Link Protein 1 Is Involved in the Activity-Dependent Modulation of Perineuronal Nets in the Spinal Cord.

One of the challenges of the mature nervous system is to maintain the stability of neural networks while providing a degree of plasticity to generate experience-dependent modifications. This plasticity-stability dynamism is regulated by perineuronal nets (PNNs) and is crucial for the proper functioning of the system. Previously, we found a relation between spinal PNNs reduction and maladaptive plasticity after spinal cord injury (SCI), which was attenuated by maintaining PNNs with activity-dependent therapies. Moreover, transgenic mice lacking the cartilage link protein 1 (Crtl1 KO mice) showed aberrant spinal PNNs and increased spinal plasticity. Therefore, the aim of this study is to evaluate the role of link protein 1 in the activity-dependent modulation of spinal PNNs surrounding motoneurons and its impact on the maladaptive plasticity observed following SCI. We first studied the activity-dependent modulation of spinal PNNs using a voluntary wheel-running protocol. This training protocol increased spinal PNNs in WT mice but did not modify PNN components in Crtl1 KO mice, suggesting that link protein 1 mediates the activity-dependent modulation of PNNs. Secondly, a thoracic SCI was performed, and functional outcomes were evaluated for 35 days. Interestingly, hyperreflexia and hyperalgesia found at the end of the experiment in WT-injured mice were already present at basal levels in Crtl1 KO mice and remained unchanged after the injury. These findings demonstrated that link protein 1 plays a dual role in the correct formation and in activity-dependent modulation of PNNs, turning it into an essential element for the proper function of PNN in spinal circuits.

CD300f immune receptor contributes to healthy aging by regulating inflammaging, metabolism, and cognitive decline.

Emerging evidence suggests that immune receptors may participate in many aging-related processes such as energy metabolism, inflammation, and cognitive decline. CD300f, a TREM2-like lipid-sensing immune receptor, is an exceptional receptor as it integrates activating and inhibitory cell-signaling pathways that modulate inflammation, efferocytosis, and microglial metabolic fitness. We hypothesize that CD300f can regulate systemic aging-related processes and ultimately healthy lifespan. We closely followed several cohorts of two strains of CD300f-/- and WT mice of both sexes for 30 months and observed an important reduction in lifespan and healthspan in knockout mice. This was associated with systemic inflammaging, increased cognitive decline, reduced brain glucose uptake observed by 18FDG PET scans, enrichment in microglial aging/neurodegeneration phenotypes, proteostasis alterations, senescence, increased frailty, and sex-dependent systemic metabolic changes. Moreover, the absence of CD300f altered macrophage immunometabolic phenotype. Taken together, we provide strong evidence suggesting that myeloid cell CD300f immune receptor contributes to healthy aging.

Protocol for the feasibility and implementation study of a model of best practice in primary care led postdiagnostic dementia care: PriDem.

INTRODUCTION: Care is often inadequate and poorly integrated after a dementia diagnosis. Research and policy highlight the unaffordability and unsustainability of specialist-led support, and instead suggest a task-shared model, led by primary care. This study is part of the PriDem primary care led postdiagnostic dementia care research programme and will assess delivery of an evidence-informed, primary care based, person-centred intervention. The intervention involves Clinical Dementia Leads (CDLs) working in primary care to develop effective dementia care systems that build workforce capacity and support teams to deliver tailored support to people living with dementia and their carers. METHODS AND ANALYSIS: This is a 15-month mixed-methods feasibility and implementation study, situated in four National Health Service (NHS) primary care networks in England. The primary outcome is adoption of personalised care planning by participating general practices, assessed through a patient records audit. Feasibility outcomes include recruitment and retention; appropriateness and acceptability of outcome measures; acceptability, feasibility and fidelity of intervention components. People living with dementia (n=80) and carers (n=66) will be recruited through participating general practices and will complete standardised measures of health and well-being. Participant service use data will be extracted from electronic medical records. A process evaluation will explore implementation barriers and facilitators through methods including semistructured interviews with people living with dementia, carers and professionals; observation of CDL engagement with practice staff; and a practice fidelity log. Process evaluation data will be analysed qualitatively using codebook thematic analysis, and quantitatively using descriptive statistics. Economic analysis will determine intervention cost-effectiveness. ETHICS AND DISSEMINATION: The study has received favourable ethical opinion from Wales REC4. NHS Confidentiality Advisory Group support allows researchers preconsent access to patient data. Results will inform intervention adaptations and a future large-scale evaluation. Dissemination through peer-review journals, engagement with policy-makers and conferences will inform recommendations for dementia services commissioning. TRIAL REGISTRATION NUMBER: ISRCTN11677384.

