Motor Systems Flashcards

1
Q

What are the three types of motor behaviour?

A

Reflexes, Rhythmic movements, Voluntary movements

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2
Q

Define reflexes.

A

Involuntary, unconsciously organized patterns of contraction/relaxation, usually elicited by a peripheral stimulus

Spinal reflexes can be used clinically to check function of afferent/efferent pathways.

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3
Q

What factors influence spatial & temporal contraction patterns?

A

Type of sensory receptor, strength of stimulus

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4
Q

What are rhythmic movements?

A

Movements like breathing, chewing, swimming, and running involving alternating contractions and relaxations

  • controlled by circuits in spinal cord
  • can be spontaneous via volunatary control OR entrained by preripheral stimulus
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5
Q

Define entrainment in the context of rhythmic movements.

A

The process of synchronizing one system’s motion or signal frequency to another system

e.g. treadmill

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6
Q

What characterizes voluntary movements?

A

Self-initiated and under conscious control.

Improve with practice - learn how world interacts w/ body (main distinction)

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7
Q

What are the two ways the nervous system learns?

A

Feedback & feedforward control

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8
Q

What is feedback control in the nervous system?

A

Using sensory signals from the body to monitor position of limbs so it can modify position + tension as needed

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9
Q

Fill in the blank: The desired state in feedback control is compared to a _______.

A

Reference signal

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10
Q

What role does the actuator play in the nervous system’s feedback control?

A

It acts to modify position and tension in limbs
e.g. muscle

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11
Q

What term describes the dynamic system that controls execution error when processing sensory input?

A

Gain
- can be altered by providing more or less signal to correct (fine-tuning)

Gain determines the efficacy of feedback systems.

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12
Q

How can gain be altered?

A

Reduced - stability & filter disruptive/slef-generated feedback

Enhanced - facilitate online motor control & movement adaptation

Dysfunction of gain -> many pathologies

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13
Q

What is the effect of high gain in feedback systems?

A

Rapid correction of errors, vulnerability to environmental changes, prone to over-correction, leads to oscillations

High gain can destabilize the system.

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14
Q

What characterizes low gain in feedback systems?

A

Slower correction of errors, less oscillatory behavior

Most physiological feedback processes utilize low gain.

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15
Q

What is the function of sensory gain in animals?

A

Allows fine-tuning of the impact that feedback information has on motor behavioral output

This enhances adaptive responses.

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16
Q

What is feedforward control?

A

The nervous system anticipates future events and initiates pre-emptive strategies.
- acts in adavnce of certain perturbations

Experience plays a significant role in feedforward control.

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17
Q

How do cutaneous receptors contribute during the catching of a ball?

A

They send feedback when the ball is in hand, facilitating muscle contractions.

After impact, rapid stretch of muscles evokes stretch reflex (spinal circuits), opposes overstretch

This helps in adjusting grip and position.

Rapidly adapting - messner & pacinian corpuscles

Slowly adapting - merkel discs & ruffini corpuscles

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18
Q

What is the role of feedforward control when planning to catch a ball?

A

Causes both agonist and antagonist muscles to stiffen the elbow joint, suppressing the stretch reflex

This prepares the body to effectively respond to the ball.

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19
Q

3 main features of feedforward control

A

Critical for fast movements
Relies on NS abaility to predict future based on prior experience
Starts in cortex vs feedback starting from muscles

This refers to the nervous system’s predictive capabilities in motor control.

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20
Q

What are the two features of functional organization in motor control?

A

1) Motor control is hierarchical and distributed
2) Sensory information is processed dynamically and in parallel systems to motor information

This allows sensory input to influence the evolution of movement.

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21
Q

What is controlled at the first/bottom level of the motor hierarchy?

A

Reflexes and rhythmic movements controlled by spinal circuit

Examples include walking and swimming.

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22
Q

What does the second level of the motor hierarchy consist of?

A

The brain stem, which has two descending pathways that project to the spinal cord

Medial des systems deal w/ core muscles (posture)

Lateral des systems deal w/ distal muscles (voluntary directed movements

These pathways are crucial for motor control.

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23
Q

What regulates activity in brain stem descending tracts?

A

The cortex, primary motor cortex and multiple promoter areas

Highest hierarchical level

These areas directly influence the spinal cord as well.

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24
Q

Which structures play a role in regulating, planning, and coordinating voluntary movements?

A

Cerebellum and basal ganglia

They are essential for smooth execution of movements.

