Neurological 1

Advance Patho Exam 3

Part of the brain: Cerebral Cortex

Executive functions

Part of the brain: Hypothalamus

Metabolism and autonomic functions

Part of the brain: Cerebellum

Motor control

Part of the brain: Hippocampus

Memory consolidation and spatial navigation

Part of the brain: Corpus collosum

Connection of hemispheres

Part of the brain: Basal ganglia

Signal integration

Part of the brain: Substantia nigra

Reward and movement

How is blood supplied to the brain

2 carotid arteries and 2 intervertebral arteries which pool in a redundant circulatory loop and spread over the cortices of the brain, entering the tissue from the parenchyma perpendicular to the brain surface

Pearls about CSF

Contains: Proteins (albumin, antibodies) and cells common in the periphery but not found in here originally

Quantity: 125-150 mL of substance surrounding the brain and spinal cord

Choroid plexus cells produce 500 mL/day (there is consistent turnover)

Garbage: drains into the venous system

What are the functions of CSF

• Buoyancy

• Protection

• Chemical stability (waste, pH)

• Creates pressure gradient that facilitates perfusion

What are CNS ventricles

Definition: open spaces within CNS that are filled with CSF

Cells found: they are specialized epithelial cells, ependyma, which helps form a barrier between CSF and CNS

Function: passageway for CSF produced by choroid plexus, and the transfer of nutrients and components from the CSF into the brain.

• Sampling CSF can give good clues about what’s happening in the CNS tissue

What are meninges

Three membranes that envelop the brain and spinal cord:

• Dura (thick, tough)

• Arachnoid (spider-like processes)

• Pia (think, delicate)

Functions:

• Lymphatic elements

• Gateway of peripheral immune elements

  • peripheral immune elements don’t typically penetrate and get into the CNS tissue though

Common pathologies of meninges

Site of pathogen-induced inflammation and subarachnoid hemorrhages

What is between the arachnoid and pia

Subarachnoid space filled with CSF

What is grey matter

• Neuronal cell bodies

• Mostly unmyelinated axons

• Function:

  • Muscle control

  • Sensory perception such as seeing and hearing

  • Memory

  • Emotions

  • Speech

• High metabolic requirements (80% of brain)

About 50% volume

What is white matter

• Neuronal axonal tracts

• Highly myelinated

• Functions:

  • Relays action potentials between different brain regions

About 50% volume

What are neurons

• Non-proliferative cells that electrically conduct impulses responsible for function of the organism

  • Can have over 100K connections (synapses) to others

• There is no consensus on how many different types there are based upon:

  • Location

  • Shape/morphology

  • Synaptic connections

  • Functional task

  • Neurotransmitter

What is an oligodendrocyte

• Non-proliferative cell that myelinates neurons within CNS white matter

• Functions:

  • They can myelinate dozens of different axon segments

    • Very large cell with high metabolic burden

    • Axonal conduction of myelinated axons is very rapid and is a key element of long-distance signal conduction

• Difficult cell to isolate and/or transplant

The target cell of many diseases (MS, several leukodystrophies)

What are astrocytes

• Most abundant cell type in CNS

• Functions

  • A supportive cell for neurons

  • Takes on an inflammatory phenotype during injury response

  • They can take up neurotransmitters from synapses, controlling the intensity and duration of a neurotransmitter in the synapse

These are the primary dysfunction of several neurodegenerative disorders, as evidence is showing

What are microglia

• These are the macrophages of the brain with M1 and M2 phenotypes

• Functions

  • Constantly surveying the local microenvironment and rapidly responding to nearby injury by activating, proliferating, and migrating

  • Cytotoxic secretion is aimed at destroying infected neurons, virus, and bacteria, but they cause extensive collateral damage in exchange.

They perpetuate the neurotoxic and neuroinflammatory effects of astrocytes and vise versa

What are neural stem cells

• Self-renewing cells that can differentiate into neurons, oligodendrocytes and astrocytes

• Note: niches include the sub-ventricular zone and NSC near capillaries

What is a synapse

• Impulses that are transmitted by neurotransmitters

  • Neurotransmitters are formed in the neuron

  • Synaptic knobs or boutons store them.

