WEEK 1 Flashcards
levels of neurodevelopment
1) the systems level: looking at the changes in size and shape in the development of the NS - “MORPHOGENESIS”
2) the cellular level: differentiation from progenitors into mature neurons
neural induction
a portion of the ectoderm or germ layer (the neural plate) is induced to become neural tissue under signals of the mesoderm. this forms the nervous system.
neurulation
as the ectoderm becomes neural tissue, it also undergoes morphogenic changes in shape.
morphogenesis at the tailbud stage
at the tailbud stage, cranial, cordial, and lateral folding occur. These give the body a comma shape, enclose the organs in ectoderm (skin), and we start to see a head, tail, somite blocks and branchial arches (jaw and neck) + limb buds later on in development. so the major structures of the developing embryo appear by 4-5 weeks.
telencephalon
subdivision of the forebrain which gives rise to most of the cerebral hemispheres via an extensive folding process during neurodevelopment.
diencephalon
subdivision of the forebrain which gives rise to important collections of neurons such as the thalamus.
differentiation
cells progress from a multipotent population to cells of particular specialized identities or fate. we can think of cell differentiation as a decision tree, which will eventually lead to cells assuming one of a number of fates.
Waddington (on differentiation)
represented differentiation as a ball rolling down a hill, the epigenetic landscape, and then rolling into one of a number of channels. which channels it ends up in is not random, it depends on interactions which instruct cells on their next developmental step. ex: neural induction of the neural plate.
aspects of neural differentiation
1) the appearance or morphology of individual cells. ex: purkinje cells have elaborate spines, whereas pyramidal cells do not
2) the gene expression profile
3) neurotransmitter type
4) axon projections and connectivity to other neurons in the NS.
developmental steps that lead to differentiation
1) neurogenesis: cell division generates neurons
2) cell migration: young neurons migrate out of the ventricular zone
3) axogenesis: young neurons develop axons that grow out towards targets
4) synaptogenesis: axons make contact with their target neurons and other structures
5) cell death/pruning: regression events leading to the formation of mature neurons
radial glial cells and the neural tube during neurogenesis
radial glial cells are the progenitor cells of the NS. they undergo cell divisions to expand the progenitor cell population.
once a neuron is generated, it will migrate along the radial glial cells, using them as a guide towards the mantle zone where further differentiation occurs (axon extension).
three types of neuronal migration
1) radial migration (spinal)
2) tangential migration
3) neural crest cells
radial migration
in the forebrain, cells which migrate radially along radial glia give rise to neurons with long axons which project to other regions of the NS and which use glutamate. these are “excitatory projection neurons”.
tangential migration
in the forebrain, cells which migrate orthogonal to the radial axis, and intermingle with the neurons that have undergone radial migration. tangential cells give rise to neurons with short axons which use GABA. these are “inhibitory interneurons”.
neural crest cells
cells that split off from the ectoderm while neurulation is underway, migrating away from the forming neural tube to form elements of the PNS (basal root ganglia, sympathetic ganglia, cranial ganglia).
stages of axogenesis
1) neurons are round blobs
2) neurons look radially symmetrical with several neurites
3) one of the neurites becomes elected as an axon in a process of symmetry breaking
4) the axons grows and dendrites start to form out of the cell body
5) the dendritic tree becomes more elaborate, with dendritic spines forming
types of axon connections
1) axodendritic
2) axosomatic
3) axoaxonic
neuroligins, neurexins and synaptogenesis
neurologins and neurexins are families of proteins that are expressed by postsynaptic and presynaptic neurons. they bind the pre and post synaptic parts of the synapse together, and recruit specialized groups of proteins to form the synapse.
cell death and pruning
cell death: either the elimination of whole cells or parts of cells, axons, synapses, or dendrites. around 50% of motor neurons die later on in development.
pruning: from 4 to 6 years, synapse pruning and consolidation takes place and a decrease in the complexity of the brain occurs. pruning can also occur to axons and dendrites.
cell death and pruning: functions
1) eliminate unwanted or aberrant neurons or connections
2) match numbers of pre and post synaptic cells
3) ensure that synaptic transition and circuit function are optimized
neurodevelopmental disorders
- ASD
- schizophrenia
- childhood onset epilepsy
- x-linked mental retardation
caused by gene mutations that affect dendrite and synapse development, axon growth, guidance, neuronal migration, synapse formation, and function.
synaptogenesis and ASD
mutations in the Neuroligin 4 gene are linked to ASD. Nlgn4 knockout mice show that markers of inhibitory synapses are reduced in some areas of the hippocampus + social interaction and communication impairments, as well as repetitive behaviors or interests.
dendritic spines and schizophrenia
individuals with schizophrenia show reduced dendritic spines in the dorsolateral PFC. this reflects defects either in the process of dendritic development and/or pruning.
convergence
the ability of different cells to send their inputs to a single target cell - so the single cell is receiving input from multiple sources. the average neuron in the brain receives 10k inputs from 10k synapses.
divergence
the ability of a single cell to project to multiple cells. there are up to 1k different axon terminals from one single neuron.
functional division of the NS
1) CNS: brain + spinal cord
2) PNS: autonomic (unaware) NS and somatic (aware) NS.
