Nervous Embryology 2024 PDF

Embryology, Evolution and Design of the Brain Brain of LV Leborgne, studied by Pierre Paul Broca, 1861 Lecture 5.3 GMS an722 Fall 2024 Louis Toth (Coursi 1991, in Bear, M, Connors BW, Paradiso MA (2016)...

Embryology, Evolution and Design of the Brain Brain of LV Leborgne, studied by Pierre Paul Broca, 1861 Lecture 5.3 GMS an722 Fall 2024 Louis Toth (Coursi 1991, in Bear, M, Connors BW, Paradiso MA (2016) “Neuroscience: Exploring the Brain” Wolters-Kluwer) See also: Dronkers NF, et al (2007) “Paul Broca’s historic cases: high resolution MR imaging of the brains of Leborgne 1 and Lelong” Brain 130:1432-1441 doi:10.1093/brain/awm042  Topics: Basic embryological/evolutionary organization of the brain –How do we get from a neural tube to an adult brain? –How does brain development relate to evolution? Organization of Neocortex –glial cells and neurons –neurotransmitters –excitatory and inhibitory neurons –regions of unique circuitry –development of cerebral cortex Blood-Brain Barrier & surfaces of the brain –composition of BBB –production and circulation of CSF - glymphatic system 2  Topics: Basic embryological/evolutionary organization of the brain –How do we get from a neural tube to an adult brain? –How does brain development relate to evolution? Organization of Neocortex –glial cells and neurons –neurotransmitters –excitatory and inhibitory neurons –regions of unique circuitry –development of cerebral cortex Blood-Brain Barrier & surfaces of the brain –composition of BBB –production and circulation of CSF - glymphatic system 3  Early Embryonic Development The neural tube forms. After body folding, the neural tube closes except for rostral and caudal neuropores. The rostral neuropore closes first. (Carnegie stage 11, 13-20 somites, 29 days PF, 3.5mm) The caudal neuropore closes later. (Carnegie stage 12, 21-29 somites, 30 days PF, 4mm) ten Donkelaar HJ, Lammens M, Hori A (2006) Clinical Embryology, Springer Neural Embryology 4  Specification of Neural Tube - ML Molecular factors from the ectoderm and notochord control the development of zones of the neural tube. SHH (sonic hedgehog) is a “ventralizing” factor, BMP4 & 7 are “dorsalizing” factors. The neural tube differentiates into alar (roof) plate and basal (floor) plate regions, specified by gradients of Pax6, Pax3,7 ten Donkelaar HJ, Lammens M, Hori A (2006) Clinical Embryology, Springer Neural Embryology 5  Specification of Neural Tube - AP The neural tube is divided into roof and floor structures, separated by the space of the ventricle(s): roof structures: cerebellum, cortex floor structures: brainstem, thalamus From front to back, the neural tube is segmented into: prosencephalon mesencephalon rhombencephalon ten Donkelaar HJ, Lammens M, Hori A (2006) Clinical Embryology, Springer Neural Embryology 6  Like the rest of the body, the brain develops from discrete segments Lamprey ten Donkelaar HJ, Lammens M, Hori A (2006) Clinical Embryology, Springer Top and Bottom of the tube rp = roof plate ap = alar plate bp = basal plate fp = floor plate Segments r = rhombomere m = mesomere Human p = prosomere Nieuwenhuys R (2018) Neuroimage 178:749-52. Neural Embryology 7  Hox genes control AP specification Human Fruit Fly Kandel & Schwartz “Principles of Neural Science” 5th ed Neural Embryology 8  Specification of Neural Tube - ML The ganglionic eminences develop laterally on the floor plate - these disappear as they give rise to: thalamic radiations, basal ganglia, and inhibitory neurons of cortex At this point, the roof plate of the prosencephalon (telencephalon) is expanding radially (into layers) and laterally (into areas) into the cerebral cortex. ten Donkelaar HJ, Lammens M, Hori A (2006) Clinical Embryology, Springer Neural Embryology 9  Protostomes Deuterostomes 1 2 3 4 5 Protostomes represent the largest radiation of animalia Deuterostomes represent the most