• Neurotransmitters are released across the synaptic cleft, which is the space between the neurons

• Myelination facilitates rapid progress of action potentials

What are neurotransmitters

• There are more than 46 different types in 4 general categories

  • Amino acids: glutamate, GABA, aspartate

  • Monoamines: dopamine, serotonin, histamine

  • Peptides: somatostatin, opioids

  • Other misc: acetylcholine, adenosine

• Possible effects on postsynaptic neurons

  • Excitatory

    • pushes post-synaptic neuron closer to threshold potential (causing localized depolarization)

  • Inhibitory

    • Makes post-synaptic neuron locally hyperpolarized (less likely to depolarize)

What are excitatory neurotransmitters

• Example: glutamate

• It is released from pre-synaptic neurons

• Binds to the receptor on post-synaptic neuron

  • Ionotropic: ion channels open once it binds to the receptor

  • Metabotropic: non-channels that cause signaling cascade that opens other channels

• Calcium and sodium rush into the cytoplasm, altering the electric potential

What are inhibitory neurotransmitters

• Example: GABA

• It is released from pre-synaptic neurons

• Binds to the receptor on the post-synaptic neuron

  • Ionotropic: ion channels open

  • G-protein coupled: non-channels that cause signaling cascade that opens other channels

• Chloride rushes into the cytoplasm, locally altering the electric potential

What is synaptic plasticity

• The combined effect of the interactions that ultimately determines whether the individual neuron will reach the threshold potential and fire an action potential.

• Connections and the influence that a single synaptic connection has on the post-synaptic neuron can change as a result of learned experience or pathology.

What is a strengthened synape

• It is when the quantity and frequency of excitatory neurotransmitters that are released to that synapse increased.

• strong post-synaptic “spines” of neurons have a greater effect on the change in electrical potential of the post-synaptic neurons

  • Because they are bigger there is more volume that can affect the overall electric potential

  • More receptors on the post-synaptic neuron means that there can be more local depolarization upon NT release

  • Physiological and pathological mechanisms alter synaptic connections causing spine enlargement

What is a weakened synapse

• It is due to less excitatory input from pre-synaptic neurons, and it becomes smaller and plays a lesser role in influencing the activity of the post-synaptic neuron

  • Physiological and pathological mechanisms alter synaptic connections causing spine shrinkage

  • Lack of sufficient neuronal input will cause apoptosis

Pruning of neurons without enough synaptic connections

• Too many neurons (insurance)

• Lack of connectivity to other connected neurons

• Exposure to repulsive cues

Loss occurs during development and early childhood

What is excitotoxicity

When excitatory neurotransmitters are at levels that are too high and/or are too persistent

• Plays a role in reperfusion injury, where some reperfused neurons will dump large amounts of neurotransmitters and keep releasing higher than normal levels. It can affect neighboring cells

• Could cause cytoplasmic calcium to be too high for too long causing cytotoxicity

  • This would activate caspase and mess up mitochondrial function

  • This process isn’t instantaneous; it takes hours or days to play out.

    • Type of secondary injury

What is the BBB

Composed: capillaries that are made up of endothelial cells and pericytes that are enveloped in a basement membrane

• These endothelial cells express tight junctions that prevent passage of all but small lipid soluble molecules into the brain

Potential consequences of the CNS immuno-differences

• Lacks specialized cells for diverse immune functions

  • Astrocytes and microglia have important functions for normal CNS activity, bar are also major mediators of the inflammatory response

• Traumatic breach can be disastrous (lets in the riff raff)

What are the immuno-differences of the CNS

• High regulation of entry for cells and molecules via the BBB that insulates the sensitive biochemical environment

• Lymphatic system connected to CSF, but not within tissue of the brain

• T’s, B’s, macrophages, dendritic cells, and neutrophils can be found in the CSF, but generally not very many and presence is an indication of a problem

• Microglia does the work instead of the macrophages

Neuroinflammation sequence of events

Injury/infection activates CNS cells

• microglia are activated via PRRs and DRRs

• other cells via direct damage, pathogen fragments

Cytokines cause endothelial activation

Peripheral immune cells, proteins and molecules come into the CNS as BBB is made permeable

• Leukocytes, complement

Inflammation widens and the problem is eliminated

Resolution and restoration of the BBB

• M2 microglia, anti-inflammatory cytokines, tregs (if present)

What is hypersensitivity: mechanisms of neuroinflammatory CNS

• Cells are tuned to function in a highly controlled microenvironment very different than the periphery. Alterations in this homeostasis has disproportionate effects.

• Glia can be quick to activate, but slow to calm down. Molecules common in the periphery can induce them to activate and stay active

What is gliosis/glial scar

Activation and fibrous proliferation of glial cells in injured areas of the CNS

• Can form a semi-permanent structure (scar)

  • The scar serves the purpose of reestablishing a barrier function

  • Composition: reactive astrocytes, microglia, vasculature and scar EMC

• This may persist for months or years, prolonged reaction can form scares easier