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25
What areas project to the motor cortex?
Cortical areas including prefrontal, parietal, and temporal associated areas ## Footnote These areas provide inputs that affect the activation of the motor cortex.
26
Give examples of where stretch and withdrawal reflexes can occur
Stretch - muscles Waithdrawal - cutaneous receptors
27
What is the length range of smooth, cardiac & skeletal muscle?
Smooth: 30-200 um Cardiac: 50-100 um Skeletal: up to 0.3m ## Footnote Smooth muscle fibers can vary in length but typically fall within this range.
28
Describe the appearance and location of smooth muscle.
Mono-nucleated, central nucleus. Spindle-shaped, tapered ends, non-striated Location: lining of the respiratory, cardiovascular, digestive, and reproductive tract Under involuntary control (autonomic NS) ## Footnote Smooth muscle is characterized by its unique structure and locations in various body systems.
29
What is the structure of cardiac muscle?
Mono-nucleated mainly, some van be multinucleated (<5) Striated; branched Located in linign of the heart Self contractile + under involuntary control (autonomic NS) ## Footnote The branched structure of cardiac muscle allows for effective contraction and communication between cells.
30
What is the primary function of skeletal muscle?
Voluntary movement It is elongated & striated, attached to skeleton ## Footnote Skeletal muscle is responsible for movements that are consciously controlled by the somatic nervous system.
31
Describe the organizational structure of skeletal muscle.
Muscle organ -> fascicles (bundles of fibers) -> muscle fibers (cell) -> myofibrils (organelles) ## Footnote This hierarchical structure allows for efficient force generation and contraction.
32
What are striations in skeletal muscle?
Alternation of dark & light bands ## Footnote Striations are due to the arrangement of thick and thin filaments within the muscle fibers.
33
What is the smallest contractile unit in a muscle fiber?
Sarcomere: - interdigitated thick + thin filaments - each myofibril has as many as 20,000 sarcomeres in repeated subunits - thin filaments project from Z bands, thick prject from centre ## Footnote The sarcomere consists of interdigitated thick and thin filaments and is the basic unit of muscle contraction.
34
What happens to the Z lines of a sarcomere during contraction?
Pulled closer together to shorten myofibril ## Footnote This shortening is due to the sliding filament mechanism facilitated by cross-bridges between thick and thin filaments.
35
What are the components of thin filaments in skeletal muscle?
F actin, tropomyosin, troponin ## Footnote These components work together to facilitate muscle contraction and regulate interactions with myosin.
36
What are connectins in muscle fibers?
Fine, thin elastic filaments connecting ends of thick filaments with Z disks ## Footnote Connectins provide elastic properties to the muscle and help maintain structural integrity.
37
What are the two contractile proteins involved in the sliding filament theory?
Myosin (thick) and actin (thin) filaments ## Footnote Myosin and actin are essential for muscle contraction.
38
What is the role of calcium in excitation-contraction coupling?
Calcium is released from cisternae of the sarcoplasmic reticulum, diffuses along myofibrils and binds to troponin -> cross-bridge formation ## Footnote This binding enables cross-bridges to form and muscle contraction to occur.
39
How quickly is calcium released/reuptake to activate thin filaments?
Released very rapidly: 20-50 ms Reuptake also rapid: cross-bridge decrease (80-200ms) ## Footnote This rapid release is crucial for effective muscle contraction.
40
What occurs during low frequency of action potentials?
Twitches due to limited calcium release ## Footnote it allows enough time for calcium reuptake and muscle relaxation.
41
What is the effect of high frequency of action potentials on muscle contraction?
Tetani due to more calcium released -> can be helpful for powerful contractions ## Footnote This results in less time for reuptake and relaxation, leading to summation or fused contraction.
42
True or False: Fused/sustained tetanus can be associated with disease.
True ## Footnote Tetanus affects the nervous system, causing overactivation of motor neurons.
43
Describe the rest stage of the sliding filament theory
Troponin-tropomyosin complexes on thin fils block binding sites on actin, myosin heads ADP bound (cocked) low [Ca2+] in sarcoplasm, no cross bridges between thick + thin
44
Describe the activation phase of the sliding filament theory
Muscle fibre activated via T-tubule AP, Ca2+ released from cisternae of SR. Ca2+ binds troponin -> conformational changes exposes binding sites to cocked myosin heads (cross bridge formation)
45
Describe the sliding of filaments phase of the sliding filament theory
