Neuro Module 5

Passive Signal Propagation

Passive Signal Propagation

Electrotonic spread of depolarization in the membrane

Active Signal Propagation

Repeated regeneration of depolarization through voltage-gated channels.

Oligodendrocytes

Cells that produce myelin in the central nervous system.

Myelin

Lipid-rich insulation around axons, produced by oligodendrocytes or Schwann cells.

Nodes of Ranvier

Gaps in the myelin sheath where action potentials are renewed.

Astrocytes

Glial cells that regulate brain homeostasis and are diverse controllers of the CNS microenvironment.

Tripartite Synapse

Involvement of astrocytes in synapse formation and function.

Microglia

Immune cells in the CNS that contribute to brain health and disease control.

Microglia Activation

Microglia change from ramified to amoeboid morphology during activation, leading to active phagocytosis and a graded cytokine response.

Blood-Brain Barrier (BBB) Integrity

Microglia activation influences BBB integrity, with pro-inflammatory microglia reducing astrocyte support, leading to leukocyte infiltration, while anti-inflammatory microglia promote astrocyte support and release protective neurotrophins.

Gene

A gene is part of chromosomal DNA that encodes a specific protein, with non-coding regions (RNAs) also playing crucial roles.

Regulation of Gene Expression

Each human cell contains ~25,000 protein-coding genes, and the regulation of gene expression is essential for the diversity of cell types and functions.

Monogenic Diseases

Gene therapies are evolving for monogenic diseases caused by single gene defects, such as Huntington’s disease and Leukodystrophies, which are largely heritable and independent of environmental factors.

Viral Gene Therapy Vectors

Viral vectors like Adenovirus and Adeno-associated virus are used for gene delivery, with episomal vectors being safer for targeting terminally differentiated cells.

Motor Neurons

Lower motor neurons directly innervate skeletal muscles, forming the final common path for conveying movement commands, while upper motor neurons regulate local circuit neurons and alpha-motor neurons.

Motor Unit

A motor unit consists of a motor neuron and the skeletal muscle fibers it innervates, with different motor units varying in size and types of muscle fibers they innervate.

Henneman’s Size Principle

Motor unit recruitment follows a systematic order according to size, with small motor units activated first during weak contractions and larger units recruited as force requirements increase.

Local Circuit Neurons

located in the spinal cord and in the motor nuclei of the brainstem cranial nerves ; they regulate activity of lower motor neurons

Upper Motor Neurons (UMNs)

Cell bodies located in the cerebral cortex or brainstem; essential for initiation of voluntary movements and complex skilled movements; synapse with local circuit neurons and lower motor neurons.

Cerebellum and basal ganaglia

regulate activity of the upper motor neurons without direct access to either the local circuit neurons or lower motor neurons

Basal Ganglia

Suppresses unwanted movements; prepares upper motor neuron circuits for movement initiation; dysfunction leads to Parkinson’s and Huntington’s disease.

Spinal Reflex

Involuntary response mediated through spinal pathways; now viewed as highly modifiable with reflex modulation predominating.

Proprioception

Perception of body position, limb location, and effort in movement; integrates signals from muscle spindles, Golgi tendon organs, joint receptors, vestibular system, and skin mechanoreceptors.

Muscle Spindles

Sensory organs within muscles detecting changes in muscle length and velocity of movement; activated by gamma motor neurons to maintain sensitivity.

Muscle Stretch Reflex

Maintains muscle length through feedback control; detected by muscle spindles to excite alpha-motor neurons for muscle contraction.

Golgi Tendon Organs (GTO)

Distributed in tendons to provide information about muscle tension; negative feedback system to regulate muscle force and maintain steady force levels.

Protective Reflexes

Include flexion reflex pathways triggered by nociceptors; involve polysynaptic pathways and descending regulation to modulate responses.

Motor System Diseases

Include motor neuron diseases, peripheral neuropathies, neuromuscular junction disorders, myopathies, and basal ganglia-related conditions like Parkinson’s and Huntington’s disease.

Contracture

Permanent structural shortening of a muscle or joint due to prolonged hypertonic spasticity.

Babinski sign

Reversal of cutaneous flexor reflex, seen as abnormal fanning of toes and extension of the big toe.

Extensor response

Fanning out of smaller toes in infants due to incomplete myelination of corticospinal pathways.

Lower Motor Neuron (LMN) degeneration signs

Weakened reflexes, flaccidity, muscle cramps, fasciculation, muscle wasting.

Upper Motor Neuron (UMN) loss effects

Spasticity, clonus, muscle wasting, increased tendon reflexes.

Amyotrophic lateral sclerosis (ALS)

Motor neuron disease affecting UMN and LMN, leading to weakness, wasting, spasticity, and hyperreflexia.

Progressive bulbar palsy

Affects brainstem motor neurons causing symptoms like swallowing difficulty, speech loss, and emotional lability.

Primary lateral sclerosis (PLS)

UMN disorder affecting limbs and face, progressing slowly without affecting lower motor neurons.

Progressive muscular atrophy (PMA)

Slow degeneration of lower motor neurons, leading to muscle weakness, wasting, and potential progression to ALS.

Spinal Muscular Atrophy

Hereditary disease affecting lower motor neurons, caused by deficits in the SMN1 gene, leading to muscle weakness.

How it voltage across the membrane affected after injection?

1. Internal Resistance

2. Membrane resistance

What does current leakage depend on?

Membrane resistance and internal resistance

Conduction Velocity =

Speed of impulse propagation

What is conduction velocity inversely proportionate to?