recent radiation … and within the deuterostomes lie: chordates (animals with a notochord) vertebrates (animals with a backbone) fish (jawless, then jawed; cartilaginous, then bony) amphibians (water-to-land transition – gills to lungs) reptiles birds (dinosaurs remaining after mass extinction #5) mammals (mammary glands, placenta) Evolution 10  Two of the five Northern White Rhinos at San Diego Wild Animal Park in 1995. At the time there were 46 animals in the world. Today, there are two, both female. Picture by LJT Evolution 11  Protostomes worms insects butterflies vs. arthropods Deuterostomes chordata rostral disc echinodermata (e.g. starfish) vertebrata fish, birds, reptiles, mammals Carnegie stage 7 - medial view (formation of the trilaminar germ disc) mclo = cloacal membrane PN = primitive node PS = primitive streak AC = amnion SUV = yolk sac caudal disc ten Donkelaar HJ, Lammens M, Hori A (2006) Clinical Embryology, Springer In protostomes (invertebrates) the future mouth forms first In deuterostomes the future anus forms first 12 Evolution  Craniates (skull present): Non-vertebrate Pacific Hagfish (Eptatretus stoutii) chordates & craniates Chordates (notochord present): Lancelet Scientists film hagfish anti-shark slime weapon Massey Univ., New Zealand https://youtu.be/Bta18FdkVcA Sea Lamprey (Petromyzon marinus) Wikipedia tunicate (sea squirt) Wikipedia Evolution 13  Vertebrates Mader S, Windelsprecht M (2017) “Inquiry Into Life” 15th ed Evolution 14  The Neural Tube: chordates craniates & vertebrates chordate: + notochord craniate: + hard skull (cranium) vertebrate: + hard backbone (spine) agnatha: jawless vertebrates gnathostomata hinged jaw 15 Schneider (2014) Evolution  Development of Retina and Lens 1. 2. The lens originates from a spheroid invagination of surface ectoderm (at the lens placode). The retina is a bulb-shaped invagination of neural 3. 4. ectoderm, called the optic stalk. The bulb shape pinches off, then the outer portion collapses inwards to form the neural retina. Brain Development 16  Fish #1 - what am I good at? Schneider (2014) Brain Development 17  Fish #2 - what am I good at? Great Barracuda (Sphyraena barracuda) Schneider (2014) Brain Development 18  Fish #3 - what am I good at? Buffalo fish (ictiobus) Schneider (2014) Brain Development 19  Expansion of midbrain regions in mammals Echolocating animals Visual hunting animals SC = superior colliculus (optic tectum) - visual processing region IC = inferior colliculus - auditory processing region 20 Schneider (2014) Brain Development  Unique in primates is a greatly expanded neocortex Neocortex is the roof of the prosencephalon. What do we do with an expanded neocortex? vision somatosensory auditory Paul MacLean in Stetka B (2021) ”A history of the Human Brain”, Schneider (2014) Owl monkey (Aotus) MacLean (1990) “The Triune Brain in Evolution” and Sagan C (1977) ”The Dragons of Eden” Brain Development 21 Divisions of the Human Cortex Anatomical Frontal lobe Parietal lobe Temporal lobe Occipital lobe Functional Vision Audition Somatosensation Motor Association speech 22 Schneider (2014) Brain Development  Topics: Basic embryological/evolutionary organization of the brain –How do we get from a neural tube to an adult brain? –How does brain development relate to evolution? Organization of Neocortex –glial cells and neurons –neurotransmitters –excitatory and inhibitory neurons –regions of unique circuitry –development of cerebral cortex Blood-Brain Barrier & surfaces of the brain –composition of BBB –production and circulation of CSF - glymphatic system 23  Cells derived from Neural Stem Cell excitatory neurons inhibitory NSC glia astrocyte oligodendrocyte microglia Neurons and Glia 24  Glial Cell Types of the CNS 1. astrocyte 2. oligodendrocyte 3. microglial cell Neurons and Glia 25 Ross Histology 6th ed  1. Astrocyte primary structural cell end-feet on vasculature