Mech energy from dephos ATP stored in cocked mysoin released -> power stroke. Longitudinal forces pull thick + thin fils into greater overlap (~0.06um), shortening fibre Myosin heads shed bound ADP, resume relexed state but still bound by cross bridges
46
Describe the myosin detachment phase of the sliding filament theory
ATP binds myosin so it detaches from actin binding site, released to form another cross bridge -> sustained contraction
47
Describe the reactivation of myosin phase of the sliding filament theory
Thick fil: dephos of ATP -> ADP energy stored in heads (recocked) Thin fil: high [Ca2+] system remains activated + contraction persists, low [Ca2+] it retrurns to retsing state so myosin heads cocked but cannot form cross-bridges
48
What is the length tension relationship?
100% overlap when contracted, no overlap when fully stretched. Dictated by number of cross-bridge connections available: - too stretched -> less available -> less force - too contracted -> all are occupied -> no additional force available
49
Red muscles
Anti-gravity + postural e.g. standing walking - mainly slow twitch (type I) - resitant to fatigue, small amounts tension for long periods of time - aerobic metabolism, many mt & capillaries, myoglobin rich
50
Pale muscles
Shorter bursts activity, less mt, less myoglobin - mix of fast (type II) & slow twitch
51
Describe type I fibres
- slow contraction (50-110ms) - small force (20g tet. tension) - resistant to fatigue (ox metab, many mt, good blood supply) - recruited first in contraction
52
Describe type IIA fibres
- fasct contraction (25-45ms) - intermediate force (20-60g tet tension) - resistant to fatigue (ox metab + anaerobic - intermediate recuitment order
53
Describe type IIB fibres
- Very fast contraction (<10ms), fast myosin isoform - High force (50-150g), has many large muscle fibres - Fatigue easily (anaerobic metab, glycogen store, few mt) - Recruited last during contraction
54
What is muscle fibre type primarily governed by?
Genetic disposition Training & exercise can enable fibres to shift between type -> hybrids ## Footnote Hybrid fibre types do exist - express more than one MHC type
55
Where do upper motor neurons (MNs) originate and what are their features?
Motor/premotor cortex, axons extend to brai stem + spinal cord - pyramidal cells - glutamatergic transmission - various pathways
56
What are the primary pathways from the motor cortex to lower motor neurons?
* Corticospinal tract * Corticobulbar tract * Corticopontine tract * Rubrospinal tract * Reticulospinal tract
57
What type of transmission is involved in lower motor neuron pathways?
Cholinergic transmission
58
What rule describes the organization of motor neuron pools?
Proximal-distal rule
59
Describe lower motor neurons & where they are located.
Cholinergic transmission, large neurons, cell bodies are covergence of sensory fibres, interneuorns & descending pathways (many inputs) Originate in SC + axons extend down to skl muscle, located in central horn of the spinal cord and cranial nerve nuclei in the brainstem ## Footnote Organised in MN pools - groups fo MNs that supply individual muscles, arranged in longitudinal columns spannig several segments
60
What do medial motor neuron pools in the spinal cord innervate?
Axial/proximal muscles ## Footnote e.g. axial, shoulder
61
What do lateral motor neuron pools in the spinal cord innervate?
Distal muscles ## Footnote e.g. wrists & digits
62
What is a motor unit?
Motor neuron & the skeletal muscle fibre it innervates - forms basic unit of contraction - has 10s to 1000s of muscle fibres ## Footnote CNS controls motor units, not single muscle fibres
63
What is the strength of contraction controlled by?
1) firing rates of MUs (summation of twitches + tetani) 2) recruitment of MUs Recruitment is major mechanism at low force levels, follows size principle ## Footnote size principle - small MNs always activated before large MNs
64
How are motor neurons recruited?
Small MNs recruited first due to small SA (Henneman) Smaller MNs have: - high density electrical inputs (small SA) - high electrical input reistance -> will exceed AP threshold, recurited before large MN ## Footnote Provides graded muscle contraction depending on force needed.
65
What are the 2 main types of lower motor neurons?
Alpha - supply extrafusal muscle fibres, large soma, fast/large myelinated axons -> control muscle force generation Gamma - supply itrafusal fibres (spindle), smaller soma, smaller/slower myelinated axons -> control muscle spindle responsiveness ## Footnote Beta supply intra and extrafusal, more rare
66
Adavantages of the size principle
- Non-fatigable fibres used for most tasks, fatigable fibres used sparingly - Increments in contractile force (recruitment) roughly proportional to current force ○ Fine movements : small increments ○ Grosser movements : larger increments
67
What are peripheral neuropathies characterized by?
Dysfunction of motor neuron axons.
68
What condition is characterized by rapid onset muscle weakness due to autoimmune attack?
Guillain-Barré Syndrome.
69
What can cause autoimmune attack in Guillain-Barré Syndrome?
