NEU 490 Quiz 1 Flashcards
Microglia – The sentinel of the central nervous system
Sentinel:
Microglial Functions in the Adult Brain Sick:
Role in healthy CNS:
Sentinel: constantly surveying for injury or insult like inflammation or infection - act as a first line in defense and clean up debris
Sick Functions:
- Myeloid phagocyte(to eat up debris or damaged tissue)
- Only innate immune cell of the NS in the CNS
- 5-12% of all cells in CNS are variable densities
- Immune defense and CNS maintenance
Role in healthy CNS:
- Development of CNS
- Connectivity
- CNS homeostasis throughout life
- Synaptic Plasticity
- Monitoring neuronal activity
- More than just diseased state
Location in the CNS
what % of CNS glia population?
how dispersed?
occupy what territory?
what happens after pathological event?
what happens during transformation?
have the capacity for what?
can have local what? can recruit who?
- Constitutes 20% of total CNS glia population, on average 10,000 microglia per mm3
- In the mature brain, they are found almost evenly dispersed throughout the CNS - Resident immune cell and play role of multiple peripheral immune cell
- Each cell seems to occupy a defined territory so don’t overlap
- After a pathological event (injury or invasion of pathogens), these cells undergo a transformation
- Transformed cells acquire amoeboid shape
- Have the capacity to migrate(microglia can move towards threat), proliferate, and phagocytose
- Can have some local proliferation and recruit circulating macrophages → insert into network of microglia
Our CNS Immune Cell
network of surveillance cells is called? responds to?
who is first line of defense?
what kind of cells? what do they release?
Pro- and anti-inflammatory?
- Network of surveillance cells - sentinel
respond to slightest alteration (pathogen/invasion/damage) in their environment - Resident immune cells – first line of defense in CNS
- Antigen-presenting cells(present to T-cells and eat up debris), phagocytose debris, communicate with nearby neurons. Perform fixes of several peripheral innate immune cells, Release cytokines and ATP
- Pro- and anti-inflammatory – distinct morphology depending on activation state. Can be beneficial for
—- Beneficial to repair
—- Inflammation → brings in more immune cells
—- Phagocytose(is the process by which a cell uses its plasma membrane to engulf a large particle)
what is synapse pruning?
What are some potential reasons for synapse pruning, during development and adulthood?
During development: synaptic pruning - getting rid of inactive synapse
In adults: maintenance of neural circuits, modification of connections – conserve energy (use it or lose it) depletion of microglia significantly reducing plus myelination
Microglial contributions to adult brain function include:
Adjusting neuronal firing rates to optimize network properties - sculpt activity like nitric oxide
Producing neuromodulatory factors that support synaptic plasticity and learning - creation of new synapses and pro growth factors
Responding to inflammation, disease states, or injury, in both protective and deleterious ways - improve recovery or impede recovery and reduce positive outcomes
Additional functions in synapse remodeling, neuronal function, supporting myelination, vasculogenesis(vascular formation and facilitate optimal vascular complexity), and BBB permeability(BBB integrating when active impairment of BB fix hyperpermeability and aberrant infiltration)
Microglia constitute _________________ percent of all cells in the brain and ________________ percent of the glia population
5-12%, 20%
What are some of the functions of microglia in the developing nervous system?
synaptic pruning, synapse remodeling, neuronal function, supporting myelination, vasculogenesis, and BB permeability
True or false: Depletion of microglia leads to increased vascular branching and complexity
False
Origin Of Microglia? YK? BBB start?
Microglia are of myeloid origin, arising from yolk sac (YS) primitive macrophages, which persist in the CNS into adulthood.
Primitive macrophages exit the yolk sac blood islands at the onset of circulation and colonize the neuroepithelium from E9.5 to give rise to microglia.
BBB stars at 13 days and isolate developing brain from hematopoiesis
Numbers increases throughout the first two postnatal weeks via in situ proliferation
Embryonic microglia expand and colonize? Until full adulthood?
During inflammation - for example bone marrow?
Microglia reside?