are part of BBB mediates ionic milieu of ECF “protoplasmic” (upper) and “fibrous” (lower) astrocytes Ross Histology 6th ed Neurons and Glia 26  The Big Three Neurodegenerative Diseases Alzheimer’s disease - characterized by accumulation of Aβ plaques extracellularly Parkinson’s disease - resting tremor and inability to initiate movements - loss of dopamine synthesizing neurons in the substantia nigra Huntington’s disease - uncontrollable ‘chorea’ - Huntingtin gene (HTT, discovered 1993) From fig 1 in Ki SM, Jeong HS, Lee JE (2021) “Primary cilia in glial cells: an oasis in the journey to overcoming neurodegenerative diseases” Front in Neurosci 15:736888 Astrocytes have primary cilia (9+0), used to sense their environment & determine reactivity. All three major diseases show altered primary cilium function. Neurons and Glia 27  2. Oligodendrocyte myelinates axons in the CNS homologous (but not identical to) peripheral Schwann cells Ross Histology 6th ed 28 Wendy Macklin lab, UC Boulder Neurons and Glia  3. Microglial Cell macrophage of CNS derived from monocyte progenitors enters brain during development Ross Histology 6th ed Microglia have an ‘activated’ state, which can be used as a marker of pathologies Schwabenland M et al (2021) “Analyzing microglial phenotypes across neuropathologies: a practical guide” Acta Neuropathologica doi:10.1007/s00401-021-02370-8 Neurons and Glia 29  scRNAseq in Brain Some early takeaways: There are three major categories of cells: non-neuronal cells (glia) excitatory neurons inhibitory neurons Cell types segregate by general anatomical position within the cortical sheet (i.e. frontal areas, parietal/temporal, occipital) Cell types segregate by cortical layer (i.e. radially within the sheet) Some excitatory neuron types are common across all brain regions. But, each functional area also has excitatory neuron types that are unique to that area. Inhibitory neurons types are more homogenous across the cortical sheet. Neurons and Glia 30  Excitation and Inhibition Excitatory neurons have well-defined dendritic trees, with long axons. Inhibitory neurons have local, diffuse arborizations. 31 British Gray’s Neurons and Glia  Neurotransmitters Fast (ionotropic receptors) Slow (metabotropic receptors) Monoamine Neurotransmitters (regulatory in CNS) dopamine reward, motivation glutamate (glutamic acid) substantia nigra major excitatory neurotransmitter of cortex deficit causes Parkinson’s disease serotonin mood raphe nucleus antidepressants (SSRIs) GABA (γ-aminobutyric acid) major inhibitory neurotransmitter of cortex norepinephrine (noradrenaline) fight-or-flight response locus ceruleus Fast and Slow (ionotropic and metabotropic receptors) acetylcholine epinephrine (adrenaline) neuromuscular junction arousal Neurons and Glia 32  Neurons of the CNS The exquisitely complex and varied range of neuronal morphologies was captured first by Camillo Golgi and best by Ramón y Cajal, and Rafael Lorente de Nó, working ~1870-1920 They used the “Golgi stain” – a type of silver stain – in which only 1 out of every 1000 or so neurons is stained. Today, we still don’t know why this happens, but the discovery of that stain was fortuitous for the field of neuroanatomy! This stain allowed the discovery of repeated, stereotypical circuits in three major brain regions. In 1970s, David Marr developed computational based hypotheses for how they work. cerebellum (fine motor movements) hippocampus (memory consolidation) neocortex (”conscious thought”) Bonne (1906) reprinted in DeFelipe (2010) “Cajal’s Butterflies of the Soul” Oxford Press Unique Brain Regions 33  Cerebellar architecture Purkinje cells inhibitory interneurons granule cells climbing fibers, mossy fibers Unique Brain Regions 34 British Gray’s  Hippocampal architecture Wikipedia - original by Ramón y Cajal (1911) ten Donkelaar HJ, Lammens M, Hori A (2006) Clinical Embryology, Springer