Preceding infection produces antibodies that target peripheral myelin Associated w/ bacterial/viral infections such as gastroenteritis, EBV, Zika.
70
What are common symptoms of Guillain-Barré Syndrome and how can it be diagnosed/treated?
Numbness, pain in distal limbs, facial weakness, respiratory failure, paralysis. Can be diagnosed w/ CSF analysis & nerve conudction analysis. Treatments: IV immunoglobins, plasma exchange, supportive care, rehabilitation. ## Footnote 5% die, 15% w/ disability
71
What is the primary dysfunction in neuromuscular disorders?
Dysfunction of the synapse between motor neuron and muscle fiber.
72
What is Myasthenia Gravis?
An autoimmune attack on skeletal muscle affecting signal transmission at the neuromuscular junction. Mostly affects women aged 20-40
73
What are the causes of Myasthenia Gravis?
Antibodies specific to nAChR a-subunit on muscle membrane - main immunogenic region between a.acids 67-76 Can also be: Congenital - transfer of AChR antibodies across placenta from mother Inherited - mutations that affect gating, mutated a-subunit of nAChR (V249F), 2 residues below Leu gate
74
What are the three mechanisms by which antibodies affect neuromuscular transmission in Myasthenia Gravis?
* Receptors internalized by endocytosis. * Destruction/simplification of endplate, complement attack reduces junctional folds, synapse widened * Block of ACh binding sites (antibody binding), sompetitive antagonism
75
What is Duchenne muscular dystrophy?
A progressive skeletal muscle degeneration/weakness. Is X-linked recessive for mutant dystrophin. Primarily affects boys, diagnosed w/ Gowers sign, life expectancy = 22 years
76
What is the role of healthy dystrophin in muscle cells?
Links actin cytoskeleton to extracellular matrix, providing support and membrane stabilization.
77
What are the current treatment options for Duchenne muscular dystrophy?
Palliative care BUT early clinical trials of antisense oligonucleotides show motor function improvement. -> induces exon skipping in mutated dystrophin exon
78
What are the 4 classifications of motor unit disease?
1) Dysfunction of motor neuron cell body (motor neuron diseases) 2) Dysfunction of motor neuron axons (peripheral neuropathies) e.g. GBS 3) Dysfunction of synapse between MN & muscle fibre (neuromuscular) e.g. MG 4) Dysfunctions of muscle fibres (myopathies) e.g. DMD
79
80
What types of neurons are contained in the brain and spinal cord?
Relay neurons (interneurons), sensory neurons, motor neurons ## Footnote Relay neurons are entirely within the CNS, while sensory neurons have axons that transmit sensory information, and motor neurons have cell bodies that send signals to muscles.
81
How is the spinal cord organized?
Segmented ## Footnote The segmentation of the spinal cord corresponds to the arrangement of spinal nerves.
82
What is the function of Renshaw cells (RC)? ## Footnote Type of interneuron
Recurrent inhibition of the same motor neuron pool - input is collateral axons of MN ## Footnote Renshaw cells provide negative feedback control to reduce contraction of synergistic muscles and are important for descending control.
83
What are Rexed's Laminae?
Organized into 10 layers Classify the grey matter of the spinal cord based on the arrangement of neurons
84
What are the classifications of spinal cord cells?
Motor neurons, interneurons, sensory neurons ## Footnote Interneurons link sensory and motor neurons and are essential for reflexes and neural circuits.
85
Fill in the blank: The white matter tracts in the spinal cord are primarily composed of _______.
Axons ## Footnote White matter contains myelinated axons that facilitate communication between different parts of the CNS.
86
What is the role of the central canal in the spinal cord?
Contains cerebrospinal fluid ## Footnote The central canal is a fluid-filled space that helps protect and nourish the spinal cord.
87
What is the primary function of the intermediate zone of the spinal cord?
Contains interneurons that link to specific functional motifs ## Footnote These interneurons play a crucial role in coordinating reflexes and motor patterns.
88
How are motor neurons organised?
Retrograde labelling shows MN pools clustered along ristrocaudal axis. MNs innervating axial + distal muscles located along mediolateral axis of ventral horn. ## Footnote - proximal muscles controlled by MNs close to midline - distal muscles controlled by more lateral MNs
89
Pros & cons of electrophysiological classification
+: can link interneurons to specific functional motifs -: expression of functional motifs can be flexible depending on behavioural state
90
What is the function of Ia inhibitory interneurons?
Prevent synergistic & antagonistic muscles working against each other, receive input from muscle spindle receptors -> function to inhibit antagonistic MN motor pool ## Footnote - reduce antagonistic muscle contraction - important for stretch reflex
91
What is the function of Ib inhibitory interneurons?