Generation and characterization of Ccdc28b mutant mice links the Bardet-Biedl associated gene with mild social behavioral phenotypes.

CCDC28B (coiled-coil domain-containing protein 28B) was identified as a modifier in the ciliopathy Bardet-Biedl syndrome (BBS). Our previous work in cells and zebrafish showed that CCDC28B plays a role regulating cilia length in a mechanism that is not completely understood. Here we report the generation of a Ccdc28b mutant mouse using CRISPR/Cas9 (Ccdc28b mut). Depletion of CCDC28B resulted in a mild phenotype. Ccdc28b mut animals i) do not present clear structural cilia affectation, although we did observe mild defects in cilia density and cilia length in some tissues, ii) reproduce normally, and iii) do not develop retinal degeneration or obesity, two hallmark features of reported BBS murine models. In contrast, Ccdc28b mut mice did show clear social interaction defects as well as stereotypical behaviors. This finding is indeed relevant regarding CCDC28B as a modifier of BBS since behavioral phenotypes have been documented in BBS. Overall, this work reports a novel mouse model that will be key to continue evaluating genetic interactions in BBS, deciphering the contribution of CCDC28B to modulate the presentation of BBS phenotypes. In addition, our data underscores a novel link between CCDC28B and behavioral defects, providing a novel opportunity to further our understanding of the genetic, cellular, and molecular basis of these complex phenotypes.

CD200R1 Contributes to Successful Functional Reinnervation after a Sciatic Nerve Injury.

Activating and inhibitory immune receptors play a critical role in regulating systemic and central nervous system (CNS) immune and inflammatory processes. The CD200R1 immunoreceptor induces a restraining signal modulating inflammation and phagocytosis in the CNS under different inflammatory conditions. However, it remains unknown whether CD200R1 has a role in modulating the inflammatory response after a peripheral nerve injury, an essential component of the successful regeneration. Expression of CD200R1 and its ligand CD200 was analyzed during homeostasis and after a sciatic nerve crush injury in C57Bl/6 mice. The role of CD200R1 in Wallerian Degeneration (WD) and nerve regeneration was studied using a specific antibody against CD200R1 injected into the nerve at the time of injury. We found an upregulation of CD200R1 mRNA after injury whereas CD200 was downregulated acutely after nerve injury. Blockade of CD200R1 significantly reduced the acute entrance of both neutrophils and monocytes from blood after nerve injury. When long term regeneration and functional recovery were evaluated, we found that blockade of CD200R1 had a significant effect impairing the spontaneous functional recovery. Taken together, these results show that CD200R1 has a role in mounting a successful acute inflammatory reaction after injury, and contributes to an effective functional recovery.

Sex-dependent role of CD300f immune receptor in generalized anxiety disorder.

Generalized Anxiety Disorder (GAD) presents a high prevalence in the population, leading to distress and disability. Immune system alterations have been associated with anxiety-related behaviors in rodents and GAD patients. CD300f immune receptors are highly expressed in microglia and participate not only in the modulation of immune responses but also in pruning and reshaping synapses. It was recently demonstrated that CD300f might be influential in the pathogenesis of depression in a sex-dependent manner. Here, we evaluated the role of CD300f immune receptor in anxiety, using CD300f knockout mice (CD300f-/-) and patients with GAD. We observed that male CD300f-/- mice had numerous behavioral changes associated with a low-anxiety phenotype, including increased open field central locomotion and rearing behaviors, more exploration in the open arms of the elevated plus-maze test, and decreased latency to eat in the novelty suppressed feeding test. In a cross-sectional population-based study, including 1111 subjects, we evaluated a common single-nucleotide polymorphism rs2034310 (C/T) in the cytoplasmatic tail of CD300f gene in individuals with GAD. Notably, we observed that the T allele of the rs2034310 polymorphism conferred protection against GAD in men, even after adjusting for confounding variables. Overall, our data demonstrate that CD300f immune receptors are involved in the modulation of pathological anxiety behaviors in a sex-dependent manner. The biological basis of these sex differences is still poorly understood, but it may provide significant clues regarding the neuropathophysiological mechanisms of GAD and can pave the way for future specific pharmacological interventions.