Unique Brain Regions 35  Cerebral Cortex architecture afferent, efferent, intracortical Unique Brain Regions 36 British Gray’s  Development of Inhibitory Neurons Inhibitory neurons migrate in a tangential direction across the cortical surface from subpallial (ventricular floor) areas. Disorders of inhibitory migration may lead to epilepsy. Marin O, Rubenstein JLR (2001) “A long, remarkable journey: tangential migration in the telencephalon” Nat Neurosci Rev 2:780-90. Unique Brain Regions 37  Development of Cortex In early stages of development, neural progenitors are located in the ventricular zone (VZ). Neurons migrate along radial glia & build the cortex from inside to outside. Transient structures include the cortical plate (CP), preplate (PP), subplate (SP) and marginal zone (MZ). In the adult, cortex has between 3-6 defined layers based on cytoarchitecture & connectivity. White matter (long-range axons) lies below, towards the ventricle. Various mutants are known that cause perturbations in cortical layering. Cortex in birds lacks any layering! Kandel & Schwartz 5th ed Unique Brain Regions 38  Cortical organization in birds Birds lack genes that are critical for forming layers.Some excitatory neuron types are common across all brain regions. The reeler mutant mouse was an early (1951) model of disrupted cortical lamination. A responsible protein (subsequently named reelin) was found to act through LDL receptors and the Deb1-Akt pathway. Unique Brain Regions 39  Highly folded* cortical sheet * gyrencephalic 40 Brain Extracellular Matrix and Blood-Brain Barrier  Smooth* cortical sheet * lissencephalic 41 Brain Extracellular Matrix and Blood-Brain Barrier  Grey and White Matter Major fiber tracts T1 MRI CSF grey matter white matter Schneider (2014) Unique Brain Regions 42 Nagel BJ, Kroenke CD “The use of magnetic resonance spectroscopy and MRI in alcohol research” NIAAA  Development of Myelination Myelination of some cortico-cortical fiber tracts continues into adolescence T1 MRI Zilles K, (2018) “Brodmann: a pioneer of human brain mapping – his ten Donkelaar HJ, Lammens M, Hori A (2006) Clinical Embryology, Springer impact on concepts of cortical organization” Brain doi:10.1093/brain/awy273 Unique Brain Regions 43  Functional Specializations in Cortex Some cortical areas are ”activity-dependent” - specified by neural activity during their development. Ocular dominance domains in monkey visual cortex Barrel-fields in rat somatosensory cortex Schneider (2014) Unique Brain Regions 44  Topics: Basic embryological/evolutionary organization of the brain –How do we get from a neural tube to an adult brain? –How does brain development relate to evolution? Organization of Neocortex –glial cells and neurons –neurotransmitters –excitatory and inhibitory neurons –regions of unique circuitry –development of cerebral cortex Blood-Brain Barrier & surfaces of the brain –composition of BBB –production and circulation of CSF - glymphatic system 45  Development of Brain Vascularization Vessels enter the neuroepithelium, but maintain their CT compartmentalization as they do so by “pulling” CT and an “outer” layer of epithelial cells along with them. Astrocytes maintain the “basal” neuroepithelial surface against the vasculature. Youmans & Winn Neurological Surgery, 8th ed. Elsevier Brain Extracellular Matrix and Blood-Brain Barrier 46  Composition of BBB … from the blood endothelium basement membrane of endothelium CT compartment (fibers & cells) these are only sometimes present pericytes basement membrane of astrocyte foot process of astrocyte … to the neurons! Brain Extracellular Matrix and Blood-Brain Barrier 47 British Gray’s  Composition of BBB British Gray’s The endothelium wall is continuous and contains tight junctions. It has the major responsibility (in humans) for the BBB A presumptive evolution of the blood-brain barrier… O’Brown NM, Pfau SJ, Gu C (2022) “Bridging barriers: a comparative look at the Brain Extracellular Matrix and Blood-Brain Barrier 48 blood-brain barrier across organisms” Genes & Development 32:466-478. www.genesdev.org/cgi/doi/10.1101/gad.309823. 