Lecture 3

Are there negative consequences for extreme neuronal diversity?

regrowth can be done incorrectly and can cause more harm than good.

what are glial cells (glia)?

cells that support neurons to keep them perform at their best

what percentage of cells are glia cells in the CNS?

50% of cells

what technique was used to found the modern percentage of glia cells? Describe the technique.

isotropic fractionation:

1. Brain tissue is ground up in a detergent solution, leaving only cell nuclei intact.

2. fluorescent antibodies added (GFAP labels glial cells)

3. Cell-sorting counts GFAP tagged cells

What is the overall human brain glia:neurons ratio?

1:1 in the human brain

what are the four major classes of glial cells in vertebrate nervous systems?

1. Microglia

2. ependymal cells

3. astrocytes

4. myelinating cells

what are myelinating cells called in the CNS, and what makes them special?

oligodendrocytes

• Special because they can myelinate multiple axon segments

why do oligodendrocytes have incomplete myelination?

• incomplete myelination because oligodendrocytes actively adapt to facilitate learning and working memory

→ less learning/memory = less oligodendrocyte myelination

What are myelinating cells in the PNS called, what makes them special?

Schwann cells (multiple schwann cells wrap around a PNS axon)

• special because they help with axonal regrowth in PNS

what is the functions of both types of myelinating cells?

1. provide elcetrical insulation (faster movement of signals)

2. trophic support (provide nutrients and “medicine” for cells)

what is white matter made up of?

myelin

What are corpuscles and what are they made up of?

Corpuscles are specialized free-floating nerve endings are made up of schwann cells

what is microglia?

primary immune cells of the CNS (since other immune system cells cannot pass through the BBB)

what is microglia responsible for?

Neural gardeners → synaptic pruning, debris clearing, surveillance (actual macrophages and WBCs can enter the brain during injury or disease), and mediating inflammation

what are non-glial CNS support systems?

1. meninges

2. the neurovascular unit & hemodynamic response

3. Blood-brain barrier

4. glymphatic system

what makes microglia impressive?

become mobile when activated → they rearrange cytoskeleton to move

Why is debris cleaning and mediating inflammation by microglia important?

Calcium deposits can form, leading to early age-related brain pathologies

what gene promoter is responsible for microglia in mice?

gene promoter = FIRE

What is the most common and most diverse glial cell type in CNS?

astrocytes

What is the function of astrocytes?

• buffer extracellular ions (K+)

• supply nutrients (lactate shuttle from glycolytic soma to axon terminals)

• Recycle NTs from the synaptic cleft (glutamate, GABA)

• secretes neurotrophic and synaptogenic signalling molecules to promote neuron/synapse growth

• target unneeded/inactive synapses for pruning

• participates in “tripartite synapse,” helping synaptic transmission between nerurons

• regulate neuron and blood vessel interactions

what is an astrocytes major role?

The BBB (not involved in physical barrier)

• secrete key signaling molecules that maintain structural integrity, regulate vascular function, and provide neuroprotection

What is creating a physical barrier in BBB?

endothelial cells (in the capillary itself)

what are satellite glial cells?

function like astrocytes, but are found in the PNS

How do astrocytes respond to stimuli if they are not electrically excitable?

They respond to NT (glutamate ) release by cytosolic Ca2+ elevations that spread to neighboring cells (spreading like waves across a brain region)

what are pericytes?

• a diverse cell type associated with capillaries (not glial cells)

• muscle-like, allowing them to contract and restrict movement through blood vessels (vascular function)

What is the hemodynamic response in response to neural activity?

triggers astrocyte end-feet to release chemical signals to surrounding pericytes, causing them to relax and dilate blood vessels to delivers glucose and oxygen.

• neural activity → NT release → elevated Ca2+ → endfeet release signals → pericyte relaxation → increased perfusion (high delivery of glucose and oxygen)

What is astrocytes role in the BBB?

astrocytes secrete key signaling molecules (ANG-1, SHh, retinoic acid, GDNF, FGF, apoE) that maintain structural integrity, regulate vascular function, and provide neuroprotection

What is the role of astrocytes in the glymphatic system (of neurovascular unit)?

Facilitate the movement of CSF through brain tissue, which drives local hemodynamic responses (blood flow and oxygen level changes in blood tissue) to pump CSF from the brain.

what is the choroid plexus?

a specialized network of cells located within the ventricles of the brain

How is CSF produced and secreted?

CSF flows through the ventricles into the subarachnoid space

Where does the CSF drain back into the bloodstream?

At the sagittal sinus

What are tanycytes?

• type of ependymal cell

• lines the walls of the ventricles as well as the membranes of the choroid plexus

What’s the role of tancycyte?

ventricular tanycytes help regulate the movement to CSF into brain tissue

Describe the blood-CSF barrier

ependymal cells in the choroid plexus maintain a more permissive barrier than BBB, where water and ions secrete continuously.

What are some other functions of ependymal cells?

immune responses

• systemic communication - the choroid plexus acts as a key signalling hub between the CSF and the systemic immune system

• WBC entry - during inflammatory responses, the choroid plexus recruits WBCs and facilitates their entry into the CNS

What has dye injection (Trypan Blue) experiments on the BBB show?

BBB is not uniformly tight everywhere → intentionally leaky in specific locations (primarily around the hypothalamus)

why would the BBB be leaky around the hypothalamus?

The hypothalamus releases lots of hormones that have to make there way into the blood

What are circumventricular organs (CVOs)?

specialized structures surround the ventricles that lack a BBB

Why else would the brain have more leaky regions, besides hormone release?

local permeability allows the brain to monitor blood composition

what types of cells regulate the leaky BBB regions?

astrocytes and tanycytes dynamically regulate this local permeability

What does it mean by “the BBB is temporal”?

The BBB can temporarily become more permissive or “leaky” in response to specific physiological or environmental states

What is an example of a BBB varying over time?

• systemic inflammation

• fasting

→ Evan blue dye (tracer) diffuses through BBB in experiments during these times

How do astrocytes regulate fluid exchange in two ways:

1. trigger arterial pulsations via the hemodynamic response

2. facilitate the physical movement of water and ions through specialized channels and aquaporin channels in their end-feet

How are glymphatic flow rates dynamically controlled?

circadian rhythms → highest activity during sleep

What was the key finding of vessel dilation and contraction in response to pulsing light and sound at various frequencies?

sensory stimuli repeating at 40Hz produce the strongest vasomotor response (vessel pumping motion), effectively stimulating glymphatic fluid movement.

How could 40Hz stimulation help with early-onset Alzheimer’s disease?

40Hz stimulation significantly enhanced the clearance and reduction of beta-amyloid plaques (hallmark protein of alzheimers disease.

→ drives the glymphatic waste-clearing process in mice (could work for humans)