Prevents excessive muscle elongation, receive excitation from golgi tendon organs (sense stretch) - Ib afferents. --> function to inhibit same MN motor pool, non-reciprocal inhibition ## Footnote - reduce cotraction of synergistic muscles - important for tendon reflex
92
Pro sand cons of developmental genetics classification
+: based on neurodevelopment, used to identify distinct cell types -: can't always map neuronal function to distinct genetic sub-types ## Footnote 11 progenitor domains give rise to cardinal classes w/ unique TFs - RCs make up 5% of V1 class - Ia inhib from V1 (inhibit flexors) & V2B (inhibit extensors)
93
Name the different ascending tracts & describe their function
Dorsal column: - Skin, muscles & Golgi tendon receptors - Fine touch, tactile discrimination, vibrations, control of fine movements Spinothalamic: - Carry nociceptive, temperature, crude touch & pressure from skin to somatosensory area of thalamus - Responsible for quick withdraw reaction to painful stimulus
94
How are descending tracts classified?
Pyramidal: - Lateral corticospinal - Ventral corticospinal Non-pyramidal: - reticulospinal - rubrospinal - vestibulospinal - tectospinal
95
Describe structure & function of corticospinal tract ## Footnote Descending
Originate in upper MN + premotor cortex. Function to control contralateral movements (due to decussation) Lateral: cross over in pyramids, extremity muscles, upper MNs innervate single muscles or small set muscles (fine motor control Anterior/ventral: cross over spinal cord, control in axial muscles (more proximal e.g. neck) ## Footnote Pyramidal
96
Discovery of extrapyramidal tracts & their function
1898 Prus could not stop epileptic motor activity by disturbing pyramids Function to control learned or involuntary movements, muscle tone, posture & reflexes/orienting responses to stimuli.
97
Describe the reticulospinal tract
Controls posture + gross movements, neurons branch extensively contracting many MN pools controlling synergistic muscles. Single axons innvervate muscles on both sides.
98
Describe the rubrospinal tract
Originates in Red Nucleus (pink to Fe/Hb), transmit signals from cerebellum & motor cortex -> controls muscle tone + arm muscles
99
Describe the vestibulospinal tract
Receive info from vestibulococlear crania nerve about angular & linear head accelerations, originates from vestibular nuclei in the pons. Medial - stabilises head position by innvervating neck muscles Lateral - controls 'antigravity' muscles, extensor muscles of leg.
100
Describe the tectospinal tract
Originates in superior colliculus (optic tectum in non-mammalian vertebrates) -> important centre for multisensory & sensorimotor integration Combines info to detect salient stimuli & orient animal towards them
101
Describe myostatic (stretch) reflexes
Monosynaptic: Ia afferent fibres excited by muscle elongation SO excite motor neurons from the same and synergistic muscles to contract (one synapse) Disynaptic: Ia afferent fibers excited by muscle elongation SO excite Ia inhibitory interneurons -> Ia inhibitory interneurons inhibit muscle contraction in antagonist muscles
102
Ipsilateral withdrawal reflex
- noiciceptive-ad fibres excite spinal sensory neurons - spinal sensory neurons indirectly promote flexor muscle contraction via inhibitory & excitatory interneuron ## Footnote Polysynaptic
103
Contralateral withdrawal reflex
- Spinal sensory neurons contact commissural neurons - Commissural neurons indirectly promote flexor muscle relaxation and extensor muscle contraction Responsible for left-right alternation, same circuitry for locomotion
104
How are renshaw cells used for efficient descending control?
Produce recurrent inhibition of activated muscles through MN collaterals Also inhibits Ia inhibitory interneurons, so indirectly excites antagonist muscles ## Footnote Double action controlled by des pathways -> single projection onto RCs
105
Tendon reflex
Stimulation of Ib sensory afferent induces: - non-reciprocal inhibition of muscle at rest - excitation of muscle during walking Ib interneurons + excitatory interneurons controlled by des pathways according to behavioural state (rest vs walking)
106
Genetic features of ALS
5-10% hereditary, remainder sporadic. Very heterogeneous disease, some mutants cause both ALS & FTD ## Footnote Very rare for ALS causing mutations to occur sporadically.
107
What is motor neuron disease?
An umbrella term for a group of neurodegenerative diseases with inconsistent nomenclature ## Footnote Includes conditions like ALS, PLS, PMA, and PBP.
108
What does ALS stand for?
Amyotrophic lateral sclerosis ## Footnote Also known as Lou Gehrig's disease.
109
What is the estimated prevalence of ALS?
~1-2 in 100,000 ## Footnote ALS is considered quite rare.
110
What are the two main types of onset for ALS?
* Limb/spinal onset * Bulbar onset
111
What is the prognosis for limb/spinal onset ALS?
Fatal within 2-5 years of symptomatic onset ## Footnote Limited treatment options necessitate urgent research.