Nem mãezinha, nem mãezona. Mães, familiares e ativismo nos arredores da prisão / Not a mommy, not a mamma. Mothers, family and activism around the prison / Ni mamita, ni madraza. Madres, familiares y activismo en los alrededores de la prisión

Resumo O artigo aborda as ambiguidades dos lugares ocupados pelas mães e familiares a partir de limites e possibilidades de agenciamento no ativismo em torno das prisões. Discuto a atuação de mães em uma associação de familiares de presos chamada Amparar, com sede em São Paulo, seguindo os trajetos de Railda Alves, uma de suas fundadoras. A Amparar existe desde 2004 e desenvolve suas atividades em articulação com outras organizações que atuam no campo dos Direitos Humanos. O reconhecimento como mãe de preso e a enunciação tanto da potência do vínculo materno quanto do sofrimento dele decorrente fazem parte das negociações que envolvem o diálogo e o trabalho em rede com outras organizações, ativistas e instituições estatais. A figura da mãe permite a participação em determinadas atividades e a construção de trajetórias ativistas, mas opera também como limitadora em contextos que envolvem, sobretudo, as negociações com o Estado.

Abstract The article addresses the ambiguities of being mothers and family members con- sidering the limits and possibilities of agency in activism around prisons. I discuss the role of mothers in a Prisoners' Family Association named Amparar, located in São Paulo, following the paths of Railda Alves, one of its founders. Amparar exists since 2004 and develops its activities in conjunction with other organizations working in the field of Human Rights. The recognition as a prisoner's mother and the statement of both the strength of the maternal bond and the resulting suffering from it are part of the negotiations that involve dialogue and networking with other organizations, activists, and state institutions. The figure of the mother allows participation in certain activities and the construction of activist trajectories, but it also operates as a limiter in contexts that involve negotiations with the State.

Resumen El artículo aborda las ambigüedades de los lugares ocupados por madres y fami- liares desde los límites y posibilidades de agencia en el activismo en torno a las cárceles. Mi análisis si construye desde el papel de las madres en una asociación de familiares de presos llamada Amparar, con sede en São Paulo, siguiendo los caminos de Railda Alves, una de sus fundadoras. Amparar existe desde 2004 y desarrolla sus actividades en conjunto con otras organizaciones que trabajan en el campo de los Derechos Humanos. El reconocimiento como madre de un preso y la declaración tanto de la fuerza del vínculo materno como del sufrimien- to resultante son parte de las negociaciones que implican el diálogo y el networking con otras organizaciones, activistas e instituciones estatales. La figura de la madre permite la partici- pación en determinadas actividades y la construcción de trayectorias activistas, pero también opera como limitante en contextos que involucran, sobre todo, negociaciones con el Estado.

Mães e lutas por justiça. Encontros entre produção de conhecimento, ativismos e democracia / Mothers and struggles for justice. A meeting point between knowledge production, activism and democracy / Madres y luchas por la justicia. Encuentros entre producción de conocimiento, activismo y democracia

Resumo O artigo discute algumas das relações entre mães e processos de Estado, tendo em vista sobretudo os movimentos de mães e familiares de vítimas de violência institucional, as análises inaugurais a esse respeito nas ciências sociais brasileiras, as implicações dessas mães e familiares nas políticas de produção de conhecimento e na crise democrática que atravessamos. Na primeira parte do artigo, retomamos pesquisas fundamentais que constituíram o campo de estudos que pensa desde a perspectiva do envolvimento de mães em movimentos de reivindicação por direitos e justiça. A segunda parte do artigo propõe-se à apresentação de alguns dos desdobramentos, em nossas próprias pesquisas, desse envolvimento e da produção de um conhecimento compartilhado entre pesquisadoras e o que se denomina usualmente como "interlocutoras". A última parte do artigo discute a posicionalidade dos movimentos de mães e familiares de vítimas de violência junto ao que se tem chamado de "crise democrática brasileira". Com isso, buscamos oferecer uma contribuição para o campo de pesquisas que se voltam, já há algum tempo, à produção recíproca entre gênero e Estado.

