Regenerative Neurobiology 2024Fall PDF

Regenerative Biology and Disease Regenerative Neurobiology Dr. Vijendra Sharma University of Windsor – Department of Biomedical Sciences Nervous system includes all neural tissue in body Central Nervous System  Brain and spinal cord  Central axons regenerate o...

Regenerative Biology and Disease Regenerative Neurobiology Dr. Vijendra Sharma University of Windsor – Department of Biomedical Sciences Nervous system includes all neural tissue in body Central Nervous System  Brain and spinal cord  Central axons regenerate only in certain aquatic or semi-aquatic vertebrates such as fish and amphibians. Peripheral Nervous System  All neural tissue outside CNS  Peripheral nerve axons of all vertebrates can regenerate under the proper circumstances. Cells in Nervous Tissue Neurons Neuroglia Neurons What is the main defining characteristic of neurons? Have the property of electrical excitability - ability to produce action potentials or impulses in response to stimuli Representative Neuron Rough ER & free ribosomes for protein synthesis ? Proteins then replace neuronal cellular components for growth and repair of damaged axons in the PNS Owens et al 2017 Representative Neuron Anatomy of two representative neurons in the brain and a synapse between them. Path of electrical current indicated with yellow arrows. Inset, close-up view of the synapse. Owens et al 2017 Neuroglia (Glia) About half the volume of cells in the CNS Smaller than neurons 5 to 50 times more numerous Do NOT generate electrical impulses Divide by mitosis Four types in the CNS o Astrocytes o Oligodendrocytes o Microglia o Ependymal cells  Cells in Nervous Tissue Lago-Baldaia et al., 2020 Microglia Few processes Derived from mesodermal cells that also give rise to monocytes and macrophages Small cells found near blood vessels Phagocytic role - clear away dead cells Protect CNS from disease through phagocytosis of microbes Migrate to areas of injury where they clear away debris of injured cells - may also kill healthy cells Thickening of Microglia during infectious disease Astrocytes Largest of glial cells Most numerous Star shaped with many processes projecting from the cell body Help form and maintain blood-brain barrier Provide structural support for neurons Maintain the appropriate chemical environment for generation of nerve impulses/action potentials Regulate nutrient concentrations for neuron survival Regulate ion concentrations - generation of action potentials by neurons Take up excess neurotransmitters Assist in neuronal migration during brain development Perform repairs to stabilize tissue  The role of astrocytes in memory formation Astrocytic energy metabolism D-serine promotes memory Endocannabinoid’s in memory Oligodendrocytes Most common glial cell type Each forms myelin sheath around the axons of neurons in CNS Analogous to Schwann cells of PNS Form a supportive network around CNS neurons Fewer processes than astrocytes Round or oval cell body Ependymal Cells Epithelial cells arranged in a single layer Range in shape from cuboidal to columnar Form epithelial membrane lining cerebral cavities (ventricles) & central canal - that contain CSF Produce & circulate the cerebrospinal fluid (CSF) found in these chambers CSF = colourless liquid that protects the brain and SC against chemical & physical injuries, carries oxygen, glucose and other necessary chemicals from the blood to neurons and neuroglia PNS: Satellite Cells Flat cells surrounding PNS axons Support neurons in the PNS PNS: Schwann Cells Each cell surrounds multiple unmyelinated PNS axons with a single layer of its plasma membrane Each cell produces part of the myelin sheath surrounding an axon in the PNS Contributes regeneration of PNS axons  Cells in Nervous Tissue Lago-Baldaia et al., 2020 Neurogenesis in the adult CNS ? No New Neurons Dogma Neurogenesis in the CNS of vertebrates ceased after birth. Demise of the No New Neurons Dogma Studies in adult rats revealed cells actively synthesizing DNA in the hippocampus. (Messier et al., 1958; Smart, 1961; Altman, 1962, 1963).  