112
What are common clinical symptoms of limb/spinal onset ALS?
* Muscle stiffness * Cramps * Muscle twitching (fasciculations) * Weakness in legs, arms, hands, and feet * Poor grip strength
113
What are the symptoms associated with bulbar onset ALS?
* Dysphagia (swallowing difficulty) * Pooling of saliva (sialorrhea) * Spasm of vocal cords (laryngospasm) * Slow/slurred speech
114
What is the origin of the symptoms in limb/spinal onset ALS?
Corticospinal tract ## Footnote This leads to degeneration of motor neurons.
115
What is the origin of the symptoms in bulbar onset ALS?
Corticobulbar tract
116
What is a common complication of bulbar onset ALS?
Worse prognosis due to respiratory infections
117
What is the main characteristic of motor neuron degeneration in ALS?
Selectively killing neurons prematurely and progressive degeneration ## Footnote Neurons are not regenerated.
118
What are the consequences of degeneration in the corticobulbar tract?
* Wasting * Weakness * Fasciculations
119
Cognitive symptoms of motor neuron disease (ALS)
Episodic memory impairments, 15% develop frontotemporal dementia (FTD) - due to atrophy in frontal & temporal lobes Can also lead to personality changes/language disorders. ## Footnote Episodic memory is the ability to recall past events and experiences, along with the details of when and where they took place
120
SOD1 as a cause of ALS
1st ALS mutant discovered, 10-20% FALS, 1-2% SALS, many different mutants (many missense single a.acid subs) SOD1 is copper-zinc superoxide dismutase 1, antioxidant enzyme that normally hydrolyses superoxide radicals - ubiquitous (cytosol, mt, nucleus & ER) Unclear if toxicity due to LoF or GoF ## Footnote New antisense oligomer (ASO treatment) - Tofersen - Administered via CSF injections
121
C9orf72 as a cause of ALS
~1 in 12 of all cases, most common cause of ALS & FTD Repeat expansion of large hexanucleotide (GGGGCC) - mutation in nc region (intron 1 or promoter) - patients 50% less C9orf72 expression (but not main cause) Expansion still gets TRANSCRIBED, forms folded G quadruplex tricks machiner into thinking it has ATG start codon
122
How does C9orf72 transcription despite expansion cause ALS?
Depending on initiation site, 5 different repetitive dipeptides formed on both strands. -> Dipeptide repeat proteins (DPRs), e.g. AP is alanine-proline Also RNA foci formed from transcript in nucleus. BOTH RNA foci & DPRs form inclusions in brain -> toxicity.
123
What does ALS affect in the motor unit?
ALS affects the whole motor unit, causing motor neuron degeneration and damage to the neuromuscular junction (NMJ) ## Footnote This leads to muscle wastage.
124
How can changes in motor neurons be observed in ALS?
Changes can be observed through physical brain defects or immunohistochemistry ## Footnote Immunohistochemistry allows for the visualization of specific proteins in the tissue.
125
What are the characteristics of ALS patient neurons?
ALS patients have far fewer visible neurons, with less structure and order ## Footnote This indicates significant neurodegeneration.
126
What is common across all neurodegenerative diseases?
Insoluble intraneuronal protein aggregates/inclusions ## Footnote These aggregates are a hallmark of neurodegeneration.
127
What are the roles of ubiquitination and phosphorylation in protein degradation?
Proteins are ubiquitinated and phosphorylated for proteasome degradation, but the system can become overwhelmed ## Footnote This leads to the accumulation of protein aggregates.
128
What happens to TDP-43 in the disease state?
TDP-43 is mislocalized to the cytosol instead of remaining in the nucleus, leading to aggregation ## Footnote This mislocalization is a key feature of ALS pathology.
129
What is the significance of RAN translation in ALS?
RAN translation produces repeat-associated non-ATG dipeptides, which form insoluble aggregates ## Footnote This process contributes to the complexity of protein aggregation in ALS.
130
TARDBP as a cause of ALS
Rare, ~1-3% of all ALS. Encodes TDP-43, an RNA & DNA binding protein primarily found in nucleus. Many roles in DNA repair & RNA processing: - Regulating transcription, translation, splicing >40 mutations (most missense) linked to ALS, majority in glycine rich region of gene (binding domain).
131
Methods of studying ALS
- Post mortem patient tissue, brains & spinal cord - Clinical imaging e.g. PET - Patient blood/CSF samples - In vitro disease models: ○ Immortalised cell lines (Hela cells, difficult to compare to neuron) ○ Human iPSC-derived neurons (derived from fibroblast) ○ Primary cell cultures from animals - In vivo disease models: ○ Rodents, drosophila, zebrafish, C. elegans
132
Function of KO models in ALS ## Footnote Transgenic
Investigate normal function & investigate whether LoF causes disease
133
Function of KI transgenic models in ALS