Abstract The article discusses some of the relationships between mothers and State processes, especially in view of the movements of mothers and family members of victims of institutional violence, the inaugural analyzes in this regard in Brazilian social sciences, the implications of these mothers and family members in knowledge production, and the democratic crisis that we are going through. In the first section of the article, we return to fundamental research that has constituted the field of studies which think since the involvement of mothers in movements for rights and justice. The second section of the article presents someof the developments, in our own research, of this involvement and the shared knowledge production between researchers and what is usually called as "interlocutors". The last section of the article discusses the positionality of the movements of mothers and family members of victims of violence in what has been called the "Brazilian democratic crisis". Thereby, we seek to offer a contribution to the field of research that has been, for some time now, focused on the reciprocal production between gender and the State.

Resumen El artículo discute algunas de las relaciones entre las madres y los procesos del Estado, especialmente en vista de los movimientos de madres y familiares de víctimas de violencia institucional, los análisis inaugurales al respecto en las ciencias sociales brasileñas, las implicaciones de estas madres y familiares en las políticas de producción de conocimiento y la crisis democrática que atravesamos. En la primera parte del artículo, volvemos a las investigaciones fundamentales que constituyen el campo de estudios que piensa desde la implicación de las madres en movimientos de reivindicación de derechos y justicia. La segunda parte del artículo propone presentar algunos de los desarrollos, en nuestra propia investigación, de esta implicación y producción de conocimiento compartido entre investigadores y lo que habitualmente se denomina "interlocutores". La última parte del artículo analiza la posicionalidad de los movimientos de madres y familiares de víctimas de la violencia en lo que se ha denominado la "crisis democrática brasileña". Con ello, buscamos ofrecer un aporte al campo de las investigaciones que desde hace un tiempo están enfocadas en la producción recíproca entre género y Estado.

Mitochondrial bioenergetics, glial reactivity, and pain-related behavior can be restored by dichloroacetate treatment in rodent pain models.

Glial reactivity in the dorsal horn of the spinal cord is a hallmark in most chronic pain conditions. Neuroinflammation-associated reactive glia, in particular astrocytes, have been shown to exhibit reduced mitochondrial respiratory function. Here, we studied the mitochondrial function at the lumbar spinal cord tissue from complete Freund's adjuvant-induced inflammatory pain rat and chronic constriction injury mouse models by high-resolution respirometry. A significant decrease in mitochondrial bioenergetic parameters at the injury-related spinal cord level coincided with highest astrocytosis. Oral administration of dichloroacetate (DCA) significantly increased mitochondrial respiratory function by inhibiting pyruvate dehydrogenase kinase and decreased glial fibrillary acidic protein and Iba-1 immunoreactivity in spinal cord. Importantly, DCA treatment significantly reduced the ipsilateral pain-related behavior without affecting contralateral sensitivity in both pain models. Our results indicate that mitochondrial metabolic modulation with DCA may offer an alternative therapeutic strategy to alleviate chronic and persistent inflammatory pain.

CD300f immunoreceptor is associated with major depressive disorder and decreased microglial metabolic fitness.

A role for microglia in neuropsychiatric diseases, including major depressive disorder (MDD), has been postulated. Regulation of microglial phenotype by immune receptors has become a central topic in many neurological conditions. We explored preclinical and clinical evidence for the role of the CD300f immune receptor in the fine regulation of microglial phenotype and its contribution to MDD. We found that a prevalent nonsynonymous single-nucleotide polymorphism (C/T, rs2034310) of the human CD300f receptor cytoplasmic tail inhibits the protein kinase C phosphorylation of a threonine and is associated with protection against MDD, mainly in women. Interestingly, CD300f-/- mice displayed several characteristic MDD traits such as augmented microglial numbers, increased interleukin 6 and interleukin 1 receptor antagonist messenger RNA, alterations in synaptic strength, and noradrenaline-dependent and persistent depressive-like and anhedonic behaviors in females. This behavioral phenotype could be potentiated inducing the lipopolysaccharide depression model. RNA sequencing and biochemical studies revealed an association with impaired microglial metabolic fitness. In conclusion, we report a clear association that links the function of the CD300f immune receptor with MDD in humans, depressive-like and anhedonic behaviors in female mice, and altered microglial metabolic reprogramming.

