PNB 3251 Part 2: Motor Systems and Neurobiology

• PNB 3251 Part 2 course information is available from Joseph Loturco at [email protected].
• Office hours are Tuesdays 12:30-2:00 pm or by appointment in PBB 205C.
• The course covers Lower Motor Neuron Circuits, Upper Motor Neuron Circuits, Basal Ganglia and Cerebellum, Visual System 1 and 2, Auditory System, Vestibular System and Sensory Motor Integration, and Neurobiology of Speech & Language.
• Midterm #2 will cover Lectures 9-16.
• Homework 2-1 on lectures 9 & 10 is due by Feb 27th, and is worth 2 points per question for 5 questions.
• Homework 2-2 on lectures 11 & 12 is due by March 6th, and is worth 2 points per question for 5 questions.
• Homework 2-3 on lectures 13 & 14 is due by March 13th and is worth 2 points per question for 5 questions.
• Homework must be on time to receive credit.
• Part 2 Exam on March 27th will cover material from lectures 9-16, and is worth 2 points per question for 35 questions.

Lecture 9 Study Questions

• Define 'motor neuron pool', 'motor unit', and describe the somatotopic organization of motor neuron pools for proximal and distal muscles.
• Describe how different force magnitudes are generated by motor units, consider the role of the motor unit connections to muscles, fused tetanus, and motor unit recruitment.
• Explain the structure and function of the muscle spindle, including what information Group 1a and Group II afferents carry from the muscle spindle, the role of γ-motor neurons to the muscle spindle, and the purpose of coactivation of alpha(α) and gamma(γ) motor neurons.
• Identify the main diseases that cause degeneration of motor neurons, and how ALS affects motor units.
• Explain the structure and function of the Golgi tendon organ and the effect of activating Ib afferents on alpha motor neurons of the same and opposing muscle (flexor / extensor pair).
• Define a central pattern generator (CPG) including how reciprocal inhibition or reciprocal excitation can generate oscillatory rhythms in CPGs, and why CPGs are disrupted in HSP.
• Describe the critical circuit elements needed for CPGs in locomotion, swimming and walking rhythms, generated in the lamprey and mammalian spinal cord respectively, including how reciprocal inhibitory circuits coordinate extensor and flexor activity in limbs.
• Describe how switching between different CPGs can change modes of locomotion.

Skeletal Muscle System

• There are approximately 650 skeletal muscles in the human body.
• Skeletal muscles are made up of multiple muscle fibers, each receiving input from one motor neuron via a neuromuscular junction (NMJ).
• There are "Red" (fatigue resistant) and "White" (fast fatigable) muscle types differentiated by size, color and resistance.

Muscle Contraction Coupling

• Excitation contraction coupling occurs when more calcium in a fiber causes more contraction in a fiber.
• Tropomyosin blocks myosin-binding sites on actin at rest.
• Calcium influx – Ca2+ binds to troponin (TnC), shifting tropomyosin and exposing binding sites.
• Myosin binds actin – Myosin ATPase hydrolyzes ATP, powering contraction.
• ATP binding to myosin causes myosin to release actin, resetting for the next cycle.

Action Potential Rate and Muscle Force Generation

• During fused tetatunus action potentials in muscles keep calcium high, and actin/myosin bands remain contracted.

Motor Neuron Size Principle and Force Generation

• Small motor neurons innervate fewer muscle fibers, generating low force and are known as ‘red muscle’ fibers, which generate small forces, contract slowly, and are fatigue resistant.
• Larger motor neurons innervate more muscle fibers, generating a higher force are referred to as ‘pale muscle’ fibers, generate large forces, contract quickly and are easily fatigued.

Motor Neurons

• Alpha (α) motor neurons (Lower Motor Neurons) located in the ventral horn of the spinal cord and brain stem (head and neck muscles) innervate all striated muscle fibers.
• A single extrafusal muscle fiber is innervated by only one α-motor neuron, but one α-motor neuron innervates many muscle fibers.
• A motor unit is all of the muscle fibers innervated by one motor neuron.
• When voluntary force is increased different and more motor units are recruited.
• A motor neuron 'pool' is the group of motor neurons that innervate all of the muscle fibers within a single muscle.
• Motor neuron pools are somatotopically organized in the spinal cord, and in the brainstem for face and neck muscle control.

Lower Motor Neuron Diseases

• Amyotrophic Lateral Sclerosis (ALS) is a rare progressive neurodegenerative disorder affecting upper and lower motor neurons (1-2 per 100,000).
• ALS is caused by genetic mutations (SOD1, C9orf72, TARDBP, FUS), environmental factors (toxins, heavy metals), and pathophysiology (accumulation of misfolded proteins, oxidative stress, glutamate excitotoxicity, and mitochondrial dysfunction).
• ALS results in muscle weakness, fasciculations, atrophy, spasticity, and eventual respiratory failure.
• There are three FDA-Approved Treatments for ALS which include, Riluzole, Edaravone, and Tofersen.
• Spinal Muscular Atrophy (SMA) is a group of rare genetic disorders (1 in 10,000 births) characterized by the loss of lower motor neurons.
• SMA is caused by genetic mutations in the SMN1 gene, leading to reduced survival motor neuron (SMN) protein levels.
• Types of SMA include SMA Type 1 (Severe, infantile-onset, respiratory failure within the first year), SMA Type 2 (Intermediate severity, delayed milestones), and SMA Type 3 and 4 (Milder, later onset).
• SMA leads to Hypotonia and symmetrical weakness.
• FDA-Approved Treatments for SMA include, Nusinersen, Onasemnogene Abeparvovec, and Risdiplam.
• Poliomyelitis and Post-Polio Syndrome are caused by a viral infection from the poliovirus that causes motor neuron damage in the spinal cord.
• Acute Polio leads to destruction of motor neurons by viral infection, while Post-Polio Syndrome causes gradual loss of remaining motor neurons decades after recovery.
• Poliomyelitis and Post-Polio Syndrome leads to acute weakness, paralysis, muscle atrophy, and fatigue.
• Poliomyelitis was eradicated by vaccination, but is appearing again in small clusters due to challenges in vaccinations in some parts of the world.