Embryonic microglia expand and colonize the whole CNS until adulthood, and locally proliferate, particularly during inflammatory conditions.
Until full adulthood maintain via local proliferation and during steady state
During inflammation - for example bone marrow, transplant recruitment of monocytes and other bone marrow derived progenitors that can supplement microglia population to some extent
- We do not understand yet whether these cells persist and become integrated in the microglial network, or are a temporary addition to the endogenous population.
Microglia reside in the brain throughout life, and maintain their numbers through a process of self-renewal
Which of the following are ways you can attempt to differentiate between a microglia and a macrophage?
Examine morphology shape/size, determine location of cell, follow them throughout development to determine source
Discovery of Microglia who?
Pio del Rio-Hortega - Father of modern microglia biology in early 1900’s - Student of Cajal
Microglial Structural Diversity – reflecting brain area populated
Microglial Activation States
Old View VS New View
microglial activation is?
The activation states of microglia are hotly contested. For many years it was thought that they primarily existed in two different states – M1, or pro-inflammatory, or M2, or anti-inflammatory.
New research has thrown that categorization into question.
New understanding and state-dependent microglial activation
Old View: rigid, dichotomic categorization - m2 vs m1, resting vs activated, ramified vs ameboid, anti vs pro inflammatory
New View: based on coexistence of multiple states - proteomic, metabolomic, transcriptomic, morphological, epigenetic
Ramified (Resting) Microglia - More accurately BLANK
Ramified are highly?
What type of cell body?
Important for?
Mobility?
Ramified (Resting) Microglia - More accurately surveillance
- smaller cell bodies and constantly moving at 360 degree to assess the area
Ramified microglia are highly branched with multiple primary and secondary processes
Small somata (cell bodies) and fine ramifications
Extend far away from cell body long and branched
Surveillance microglia – important for maintaining homeostasis
Processes constantly moving - located close to neurons and other glia, Ramified microglia have fine processes capable of moving around
Ramified (Resting) Microglia
“Resting” while working
Pinocytosis?
First line?
Assessing?
DAMP/PAMP?
Pinocytosis: sipping away at the ECF → taking up small amounts of extracellular fluid as samples to see what is going on nearby as the first line of defense
- extracellular fluid to see if damage or anything being released to survey environment
First line of defense, so constant surveilling is important → prompt response to threats
Assessing neuronal activity, potential insults, or injury
Have receptors for neurotransmitters, have DAMP (damage associated molecular patterns - things released by damaged cells) receptors, have PAMP receptors (pathogen associated molecular patterns like bacteria, virus, and fungi)
Activated Microglia (mobile)
Change shape and size in response to? Become?
Migration toward?
Primary goal?
Factors?
Phagocytes?
Busy hypertrophic and release cytokines and growth factors and try to repair and not reach cell death
Change shape and size in response to threats – become large and bushy → hypertrophic
- In response to changes in extracellular environment (pH, ions, DAMPS and PAMPS)
- In response to loss of calcium signals - microglia have intracellular calcium
Directional migration toward site of injury - movement of microglia
Primary goal: repair and recruitment
Neurotrophic factors (growth factors) and pro- inflammatory cytokines (recruit other cells)
We are not phagocytes yet bc it is still trying to repair not at a lost cause
Reactive Microglia
What shape/ other name?
Phagocytic?
1,2,3?
Ameboid shaped - small round fat
Reactive circles and engulf or eat up any dead tissue and will not release cytokines bc past the point of no return
Phagocytic: ingestion of particulate matter from the ECF - taken to intracellular compartments of microglia to destroy
- Development: Synaptic stripping or pruning - change in morphology even though this is normal - change in morphology aids in change in function
- Damage: Clearance of debris (pieces of dead cells or pathogens)
- Disease: Participant or Proponent(is phagocytosis a good thing? Sometimes for example Alzheimer’s?) - Pieces of dead cells or pathogens
Microglia that are round and have little to no processes are BLANK, ones that are large and bushy are BLANK, and ones with small cell bodies and thin longer branched processes are BLANK.