CD200 modulates spinal cord injury neuroinflammation and outcome through CD200R1.

The interaction between CD200 and its receptor CD200R1 is among the central regulators of microglia and macrophage phenotype. However, it remains to be established whether, in the context of a traumatic CNS injury, CD200R1 act as a negative regulator of these particular innate immune cells, and if the exogenous delivery of CD200 may ameliorate neurological deficits. In the present study, we first evaluated whether preventing the local interaction between the pair CD200-CD200R1, by using a selective blocking antibody against CD200R1, has a role on functional and inflammatory outcome after contusion-induced spinal cord injury (SCI) in mice. The injection of the αCD200R1, but not control IgG1, into the lesioned spinal cord immediately after the SCI worsened locomotor performance and exacerbated neuronal loss and demyelination. At the neuroimmunological level, we observed that microglial cells and macrophages showed increased levels of iNOS and Ly6C upon CD200R1 blockade, indicating that the disruption of CD200R1 drove these cells towards a more pro-inflammatory phenotype. Moreover, although CD200R1 blockade had no effect in the initial infiltration of neutrophils into the lesioned spinal cord, it significantly impaired their clearance, which is a key sign of excessive inflammation. Interestingly, intraparenchymal injection of recombinant CD200-His immediately after the injury induced neuroprotection and robust and long-lasting locomotor recovery. In conclusion, this study reveals that interaction of CD200-CD200R1 plays a crucial role in limiting inflammation and lesion progression after SCI, and that boosting the stimulation of this pathway may constitute a new therapeutic approach.

Thy1-YFP-H Mice and the Parallel Rod Floor Test to Evaluate Short- and Long-Term Progression of Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of death and disability and is a risk factor for the later development of neuropsychiatric disorders and neurodegenerative diseases. Many models of TBI have been developed, but their further refinement and a more detailed long-term follow-up is needed. We have used the Thy1-YFP-H transgenic mouse line and the parallel rod floor test to produce an unbiased and robust method for the evaluation of the multiple effects of a validated model of controlled cortical injury. This approach reveals short- and long-term progressive changes, including compromised biphasic motor function up to 85 days post-lesion, which correlates with neuronal atrophy, dendrite and spine loss, and long-term axonal pathology evidenced by axon spheroids and fragmentation. Here we present methods for inducing a controlled cortical injury in the Thy1-YFP-H transgenic mouse line and for evaluating the resulting deficits in the parallel rod floor test. This technique constitutes a new, unbiased, and robust method for the evaluation of motor and behavioral alterations after TBI. © 2018 by John Wiley & Sons, Inc.

Focal Transplantation of Aberrant Glial Cells Carrying the SOD1G93A Mutation into Rat Spinal Cord Induces Extensive Gliosis.

OBJECTIVE: We aimed to determine the potential of aberrant glial cells (AbAs) isolated from the spinal cord of adult SOD1G93A symptomatic rats to induce gliosis and neuronal damage following focal transplantation into the lumbar spinal cord of wild-type rats. METHODS: AbAs were obtained from the spinal cords of SOD1G93A symptomatic rats. One hundred thousand cells were injected using a glass micropipette into the lumbar spinal cords (L3-L5) of syngeneic wild-type adult rats. Equal volumes of culture medium or wild-type neonatal microglia were used as controls. Seven days after transplantation, immunohistochemistry analysis was carried out using astrocytic and microglia cell markers. Transplanted SOD1G93A AbAs were recognized by specific antibodies to human SOD1 (hSOD1) or misfolded human SOD1. RESULTS: Seven days after transplantation, AbAs were mainly detected in the medial region of the lumbar ventral horn as a well-limited cell cluster formed at the site of injection by their immunoreactivity to either misfolded SOD1 or normally folded hSOD1. Compared with controls, transplanted AbAs were surrounded by marked microgliosis and reactive astrocytes. Marked microgliosis was observed to extend bilaterally up to the cervical cord. Motor neurons close to AbA transplants were surrounded by activated glial cells and displayed ubiquitin aggregation. CONCLUSIONS: AbAs bearing mutant SOD1G93A have the potential to induce neuroinflammation along the spinal cord and incipient damage to the motor neurons. The emergence of AbAs during amyotrophic lateral sclerosis pathogenesis may therefore be a mechanism to boost neuroinflammation and spread motor neuron damage along the neuroaxis.

