language (CLAN) program, we extracted several measurements from the observed verbalizations, including number of utterances and words, utterance/word duration, and exploration time. Using the Word2Vec natural language processing technique we operationalized semantic content from the relative distances between the names provided. Furthermore, we conducted an observational content analysis in which three judges categorized verbalizations according to a rating scale assessing verbalization content. Results consistently indicated across all measures that the CTB children were faster and semantically more precise than their VI counterparts in the first identification test, however, the VI children reached the same level of precision and speed as the CTB children at retest. Overall, the task was harder for the VI group. Consistent with current neuroscience literature, the prominent role of speech in CTB and VI children's data suggests that an underlying cross-modal involvement of integrated brain networks, notably associated with Broca's network, likely also influenced by Braille, could play a key role in compensatory plasticity via the mediational mechanism postulated by Luria.

Differential expression of GluN2 NMDA receptor subunits in the dorsal horn of male and female rats.

N-methyl-D-aspartate receptors (NMDARs) are excitatory ionotropic glutamate receptors expressed throughout the CNS, including in the spinal dorsal horn. The GluN2 subtypes of NMDAR subunit, which include GluN2A, GluN2B, and GluN2D in the dorsal horn, confer NMDARs with structural and functional variability, enabling heterogeneity in synaptic transmission and plasticity. Despite essential roles for NMDARs in physiological and pathological pain processing, the distribution and function of these specific GluN2 isoforms across dorsal horn laminae remain poorly understood. Surprisingly, there is a complete lack of knowledge of GluN2 expression in female rodents. We, therefore, investigated the relative expression of specific GluN2 variants in the dorsal horn of lumbar (L4/L5) spinal cord from both male and female rats. In order to detect synaptic GluN2 isoforms, we used pepsin antigen-retrieval to unmask these highly cross-linked protein complexes. We found that GluN2B and GluN2D are preferentially localized to the pain-processing superficial regions of the dorsal horn in males, while only GluN2B is predominantly localized to the superficial dorsal horn of female rats. The GluN2A subunit is diffusely localized to neuropil throughout the dorsal horn of both males and females, while GluN2B and GluN2D immunolabelling are found both in the neuropil and on the soma of dorsal horn neurons. Finally, we identified an unexpected enhanced expression of GluN2B in the medial division of the superficial dorsal horn, but in males only. These sex-specific localization patterns of GluN2-NMDAR subunits across dorsal horn laminae have significant implications for the understanding of divergent spinal mechanisms of pain processing.