The time constant (smaller time → charge spreads faster)

How can you increase conduction velocity?

Increase axon diameter and increase insulation

What does myelin consist of ?

Condensed phospholipid bilayers helically wrapped around axons

what is the g-ratio?

The thickness of the myelin sheath relative to the axon size

What does a lower g-ratio indicate?

Faster conduction velocity

Saltatory impulse propagation speeds up…

Active signal propagation

In saltatory conduction, the signal …

jumps from node to node

Electrical insulation

enables saltatory impulse propagation (decrease capacitance and increase membrane resistance)

Potassium buffering

promotes sufficiently rapid recovery from repetitive firing → seizure prevention

Trophic support

provides energy requires to sustain repetitive action potential firing

Paranode

Attachment of myelin membrane via Caspr, Contactin & NF155

Juxtaparanode

Clustered voltage-gated potassium channels, Na+/K+ ATPase

Internode

Compact Myelin, Na+/K+ ATPase

Long axons need ____ to function properly

Trophic support

Axonal transport is…

Slow, meaning axons need a lot of energy

What provides trophic support to meet energy needs ot active neurons?

Oligodendrocytes

Oligodendrocytes transfer glycolysis products _____ and ____ to axons through MCT transporters which is metabolised in neuronal ____ (axon) to generate energy required for impulse propagation

pyruvate, lactate, mitachondria

Exosomes transfer proteins and RNAs between….

oligodendrocytes and neurons

_____ myelination is critical for learning

Adaptive

What is the effect of inhibition of oligodendrocytes differentiation?

New skill acquisition, learning and memory are impaired

What is the effect of prolonged decrease in axonal firing?

Decreased myelination of an axon

Myrf

transcription factor driving oligodendrocyte maturation and myelination

What has a longer distance between Nodes of Ravier: Schwann Cells or Oligodendrocytes?

Schwann Cells

Myelin compacting protein of Schwann Cells

P0, PMP2

Myelin compacting proteins of Oligodendrocytes

PLP1, MBP

What is Schwann cell myelin covered by?

A basal lamina

Where are astrocytes located?

Only the CNS.

One astrocyte occupies…

one region alone

What is the role of an astrocyte in homeostasis?

Each astrocyte has local control of homeostasis within the defined area its processes reach.

Extensive interaction and communication through ___ ___ with other astrocytes along ___ ___

Gap junctions, regional boundaries

How do astrocytes communicate?

Through Ca2+ waves triggered by neurotransmitters, gliotransmitters or insult

Astrocyte number, size and connections is proportional to….

brain size and cognitive capabilities

What role can astrocytes play in synapse formation, function, and decay?

Astrocytes can regulate synapse formation, function, and decay through processes such as neurotransmitter recycling and gliotransmitter secretion

Astrocytes regulate ___ ___ and ____ ____ at the neurovascular junction

nutrient supply and osmotic homeostasis

The nutrient supply and osmotic homeostasis that astrocytes maintain includes:

Local regulation of blood flow, regulation of ions pH and water, contributes to blood-brain-barrier integrity

Astrocyte Ca2+ levels control the release of:

Vasodilators and vasoconstrictors

Leber’s congenital amaurosis

Is an early onset severe retinal dystrophy and responsible for 10%-20% of all childhood blindness

3 features of monogenic diseases

Caused by a single gene defect, largely environment and lifestyle dependent, 100% heritable

3 features of polygenic diseases

Multiple genetic alterations combined cause disease, environment and lifestyle triggered, less than 100% heritable

in vivo gene therapy

Delivers the therapeutic DNA or gene therapy vector directly into the patient

ex vivo cell-based gene delivery step 1

extract patient’s stem cells

ex vivo cell-based gene delivery step 2

Add gene therapy vector to stem cell in a dish

ex vivo cell-based gene delivery step 3

Modify genome with therapeutic DNA (replacement, regulation, gene editing)

ex vivo cell-based gene delivery step 4

Expand and test modified cells in a dish

ex vivo cell-based gene delivery step 5

return modified cells to patient

How is ex vivo gene therapy different from in vivo gene therapy?

Ex vivo gene therapy involves integrating viral vectors into the host chromosome, which is passed on with cell division.

What is a characteristic of an episomal viral vector when used in vivo?

It does not integrate into the host genome and is lost in cell divisions.

Are episomal vectors safer?

Yes, but they are used to target terminally differentiated cells that do not divide any longer

properties of the gene therapy vector should…

match the pathophysiological requirements dictated by the disease.

Ex vivo gene therapy diagram

Viral vectors in gene therapy are replication…

incompetent

Three requirements of viral gene therapy vectors

1. Host cell tropism - uptake by the cell

2. Gene expression - transcription in the target cell

3. Immune response - against vector or transgene

Experiment found that promoters in gene therapy vectors can…

restrict transgene expression i.e., different promoters can target different outcomes

Gene therapies for CNS disorders are complicated by…

Brain encased in skull, blood brain barrier and the fact most neural cells do not divide

Autosomal defect

Gene defect on autosome, not sex chromosome

Recessive disease gene

One healthy copy is sufficient to prevent disease

Cause of MLD

mutations in ARSA gene → toxic accumulation of sulfatides in the CNS and spinal cord

Antisense oligonucleotide (ASO) to treat SMA

Are short synthentic oligonucleotides, that elimate/reduce/modify mRNAs, are very stable but struggle to cross BBB

SMN2

A mutated gene duplication of SMN1 with an unknown function, and shows frequent exon 7 skipping leading to a non-functional protein