CD300f immunoreceptor contributes to peripheral nerve regeneration by the modulation of macrophage inflammatory phenotype.

BACKGROUND: It has recently become evident that activating/inhibitory cell surface immune receptors play a critical role in regulating immune and inflammatory processes in the central nervous system (CNS). The immunoreceptor CD300f expressed on monocytes, neutrophils, and mast cells modulates inflammation, phagocytosis, and outcome in models of autoimmune demyelination, allergy, and systemic lupus erythematosus. On the other hand, a finely regulated inflammatory response is essential to induce regeneration after injury to peripheral nerves since hematogenous macrophages, together with resident macrophages and de-differentiated Schwann cells, phagocyte distal axonal and myelin debris in a well-orchestrated inflammatory response. The possible roles and expression of CD300f and its ligands have not been reported under these conditions. METHODS: By using quantitative PCR (QPCR) and CD300f-IgG2a fusion protein, we show the expression of CD300f and its ligands in the normal and crush injured sciatic nerve. The putative role of CD300f in peripheral nerve regeneration was analyzed by blocking receptor-ligand interaction with the same CD300f-IgG2a soluble receptor fusion protein in sciatic nerves of Thy1-YFP-H mice injected at the time of injury. Macrophage M1/M2 polarization phenotype was also analyzed by CD206 and iNOS expression. RESULTS: We found an upregulation of CD300f mRNA and protein expression after injury. Moreover, the ligands are present in restricted membrane patches of Schwann cells, which remain stable after the lesion. The lesioned sciatic nerves of Thy1-YFP-H mice injected with a single dose of CD300f-IgG2a show long lasting effects on nerve regeneration characterized by a lower number of YFP-positive fibres growing into the tibial nerve after 10 days post lesion (dpl) and a delayed functional recovery when compared to PBS- or IgG2a-administered control groups. Animals treated with CD300f-IgG2a show at 10 dpl higher numbers of macrophages and CD206-positive cells and lower levels of iNOS expression than both control groups. At later time points (28 dpl), increased numbers of macrophages and iNOS expression occur. CONCLUSIONS: Taken together, these results show that the pair CD300f ligand is implicated in Wallerian degeneration and nerve regeneration by modulating both the influx and phenotype of macrophages.

Activation of Lysophosphatidic Acid Receptor Type 1 Contributes to Pathophysiology of Spinal Cord Injury.

Lysophosphatidic acid (LPA) is an extracellular lipid mediator involved in many physiological functions that signals through six known G-protein-coupled receptors (LPA1-LPA6). A wide range of LPA effects have been identified in the CNS, including neural progenitor cell physiology, astrocyte and microglia activation, neuronal cell death, axonal retraction, and development of neuropathic pain. However, little is known about the involvement of LPA in CNS pathologies. Herein, we demonstrate for the first time that LPA signaling via LPA1 contributes to secondary damage after spinal cord injury. LPA levels increase in the contused spinal cord parenchyma during the first 14 d. To model this potential contribution of LPA in the spinal cord, we injected LPA into the normal spinal cord, revealing that LPA induces microglia/macrophage activation and demyelination. Use of a selective LPA1 antagonist or mice lacking LPA1 linked receptor-mediated signaling to demyelination, which was in part mediated by microglia. Finally, we demonstrate that selective blockade of LPA1 after spinal cord injury results in reduced demyelination and improvement in locomotor recovery. Overall, these results support LPA-LPA1 signaling as a novel pathway that contributes to secondary damage after spinal cord contusion in mice and suggest that LPA1 antagonism might be useful for the treatment of acute spinal cord injury. SIGNIFICANCE STATEMENT: This study reveals that LPA signaling via LPA receptor type 1 activation causes demyelination and functional deficits after spinal cord injury.

Absence of metallothionein-3 produces changes on MT-1/2 regulation in basal conditions and alters hypothalamic-pituitary-adrenal (HPA) axis.