117  BBB is also responsible for active removal of lipids Lipid entry into the brain is mediated by endothelial cells. Free lipids may be bound with apical transmembrane or with intracellular binding proteins Intracellularly-bound lipids are shed to the circulation in exosomes. Noack A et al (2017) “Mechanism of drug extrusion by brain endothelial cells via lysosomal drug trapping and disposal by neutrophils” PNAS 115(41)E9590-E9599 doi:10.1073/pnas.1719642115 Brain Extracellular Matrix and Blood-Brain Barrier 49 Development of Brain Vascularization embryo, 25mm Shaeffer S, Iadecola C (2021) Revisiting the neurovascular unit Nat Neurosci 24:1198-1209 Brain Extracellular Matrix and Blood-Brain Barrier 50  Cerebral Ventricles Interventricular foramen = foramen of Monro connection of lateral to third ventricles Cerebral aqueduct = aqueduct of Sylvius connection of third to fourth ventricle Brain Extracellular Matrix and Blood-Brain Barrier 51 fig 16.25 in Kardong KV, (2009) “Vertebrates Comparative Anatomy, Function, Evolution” 6ed McGraw Hill Ependymal (ventricular) Surface of the Brain Ependymal cells ciliated, simple cuboidal or columnar epithelium lining ventricles produces, absorbs, moves CSF Choroid Plexus - ependymal cells lining elaborated capillary tufts in ventricular floor - produces majority of CSF - contains superficial macrophages - “Kolmer cells” missinglink.ucsf.edu Brain Extracellular Matrix and Blood-Brain Barrier 52  Clinical Correlation – Hydrocephalus Principal causes: overproduction of fluid occlusion of aqueducts poor absorption (back to blood) International Society for Pediatric Neurosurgery - ispn.org seattlechildrens.org Sgouros S “Hydrocephalus with Myelomeningocele” ch 9 in Pediatric Hydrocephalus, Brain Extracellular Matrix and Blood-Brain Barrier 53 (2005) Cinalli G, Maixner WJ, Sainte-Rose C eds. Springer  What about Spinal Cord? central canal lined with ependymal cells filled with CSF Brain Extracellular Matrix and Blood-Brain Barrier 54  Two Circulations in the Brain Shaeffer S, Iadecola C (2021) Revisiting the neurovascular unit Nat Neurosci 24:1198-1209 Afifi – Lec 7.1 cerebrospinal fluid (CSF) formed at the choroid plexus drained at the arachnoid “macroscopic” interstitial fluid (ISF) filtrate of plasma at arterioles drains to capillaries local, “microscopic” Brinker T, Stopa E, Morrison J, Klinge P (2014) “A new look at Brain Extracellular Matrix and Blood-Brain Barrier 55 cerebrospinal fluid circulation” Fluids and Barriers of the CNS 11:10  Two Circulations in the Brain glymphatic system - control of ISF flow between the arterial & venous Virchow-Robin spaces by glial cells Brinker T, Stopa E, Morrison J, Klinge P (2014) “A new look at Brain Extracellular Matrix and Blood-Brain Barrier 56 cerebrospinal fluid circulation” Fluids and Barriers of the CNS 11:10  Topics: Basic embryological/evolutionary organization of the brain –How do we get from a neural tube to an adult brain? –How does brain development relate to evolution? Organization of Neocortex –glial cells and neurons –neurotransmitters –excitatory and inhibitory neurons –regions of unique circuitry –development of cerebral cortex Blood-Brain Barrier & surfaces of the brain –composition of BBB –production and circulation of CSF - glymphatic system 57 Principal sources for figures: Williams PL (1995) “Gray’s Anatomy” 38th ed. (Churchill Livingstone) (coll. British Gray’s Anatomy) Schneider GE (2014) “Brain Structure and Its Origins” MIT Press ten Donkelaar HJ, Lammens M, Hori A (2006) Clinical Embryology, Springer (with figures by M de Leeuw and A Gruter) Kandel & Schwartz (2013) “Principles of Neural Science” 5th ed. McGraw Hill 58