○ SOD1 G93A mice -> SOD1 pathology, motor phenotype ○ TARDBP mutations OR overexpression of human WT TDP-43 ○ C9orf72 GGGGCC expansions ○ Artificial expression of a single C9orf72 dipeptide (e.g. poly-GR) ## Footnote Can use rotor rod test to test mice motor skills, quantify length it takes to fall off
134
Main 3 causes of neurodegeneration in ALS
- excitoxicity - neuroinflammation - altered axonal transport ## Footnote Many other different causes.
135
Glutamate excitotoxicity in ALS
Too much Glu, binds AMPA/NMDA/kainate Rs causing Ca2+ influx Too much Ca2+: ○ Activation of signalling processes/enzymes e.g. proteases, endonucleases, phospholipases ○ Damage to cytoskeleton, membrane, DNA etc. ○ Mitochondria release toxic free radicals ○ Caspase cleavage -> apoptosis ## Footnote Glu reuptake transport proteins (EAATs) on neurons/astrocytes normally maintain tight control
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Evidence for Glu toxicity in ALS in patients
- Increased Glu in patient plasma & CSF - Reduced expression of glutamate transporters (e.g. EAAT2) on astrocytes in ALS patient motor cortex and spinal cord - Riluzole reduces Glu transmission, only approved ALS drug, modest therapeutic benefit
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Evidence for Glu toxicity in ALS in cell culture
- Cultured motor neurons particularly vulnerable to excitotoxicity compared to other neuronal subtypes - Patient CSF is toxic to cultured motor neurons -> rescued by glutamate receptor antagonists
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Evidence for Glu toxicity in ALS in mice
EAAT2 knockout exacerbates motor impairments and reduces survival in mSOD1 mice, reverse also true
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Axonal transport
Motor proteins (kinesins/dyneins) which bind cargoes & transport along MTs (tubulin polymers), powered by ATP hydrolysis Anterograde transport - away from cell body (kinesins) Retrograde transport - towards cell body (dyneins) ## Footnote Can be viewed w/ live fluorescent microscopy
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Evidence of abnormal axonal transport in ALS in patients
- Mutations in kinesin family proteins linked to ALS (KIR1A, KIR5A) - EM and histopatholoy of ALS patient tissue -> abnormal accumulation of vesicles, lysosomes, mitochondria, neurofilaments, microtubules etc. in motor neurons
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Evidence of abnormal axonal transport in ALS in mice & cells
* SOD1 and TARDBP mutant mice and cells have axonal transport defects * Cargoes are fluorescently labelled and tracked with live-imaging * Cargoes move more slowly/not at all in ALS models * Recent research shows similar phenotype caused by C9orf72 expansion
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C9orf72 expansion on axonal transport
Used patient iPSC MNs, fluorescentally labelled mt for live imaging -> fewer mt oving in human C9orf72 Found that poly-GR & -PR reduced mt motility - Immunohistochemistry shows that the C9orf72 dipeptides bind several axonal tranpsort proteins so cant carry out normal function -> defects ## Footnote Fumagali et al, 2021
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Neuroinflammation in ALS
- Common to all neurodegenerative diseases - Microgliosis in affected brain region: observed by immunohistochemistry/PET imaging, correlated to severity of disease progression - Increased pro-inflammatory cytokines in CSF e.g. IL-1β, IL-6, TNFα, IFN-γ…
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What morphological changes are seen in ALS microglia?
More amoeboid shape - suggesting increased microglial activation in SOD1 ## Footnote Using SHOD analysis
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How does inflammation cause damage?
Genetic evidence supports key role of microglia in inflammation e.g. TBK1, OPTN1 & VCP mutations Inflam cytokines can be toxic to neurons mSOD1 MNs protected by co-culturing w/ WT microglia BUT mSOD1 microglia toxic to cultured MNs ## Footnote IL-2 treatment can benefit
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NLRP3 inflammasome
Large intracellular multiprotein complexes, inflammasome activation -> caspase-1 activation. - Caspase-1 cleaves pro-interluekin-1B -> IL-1B release (inflam cytokine) Linked to other neurodegenerative diseases, NLRP3 inhibition rescues cognition in AD in rodents. ## Footnote NLRP3 binds ASC to activate caspase 1. Activates in response to tissue damage, pathogens or protein aggregation
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Do C9orf72 DPRs activate the inflammasome?
More IL-1B secretion = more inflammasome activation. GR activates NLRP3 in dose dependent manner by cleaving pro-IL-1B ## Footnote NLPR3 KO rescues mobility in GR mice - suggests NLRP3 contributes to neurodegeneration/ALS symptoms, highlights inflammasome as potential therapeutic target.
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What is proprioception?
The perception of joint and body movement as well as position of the body, or body segments in space ## Footnote Proprioception is crucial for balance and coordination.