- this view has limitations tho
autonomic NS
1) parasympathetic component (“rest and digest”, tho there are limitations to that)
2) sympathetic component (“fight or flight”, still, limitations)
ex: parasympathetic constricts the pupil in bright light. sympathetic dilates the pupil in darkness.
CNS or PNS neuron?
if a neuron is entirely contained within the brain and/or spinal cord, it is a CNS neuron. if any part of it (dendrites, axon, or cell body) projects outside these structures, it is a PNS neuron.
3 planes of the brain
1) horizontal, transverse sections
2) sagittal, runs through the midline
3) frontal, parallel with the plane of the face
CNS: anatomical components
1) the spinal cord, which ends at the base of the skull
2) the hindbrain, made up of the pons, cerebellum and medulla
3) the midbrain
4) the forebrain, which represents the cerebral hemispheres
cauda equina
“the horse’s tail”: any nerve below L1 and L2 has to travel down the spinal cord until it finds its corresponding foramen and exits. so there’s a group of nerves at the base of the spinal cord where there’s no tissue or cell bodies involved. this is clinically important because a needle can be placed here without damaging the spinal cord.
brainstem: functions
- most important part of the brain. “brainstem death” refers to whether someone is capable of independent life or not
- ascending somatosensory and descending motor pathways going through it, as well as important cerebellar connections
- houses most cranial nerve nuclei
- important center for chemoreception and reflexes
- life-supporting processes such as respiration and arousal centers
- 3 nuclear groups: raphe (serotonin site), locus coeurulus (adrenalin site), and substantia nigra (dopamine and movement control site)
4 lobes
1) occipital
2) parietal
3) frontal
4) temporal
note: no single function of the body is concerned with any one individual lobe. they work in tandem. ex: movement is mediated by the frontal and parietal lobes.
2 types of cortical connections
1) ascending sensory connections
2) descending motor connections
ascending sensory connections
sensory info from the body enters the spinal cord and is then transferred via the thalamus to the somatosensory cortex for processing. smell is the only sense that does not go through the thalamus - it goes directly to the olfactory cortex with no processing. the only thing the thalamus does is tell us whether we like a smell or not.
descending motor connections
from the cortex to the spinal cord through the corticospinal tract, and to nuclei within the brainstem. other pathways responsible for higher levels of motor control go to the BG, cerebellum, and the limbic system.
association fibres/neurons
connections within the cerebral cortex that occur on the same cerebral hemisphere.
commissural neurons
connections within the cerebral cortex between cerebral hemispheres. ex: corpus callosum. these let one side of the brain know what the other is thinking or doing.
projection neurons
extend long distances and connect structures from the brain to the spinal cord or vice versa. these include motor fibers that are descending from the cortex to the spinal cord, and ascending somatosensory fibers bringing in info from the spinal cord to the cortex.
diffusion tensor tractography (dti)
type of MRI that relies on looking at the ways in which water diffuses through structures. enables us to image myelin so we can plot individual pathways.
Cajal & Golgi
won the Nobel prize in physiology and medicine for their discovery that the brain was not a single continuous entity, but composed of individual cellular units.
2 major cell types of the NS
1) neurons
2) glia
neuronal communication
neurons communicate by passing electrical signals along their elongated form, and they convert it into a chemical signal to activate another electric signal in the next neuronal network.
neuronal communication speed
from 1 mph (speed of a tortoise) to 268 mph (faster than most F1 cars).
types of neurons
1) classic model neurons: receives signals from and sends signals to other neurons, long extended shape
2) sensory neurons: can be activated by skin cells, for example
3) motor neurons: can stimulate muscle movement
4) interneurons: can send and receive signals with multiple other neurons. they carry info between sensory and motor neurons
glial cells
the “glue” of the NS. they support neurons, and have three subtypes:
1) astrocytes
2) oligodendrocytes
3) microglia
astrocytes: functions
1) distribute nutrients from the blood supply to neurons
2) ensure the maintenance of extracellular ionic balance
3) tissue repair
4) regulation of synaptic activity by direct contact with synapses
5) astrocyte-astrocyte signaling via gap junctions (gaps in the cell membrane that leak charge ions)
microglia: functions
smaller than astrocytes
1) resident immune cells of the brain
2) clear debris
3) recruit other cells to sites of damage
4) aid in tissue repair
5) can also degrade synapses, essential for synaptic pruning, BUT might make matters worse when neurons undergo chronic stress during disease by preventing recovery
oligodendrocytes: functions
equivalent to Schwann cells in the PNS
1) support and insulate neuronal axons by generation of myelin sheath
2) increase speed of neuronal signaling through saltatory conduction
3) provide metabolic support
neuroinflammation
activation of glia within our NS. this may initially be a defense response to threat to protect neurons, but chronic activation can lead to the over activation of astrocytes and microglia and toxicity to neurons.
