| 1. |
- Dehnisch Ellström, Ivar
(författare)
-
Regeneration and neural circuits in the spinal cord : an imaging study on zebrafish
- 2019
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The reversal of spinal cord injury (SCI) and its devastating effect on voluntary control is one of the most provocative challenges in neuroscience research. Preclinical and clinical research has for a very long time tried to address this challenge, but there is still no effective treatment that leads to functional recovery. In simplified terms, the spinal cord resembles a highway, with outgoing commands from the brain and incoming feedback from the periphery. However, the spinal cord is an extremely complex apparatus with billions of cells, connections, and neuronal circuits. Injury to the spinal cord in humans has acute disastrous effects, followed by secondary pathophysiological events leading to a permanent loss of sensation and motor function corresponding to the site of injury. The spinal cord of humans, as far as we know, lacks the capacity to regenerate after an injury, in contrast to that of vertebrate fish, such as the zebrafish, which has an extraordinary ability to regenerate. Investigating the regenerative capacity of zebrafish can unveil mechanisms and features that may be translatable to the clinic. In paper I, we identified V2a interneurons as an intrinsic source of excitation and a necessity for the zebrafish larvae’s normal generation of locomotor rhythm. In paper II, we scaled up and developed the technique used in paper I to a robust method to induce precise spatial and temporal SCI with minimal collateral damage in zebrafish larvae. In paper III, we investigated the impact of several factors, including lesion size, hypothermia, and analgesic substances, on the functional recovery of zebrafish larvae following SCI. Furthermore, we examined intrinsic Ca2+ signaling before and after SCI. In summary, this thesis paves the way for further investigations of the remarkable regenerative capacity zebrafish possess.
|
|
| 2. |
|
|
| 3. |
- Lam, Matti, et al.
(författare)
-
Single cell analysis of autism patient with bi-allelic NRXN1-alpha deletion reveals skewed fate choice in neural progenitors and impaired neuronal functionality
- 2019
-
Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 383:1
-
Tidskriftsartikel (refereegranskat)abstract
- We generated human iPS derived neural stem cells and differentiated cells from healthy control individuals and an individual with autism spectrum disorder carrying bi-allelic NRXN1-alpha deletion. We investigated the expression of NRXN1-alpha during neural induction and neural differentiation and observed a pivotal role for NRXN1-alpha during early neural induction and neuronal differentiation. Single cell RNA-seq pinpointed neural stem cells carrying NRXN1-alpha deletion shifting towards radial glia-like cell identity and revealed higher proportion of differentiated astroglia. Furthermore, neuronal cells carrying NRXN1-alpha deletion were identified as immature by single cell RNA-seq analysis, displayed significant depression in calcium signaling activity and presented impaired maturation action potential profile in neurons investigated with electrophysiology. Our observations propose NRXN1-alpha plays an important role for the efficient establishment of neural stem cells, in neuronal differentiation and in maturation of functional excitatory neuronal cells.
|
|
| 4. |
- Niklasson, Mia, et al.
(författare)
-
Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses
- 2017
-
Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 77:7, s. 1741-1752
-
Tidskriftsartikel (refereegranskat)abstract
- Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca2+ and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown. However, using cell-based assays and integrated proteomics, phosphoproteomics, and transcriptomics analyses, we identified the downstreamsignaling events these drugs affect. Changes in plasma membrane depolarization and elevated intracellular Na+, which compromised Na+-dependent nutrient transport, were documented. Deficits in nutrient deficit acted in turn to trigger the unfolded protein response and the amino acid response, leading ultimately to nutrient starvation and GIC cell death. Our results suggest new therapeutic targets to attack aggressive gliomas.
|
|
| 5. |
- Smedler, Erik, et al.
(författare)
-
Disrupted Cacna1c gene expression perturbs spontaneous Ca2+ activity causing abnormal brain development and increased anxiety.
- 2022
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 119:7
-
Tidskriftsartikel (refereegranskat)abstract
- The L-type voltage-gated Ca2+ channel gene CACNA1C is a risk gene for various psychiatric conditions, including schizophrenia and bipolar disorder. However, the cellular mechanism by which CACNA1C contributes to psychiatric disorders has not been elucidated. Here, we report that the embryonic deletion of Cacna1c in neurons destined for the cerebral cortex using an Emx1-Cre strategy disturbs spontaneous Ca2+ activity and causes abnormal brain development and anxiety. By combining computational modeling with electrophysiological membrane potential manipulation, we found that neural network activity was driven by intrinsic spontaneous Ca2+ activity in distinct progenitor cells expressing marginally increased levels of voltage-gated Ca2+ channels. MRI examination of the Cacna1c knockout mouse brains revealed volumetric differences in the neocortex, hippocampus, and periaqueductal gray. These results suggest that Cacna1c acts as a molecular switch and that its disruption during embryogenesis can perturb Ca2+ handling and neural development, which may increase susceptibility to psychiatric disease.
|
|
| 6. |
- Sunadome, Kazunori, et al.
(författare)
-
Directionality of developing skeletal muscles is set by mechanical forces
- 2023
-
Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- The mechanisms that drive myocyte orientation and fusion to control muscle directionality are not well understood. Here authors show that the developing skeleton produces mechanical tension that instructs the directional outgrowth of skeletal muscles. Formation of oriented myofibrils is a key event in musculoskeletal development. However, the mechanisms that drive myocyte orientation and fusion to control muscle directionality in adults remain enigmatic. Here, we demonstrate that the developing skeleton instructs the directional outgrowth of skeletal muscle and other soft tissues during limb and facial morphogenesis in zebrafish and mouse. Time-lapse live imaging reveals that during early craniofacial development, myoblasts condense into round clusters corresponding to future muscle groups. These clusters undergo oriented stretch and alignment during embryonic growth. Genetic perturbation of cartilage patterning or size disrupts the directionality and number of myofibrils in vivo. Laser ablation of musculoskeletal attachment points reveals tension imposed by cartilage expansion on the forming myofibers. Application of continuous tension using artificial attachment points, or stretchable membrane substrates, is sufficient to drive polarization of myocyte populations in vitro. Overall, this work outlines a biomechanical guidance mechanism that is potentially useful for engineering functional skeletal muscle.
|
|