Muscle Spindles

• In an example of a question related to ALS which is a neurodegenerative disease that primarily affects motor neurons in the spinal cord and brainstem, leading to progressive muscle weakness and atrophy in which affects a-motor neurons, which are responsible for activating motor units which include a signal motor neuron and all the muscle fiber it innervates. The correct answer would be that surviving motor neurons in the motor pool increase their innervation to compensate for lost motor units.
• Sensory feedback controls alpha motor neurons of muscle length and force.
• Muscle length is sensed by Muscle Spindles, while muscle force is sensed by the Golgi Tendon Organ.
• The Muscle Spindle contains Group I and II afferents (sensory DRGs).
• Sensory output from spindle, Group la afferents are activated by any change in spindle length (Adapting), and Group II afferents fire at a rate proportional to absolute length (non-Adapting) allowing for proprioception, reflex control, and fine motor adjustments.
• α motor neuron contraction of the ends of the intrafusal fibers determines how much the afferent endings of the spindle are stretched and respond.
• Function:Gain Control - High: small stretch produces large effect - Low: small stretch produces small effect.
• Muscle spindle reflex is a Stretch Reflex (myotactic).
• There is excitatory feedback to MN from the spindle afferent of the same muscle, and inhibitory feedback, through interneuron, to motor neuron innervating opposing muscle
• γ α- coactivation maintains la response sensitivity throughout the range of motion.
• Diseases of Spindles and gamma MNs include, Sensory Neuropathies, Myotonic Dystrophy, Inclusion Body Myositis, ALS, Hereditary Spastic Paraplegia, Stiff-Person Syndrome, and Tetanus.

Golgi Tendon Organ (GTO)

• Sensory structure between muscle fibers and tendon and is activated when muscle exerts force on the tendon and collagen fibrils are stretched (mechanosensor).
• Group Ib afferents send input from GTO into spinal cord and brain.
• The GTO reflex is a negative feedback
• Elevated Ib activity will trigger inhibition of the muscle connected to the tendon under high force through activating an inhibitory interneuron in the spinal cord that inhibits the alpha-motor neuron innervating the muscle under tension.
• Ib afferent innervates an excitatory interneuron in the opposing muscle, and thereby increase activity in the muscle opposed to the muscle under high force.
• Reflex prevents damage to a muscle under high tension.
• Opposing muscles are Flexor and Extensors muscles.

Coordinated Movement

• There is Rhythmic Coordinated Activity of Mutiple Muscles during Waking.
• In mammals alternating extensor and flexor activity is regulated during locomotion by inhibitory circuits in the spinal cord.
• There is Muscle Coordination and Central Pattern Generators in locomotion.
• CPG rhythms don't require sensory input, but can be modulated by sensory feedback and descending control.
• Rhythm generating excitatory circuits (R) and reciprocal inhibition by commissural inhibitory neurons (CN) create left right oscillation in lamprey and tadpole swimming.
• Two simple oscillating circuits in CPGs include Reciprocal Inhibition between inhibitory neurons, and Mutual excitation between bursting neurons creating a Rhythm generating group.
• Different SC interneurons are recruited during switching modes of locomotion or gaits.
• Mouse mutants missing different excitatory and inhibitory interneurons have distinct gait disturbances.

Human Disorders Affecting CPG Function

• Human Disorders Affecting CPG function include conditions such as, Stiff-Person Syndrome (SPS) and Hereditary Spastic Paraplegia (HSP).
• Stiff-Person Syndrome (SPS) is an rare (~0.35 per 100,000) autoimmune disease that leads to hyperexcitability of motor neurons, patients have rigid and stiff movements that worsen with attempts to change speed and sudden movements, and is characterized by increased muscle rigidity when attempting rapid movement changes.
• Hereditary Spastic Paraplegia (HSP) is a group of rare genetic disorders (~10 per 100,000) characterized by gait impairments, progressive spasticity and weakness in the lower limbs from degeneration of corticospinal tracts
• Causative mutations in ~80 genes with 40% caused by autosomal dominant mutations in SPG4 (Spastin4) a gene needed for microtubule severing and endosomal trafficking.
• In an example question related to Hereditary Spastic Paraplegia (HSP) in which is genetic testing reveals a mutation in the SPG4 gene, which encodes spastin, a protein involved in microtubule severing that asks the role of central pattern generators (CPGs) in locomotion, the best answer would be Defective microtubule dynamics in corticospinal tract neurons reduce excitatory input to spinal CPGs, resulting in impaired rhythmic stepping.