Metallothioneins (MTs) are multipurpose proteins with clear antioxidant, anti-inflammatory and metal homeostasis properties. The roles of brain MT-1 and MT-2 are similar to those described in the periphery, and are inducible by metals, inflammatory and stress stimuli. MT-3, originally named growth inhibitory factor, exists mainly in the central nervous system, is hardly ever inducible and its functional role and regulation are poorly understood and controversial. In the present study we examined how absence of MT-3 affects phenotypic characteristics and its effects on MT1/2 expression in basal situation and after induction. Hyperactive behavior was found only in young male Mt-3 KO mice and disappeared in the older ones. Absence of MT-3 was associated with a significant increase of MT-1/2 protein levels in several brain areas but decreased MT-1 mRNA levels, which might be related to lower corticosterone levels. The response to stress or inflammation on corticosterone plasma levels was similar in wild type and Mt-3 KO mice, suggesting that the relevant MT-3 role as MT-1/2 regulator in basal conditions is lost when other important regulatory factors such as glucocorticoids or cytokines appear.

A regenerative microchannel neural interface for recording from and stimulating peripheral axons in vivo.

Neural interfaces are implanted devices that couple the nervous system to electronic circuitry. They are intended for long term use to control assistive technologies such as muscle stimulators or prosthetics that compensate for loss of function due to injury. Here we present a novel design of interface for peripheral nerves. Recording from axons is complicated by the small size of extracellular potentials and the concentration of current flow at nodes of Ranvier. Confining axons to microchannels of ~100 µm diameter produces amplified potentials that are independent of node position. After implantation of microchannel arrays into rat sciatic nerve, axons regenerated through the channels forming 'mini-fascicles', each typically containing ~100 myelinated fibres and one or more blood vessels. Regenerated motor axons reconnected to distal muscles, as demonstrated by the recovery of an electromyogram and partial prevention of muscle atrophy. Efferent motor potentials and afferent signals evoked by muscle stretch or cutaneous stimulation were easily recorded from the mini-fascicles and were in the range of 35-170 µV. Individual motor units in distal musculature were activated from channels using stimulus currents in the microampere range. Microchannel interfaces are a potential solution for applications such as prosthetic limb control or enhancing recovery after nerve injury.

Overexpression of the immunoreceptor CD300f has a neuroprotective role in a model of acute brain injury.

It is well known that cell surface immune receptors play a critical role in regulating immune and inflammatory processes in the central nervous system (CNS). We have analyzed the function of cluster of differentiation (CD)300f immunoreceptor in a model of excitotoxic rat brain damage. First, to explore the presence of endogenous ligand(s) for this receptor we used a human CD300f-Ig soluble protein and confocal microscopy, showing specific staining mainly in CNS white matter and on the surface of oligodendrocytes and certain astrocytes. Next, we demonstrated in a model of in vivo rat brain excitotoxic damage that the overexpression of human CD300f induced a significant reduction in the lesion volume. To validate these results, we cloned the rat ortholog of CD300f protein (rCD300f). The overexpression of rCD300f receptor had a comparable neuroprotective effect after the acute brain injury and a similar CNS staining pattern when stained with the rCD300f-Ig soluble protein. Interestingly, when we analyzed the expression pattern of rCD300f in brain cells by quantitative polymerase chain reaction and immunohistochemistry, we detected the expression of CD300f as expected in microglial cells, but also in oligodendrocytes and neurons. These data suggest that the neuroprotective role of CD300f would be the result of a complex network of cell interactions.

Axonally derived neuregulin-1 is required for remyelination and regeneration after nerve injury in adulthood.

Neuregulin-1 (NRG1) plays a crucial role in axoglial signaling during the development of the peripheral nervous system, but its importance in adulthood after peripheral nerve injury remains unclear. We used single-neuron labeling with inducible Cre-mediated knock-out animals, which enabled visualization of a subset of adult myelinated sensory and motoneurons neurons in which Nrg1 was inducibly mutated by tamoxifen treatment. In uninjured mice, NRG1-deficient axons and the associated myelin sheath were normal, and the neuromuscular junction demonstrated normal apposition of presynaptic and postsynaptic components. After sciatic nerve crush, NRG1 ablation resulted in severe defects in remyelination: axons were either hypomyelinated or had no myelin sheath. NRG1-deficient axons were also found to regenerate at a slower rate. After nerve injury, the neuromuscular junction was reinnervated, but excess terminal sprouting was observed. Juxtacrine Neuregulin-1 signaling is therefore dispensable for maintenance of the myelin sheath in adult animals but has a key role in reparative processes after nerve injury.