Reactive/Ameboid
Activated/Hypertrophied
Resting/Ramified
Ramified:
Ameboid:
Ball-and-chain:
Hyper-ramified:
Bulbous tips:
Honeycomb:
Jellyfish:
Trains of rods:
Ramified: Highly branched, Multiple primary and secondary processes, Surveillance
Ameboid: Highly rounded, Phagocytose and migrate
Ball-and-chain: Tip if a ramified can phagocytose small amounts of material like synapses or apoptotic bodies,
Synaptic pruning converses energy
Hyper-ramified: Increased branching points, On our way to activated bushy state and cell body and process increase
Bulbous tips:
Important for ATP sensing, On ramified microglia
Honeycomb: Network, BBB leakage
Jellyfish: Honeycomb translation when lots of cell death
Trains of rods: Elongate soma, Attach in trains, Respond to injury
You are assessing microglial morphology in different pathological conditions. For each of the following situations, which activation state is the microglial cell in? (Use resting, activated, and reactive)
Cell appears rounded and fat
Cell releases pro-inflammatory cytokines
Cell is taking up extracellular fluid
Cell is bushy and large
Cell is phagocytosing dead cells
Cell’s processes are constantly moving around in 360-degrees
You damage tissue, see cells moving towards the source
Cell appears rounded and fat - reactive
Cell releases pro-inflammatory cytokines - activated
Cell is taking up extracellular fluid - resting, activated, and reactive
Cell is bushy and large - activated
Cell is phagocytosing dead cells - reactive
Cell’s processes are constantly moving around in 360-degrees - resting
You damage tissue, see cells moving towards the source - activated
What are some examples of DAMPs that neurons might release when damaged or dying?
What are TWO examples of receptors on microglia activated by DAMPs or PAMPs, and what is the consequence of their activation?
What are some examples of DAMPs that neurons might release when damaged or dying? - mtDNA, histones, heat shock proteins
What are TWO examples of receptors on microglia activated by DAMPs or PAMPs, and what is the consequence of their activation? - toll like receptors (TLRs), pattern recognition receptors (PRT)
Microglia During Development - Helper of Neuronal Development
Phagocytosis of apoptotic neurons?
Microglia induce programmed cell death?
Triggered via?
Mice lacking microglia can still?
Phagocytosis of apoptotic neurons:
- About half of the neurons that are created during development undergo apoptosis and microglia induce apoptosis triggering superoxide ions
- Over 50% of neurons undergo apoptosis before adulthood → in regions where microglia are closely situated
Microglia induce programmed cell death - Superoxide ions → oxidative stress to induce apoptosis
- Triggered via CD11b and immune receptors during microglia-neuron interaction
- Possible other cells types can pick up slack
Mice lacking microglia can still remove apoptotic neurons, suggesting involvement of other cells
Trophic support of developing neurons does what?
Essential for?
Secretion of?
Secrete?
Neurotrophins are those factors that keep?
Trophic support(things that help neurons differentiate, grow, and survive) of developing neurons
Essential for survival and development of cortical layer V neurons → mice without microglia have thinner layers of cortex (the thicker layer of cortex is allows for more complexity and communication)
- Help control the size of neural precursor pools – affects cortical thickness
Secretion of growth factors
Secrete neurotrophins to induce programmed cell death → sculpting circuits
Neurotrophins are those factors that keep neurons alive and induce cell death
Neuronal Circuit Development uses the BLANK?
Blood vessels used for?
In which tissue? Begins which day?
Microglia connect sprouting blood vessels, promoting?
Depletion or absence of microglia leads to?
Guidance of developing vasculature (needed to have oxygen, nutrients, and then waste taken away)
During CNS development, blood vessels extent into the neuroectoderm to provide nutrients(glucose) and oxygen
Development of blood vessels used and routed in CNS tissue. Begins around 10 days post-conception in mice – coincides with microglial entry into neuroectoderm - blood vessels enter here to provide energy to keep the blood alive like connecting vasculature is something microglia does
Microglia connect sprouting blood vessels, promoting vessel branching
Depletion or absence of microglia leads to reduced vascular growth, branching, and density