Neural stem cells (NSCs) Derived from nervous system Can generate neural tissue Can differentiate through asymmetric cell division Have some capacity of self-renewal Adapted from Navarro Quiroz et al., 2018. NSPC Niche in mammals The spinal progenitor cells in the mammalian fetal NS are concentred in seven major areas  Olfectory bulb  Ventricularzone (VZ)  Subventricular zone(SVZ) of forebrain  Hippocampus  Cerebellum  Cerebral cortex  Spinal cord Gage el al 2000 Location of NSCs in CNS Germinal regions in adult brain capable of generating new neurons:  Subventricular zone (SVZ)  Subgranular zone (SGZ) Finkel Z et al 2021). Adult NPSCs in the Spinal Cord NSC are presented in an undifferentiated and self- renewable state in ependyma of the central canal in which stem cells are present.  Progenitor cell markers are Olig2, PDGFRa, and NG2  Extrinsic signals for neurogenesis (connexin, Notch and Wnt pathways)  Intrinsic signals, transcription factors (Nkx6.1, Pax6, and Olig6) Finkel Z et al 2021). Adult Retinal Stem Cells Adult retinal stem cell population:  Retinal pigment epithelium (RPE) stem cells (astrocytes & oligodendrocytes)  Non-pigmented ciliary epithelium (CE) cells (Sox2, Chx10 and Notch1)  Müller glia cells  Iris pigment epithelium cells  Optic nerve Finkel Z et al 2021). Tissue architecture of SVZ and SGZ neurogenic niches Location of the neurogenic niches SVZ, along the Lateral ventricles (LV), and SGZ along the Dentate Gyrus (DG) is shown with arrows. Adult Neurogenesis quiescent activated Radial Glial- Radial Glial- intermediate like (RGL) like (RGL) proliferating cells cells cells (IPC) Stage-specific protein expression Hiyaa S Ghosh 2019 Adult Neurogenesis quiescent intermediate proliferating cells Radial Glial- (IPC) like (RGL) cells J. Tiago Gonçalves et al 2016 Adult Neurogenesis in the Hippocampus Translational regulation in the NSC lineage Avni Baser et al., 2017 Translational regulation in the NSC lineage Avni Baser et al., 2017 Translational regulation in the NSC lineage Avni Baser et al., 2017 Signaling pathways regulating the translation of mRNAs Increase Mutatio Normal brain ns function Memory Motor skills Translati Vision on Breathing Protein Hunger Cellular synthesis stress Reduce Neurological disorders Fragile X syndrome, Autism, Epilepsy, Aging, Alzheimer’s (AD), and Parkinson’s diseases The mechanism of protein synthesis Translation initiation can be controlled by regulating the levels of eIF4F The process complex of initiation or eIF2-TC of translation in eukaryotes The mRNAs translation control mechanisms Eukaryotic translation initiation factor 4E-binding proteins (4E-BPs) 1978 eIF4E- Eukaryotic Initiation Factor 4E 40S Nahum eIF3 Sonenberg eIF4 eIF2-TC AUG G 4A m7G ORF eIF4F complex m7GDP eIF4E 4E-BP AUG m7G ORF Pause et. al., Nature 1994; Poulin et. al., JBC 1998  Proteins: building blocks of the body Brain Memory function Motor skills Vision Breathing Hunger Smeets et al., 2018, Brain Brain tissue protein synthesis rates are 3-4-fold higher than skeletal muscle tissue Neuronal activity induces local translation at synapses Neuron Sun et al., 2021, Sci. Adv. Cell-type-specific contribution to memory consolidation Hippocampus Excitatory neurons Inhibitory neurons 1. Somatostatin (SST) 2. Parvalbumin (PV) 3. VIP Astrocytes Microglia  Memory in Aging and Neurological Diseases Memory Aging and Gene- formatio neurodegen therapy n erative diseases Gene-therapy New Drugs Vijendra Sharma, PhD Join Our Research We welcome applications for Team! Ph.D. Master’s Undergraduate research Please submit your CV, letter of interest, and transcripts to [email protected] Address: Department of Biomedical Sciences Biology Building Room 306 University of Windsor, 401 Sunset Avenue, Windsor, ON, N9B 3P4 Adult Neurogenesis, Mental Health, and Mental Illness: Hope or Hype? Amelia et al., 2008 Alternative source of NSCs for therapy Bone marrow Blood cord Hair follicles Skin Amniotic placental fluid Human foetus (Messier et al., 1958; Smart, 1961; Altman, 1962, 1963).