purkinje cells
highly branches as they receive many inputs and are the only output of the entire cerebellar cortex.
axonal length
can vary widely, determining the distance of output in the network. the longest axon in the body is from the lower motor neurons, 1 meter in length.
if the cell body was the size of a ping pong ball, the axon would be 380 meters long, just under 4 football fields in length!
dendritic spine
small protrusions on dendrites which form the postsynaptic side of the synapse with axon terminals from other neurons. their shape and size affect how they receive and transmit input: larger surface area spines provide more space capacity for neurotransmitter receptors and from stronger, more stable synapses.
microglial morphology
microglia change morphology when they become activated or ‘reactive’, becoming rounder and more phagocytic.
- reactive microglia release more cytokines to attract more microglia to the site of perceived injury
- phagocytic microglia engulf any perceived debris, including synapses
microglial scoring system
1: ramified, normal
2: reactive
3: amoeboid
4: phagocytic
this shows progressive inflammation.
astrocytosis
an increased number of cells in a given location is due to the local recruitment or enhanced proliferation of astrocytes
neuronal substructures
1) nucleus: where all genetic info is stored
2) endoplasmic reticulum: where some new proteins are produced, sorted, and processed for delivery to their required location
3) Golgi apparatus: additional sorting and processing centre
4) mitochondria: energy generator of the cell, also have key roles in calcium buffering and cell signaling
5) lysosome: enzyme filled vesicles for the degradation of proteins and organelles when faulty
6) cell membrane: lipid bilayer containing receptors for cellular communication
unique features of a neuron
1) neurons have an unusually high energy demand, the majority of which is used to maintain electrical equilibrium (sodium potassium ATP pump). it also is used for recycling of neurotransmitters and calcium buffering
2) neurons need to transport cargo along long distances due to their extended morphology, as the majority of proteins and mitochondria are produced next to the nucleus but are needed at synapses. cargo is transported along microtubules away from the nucleus (ANTEROGRADE) or towards the nucleus (RETROGRADE).
3) neurons are vulnerable to stress: neurons are post-mitotic, meaning they cannot undergo cell division for growth or repair, making them vulnerable with age as cells deteriorate and have a reduced resistance to cell stress.
retrograde transport impairment
could lead to a buildup of dysfunctional components at the synapse and a reduction in the supply of recycled components, blocking normal synaptic function.
processes that become dysfunctional with aging
- protein clearance
- DNA repair
- mitochondrial function
neuronal plasticity
ability for neurons to adapt to stimuli, such as the growth of existing or new synapses during memory formation
renewal of proteins
via protein synthesis (through gene expression) or protein recycling
gene expression
the process by which a gene (DNA) is used to synthesize the product it encodes. this is most commonly protein, but can also include functional RNAs such as transfer RNA (tRNA) or ribosomal RNA (rRNA)
two steps of gene expression
1) transcription: the photocopying of DNA into messenger RNA (mRNA). This keeps the DNA in the nucleus where it can be protected from damage.
2) translation: the literal translation of the genetic code on the mRNA photocopy into protein
these processes are regulated so that proteins are only made when needed
transcription
the enzyme RNA polymerase moves along the DNA, copying its code (A, G, C, T) into mRNA (A, G, C, U). the DNA structure needs to be relaxed for transcription via epigenetic practices, like DNA methylation.
RNA splicing
before being exported to the cytoplasm for translation, splicing machinery slices non-coding regions (introns) at the mRNA, only leaving protein coding. alternative splicing can slice different regions, producing different RNA transcripts that encode for different proteins with different functions. this is the way in which the genetic code can increase the number of potential proteins it makes.
translation
in the cytoplasm, ribosomes read mRNA code and translate it into protein. the ribosome recognizes a 3-base pair code (1 amino acid; AUG or ATG) and brings in a tRNA carrying the appropriate amino acids. Binding them together, a polypeptide is formed, and once folded, becomes the protein.
local translation
though translation usually occurs close to the nucleus, in neurons, it occurs sometimes at sites with high protein demand, such as synapses.
protein processing and folding
protein folding occurs as soon as a protein is made, and then undergoes quality control to ensure it is correct. thus, misfolded proteins can be targeted quickly for degradation.
proteins also have post-translational modifications that modulate their folding, such as phosphorylation, greatly increasing the diversity of protein functionality.
protein misfiling is a major cause of neurodegenerative disorders, usually leading to buildup of aggregated protein in the brain.
