Central nervous system | EPFL Graph Search

The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all parts of the bodies of bilaterally symmetric and triploblastic animals—that is, all multicellular animals except sponges and diploblasts. It is a structure composed of nervous tissue positioned along the rostral (nose end) to caudal (tail end) axis of the body and may have an enlarged section at the rostral end which is a brain. Only arthropods, cephalopods and vertebrates have a true brain, though precursor structures exist in onychophorans, gastropods and lancelets. The rest of this article exclusively discusses the vertebrate central nervous system, which is radically distinct from all other animals. Overview In vertebrates, the brain and spinal cord are both enclosed in the meninges. The meninges provide a barrier to chemicals dis

Modelling and Refining Neuronal Circuits with Guidance Cues: Involvement of Semaphorins

Greta Limoni

The establishment of neuronal circuits requires neurons to develop and maintain appropriate connections with cellular partners in and out the central nervous system. These phenomena include elaboration of dendritic arborization and formation of synaptic contacts, initially made in excess. Subsequently, refinement occurs, and pruning takes places both at axonal and synaptic level, defining a homeostatic balance maintained throughout the lifespan. All these events require genetic regulations which happens cell-autonomously and are strongly influenced by environmental factors. This review aims to discuss the involvement of guidance cues from the Semaphorin family.

MDPI2021

Combinatorial targeting of angiogenesis with inducers of autophagy in the treatment of glioblastoma multiforme

Julie Laetitia Scotton

Malignant gliomas represent 80% of tumors developing in the central nervous system, with 50% being glioblastomas (GBM), the most aggressive form of the disease. The benefit from current therapies is very limited, the overall 5-year survival rate of patients with GBM being less than 5%. Thus, there is an urgent need for better therapies. It has been reported that the use of tricyclic antidepressants (TCAs) is linked with reduced incidence of gliomas. In line with these observations, our lab previously demonstrated that combining imipramine (IM), a TCA that activates adenylate cyclase and elevates production of cAMP, with ticlopidine (TIC), an inhibitor of the purinergic receptor P2Y12 that otherwise suppresses cAMP, results in a concerted increase in the levels of intracellular cAMP, which consequently stimulates increased autophagy in glioma cells, leading to autophagy-associated cell death (AACD) in culture and during orthotopic tumor growth. In several mouse models of glioma, the combination improved survival and reduced malignant grade. Seeking to assess the therapeutic translational potential of these repurposed drugs, particularly IM, we performed pre-clinical trials combining IM+/-TIC with anti-VEGF therapy, which is commonly used in patients with GBM; such anti-angiogenic therapy is associated with a transitory improvement in progression-free survival and quality of life, but does not translate into an overall survival benefit. Using genetic mouse models with enabling bioluminescent monitoring of the cancer cells, we treated established GBMs with imipramine, ticlopidine, and B20S, an anti-mouse VEGF monoclonal antibody. We observed transient stabilization of tumor growth, and the overall survival was significantly extended in the regimens combining B20S with IM +/- TIC compared to control and single treatments. Similar to clinical observations in GBM patients treated with anti-angiogenic therapy, mice treated with B20S alone had no survival benefit, implicating a synergetic effect for the combination of anti-VEGF treatment with imipramine and ticlopidine. We found that the combinatorial therapy elicited further increases in autophagy and displayed some indication of blood vessel normalization, concomitant with an elevation of CD8+T lymphocyte infiltration into the orthotopic tumors. Notably, we could partially reverse the beneficial effect of the combinations using a CD8+T cell-depleting antibody, revealing the involvement of the recruited CD8+T cells in the efficacy of the combinatorial treatment, in addition to the cell-intrinsic autophagy-associated death that is demonstrable in culture and in tumors. Together, these results suggest a strategy to improve anti-angiogenic therapy in patients with glioblastoma, by using repurposed FDA-approved drugs that markedly elevate autophagy in concert with anti-VEGF therapy. The recruitment of CD8+ T cells into the treated tumors and their evident contribution to therapeutic efficacy motivates ongoing experiments aimed to heighten and sustain the induced anti-tumor immune response.

EPFL2018

Optogenetic Interrogation of Circuits Following Neurotrauma

Steven Lee Ceto, Grégoire Courtine

Biological and engineering strategies for neural repair and recovery from neurotrauma continue to emerge at a rapid pace. Until recently, studies of the impact of neurotrauma and repair strategies on the reorganization of the central nervous system have focused on broadly defined circuits and pathways. Optogenetic modulation and recording methods now enable the interrogation of precisely defined neuronal populations in the brain and spinal cord, allowing unprecedented precision in electrophysiological and behavioral experiments. This mini-review summarizes the spectrum of light-based tools that are currently available to probe the properties and functions of well-defined neuronal subpopulations in the context of neurotrauma. In particular, we highlight the challenges to implement these tools in damaged and reorganizing tissues, and we discuss best practices to overcome these obstacles.

FRONTIERS MEDIA SA2021

Combinatorial targeting of angiogenesis with inducers of autophagy in the treatment of glioblastoma multiforme

Julie Laetitia Scotton

EPFL2018