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Define exteroception.
The perception of external/environmental stimuli acting on the body (e.g touch, vision, sound, smell) ## Footnote Exteroception allows individuals to interact with their environment.
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What are Piezo 1 and 2?
Mechanosensitive ion channels Discovered by Julius & Patapoutian (Nobel prize 2021) Piezo 2 highly expressed in proprioceptive peripheral endings ## Footnote These channels are involved in the perception of mechanical stimuli.
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What happens to Piezo channels upon delivery of mechanical force?
They open. Affects motor coordination, conditional KO in mice where piezo 2 not expressed in dorsal root ganglion proprioceptive neurons -> basic locomotion but impaired limb coordination ## Footnote Normally, these channels are invaginated in the membrane.
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What are extrafusal (EF) fibers?
Fibers that provide force to the muscle and are stimulated by alpha motor neurons ## Footnote These fibers are responsible for muscle contraction.
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What are intrafusal (IN) fibers?
Fibers that lay in parallel to EF fibers, do not provide force, and are stimulated by gamma motor neurons ## Footnote IN fibers are part of muscle spindles and provide sensory feedback.
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What are muscle spindles?
Spindle-like structures made up of intrafusal fibers. - Central MS regions are non-contractile and contain sensory endings (sensory feedback) - Contractile regions of IF fibres used to adjust length. Important to modulate sensory signalling (see gain control section) ## Footnote Muscle spindles are crucial for sensory feedback regarding muscle stretch.
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Summarise the different types of IF fibres, afferent fibres & gamma MNs?
3 types of IF fibres: dyanmic nuclear bag, static nucelar bag, nuclear chain 2 afferent types: Ia sense velocity + length, Il sense length 2 gamma MNs: dyanmic + static ## Footnote Afferent fibers provide information about muscle stretch and rate of change.
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What does aMN excitation in an isometric exercise refer to?
Stimulation of alpha motor neurons only suring sustained muscle stretch
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What is the role of gamma fibers in muscle control?
Adjust gain of sensory feedback from muscle spindles and keep muscle spindle signals within working range
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How can sensory feedback be maintained in muscles?
Muscle spindle length must be adjusted - MS signal changes in muscle length during contraction -> provides sensory feedback for motor control If muscle length change not accompanied by MS length change then sensosry feedback drops to 0
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Fill in the blank: Gamma MNs adjust _______ to maintain sensory feedback.
muscle spindle length
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What are static gamma fibers responsible for?
Increase gain of static sensory response, active during static postures/slow movements ## Footnote Static gamma fibers play a crucial role in maintaining posture and stability.
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What do dynamic gamma fibers do?
Increase gain of dynamic sensory response, active during fast, unpredictable or complex movements ## Footnote Dynamic gamma fibers are essential for quick adjustments during movement.
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What do muscle spindles (MS) signal for?
Muscle length (static) & changes in muscle length (dynamic) Differential modulation of static + dynamic fibres changes sensory feedback by altering balance between static/dynamic response. -> depends on behavioural states ## Footnote Muscle spindles provide critical information about muscle stretch and tension.
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What does gain control of tactile and proprioceptive signaling involve?
Gains dynamically adjusted during behavior, amplifying relevant feedback and suppressing less relevant ones. - proprioceptive feedback -> muscle afferent - tactile feedback -> cutaneous afferent ## Footnote This process helps prioritize sensory information during motor tasks.
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What happens to interneuron responses during movement preparation and execution?
Proprioceptive feedback response is amplified; tactile feedback response is inhibited ## Footnote This differential response is important for coordinating movement.
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What is the significance of Erg3 in muscle fibers?
Expressed selectively in intrafusal muscle fibers ## Footnote Erg3 plays a role in muscle spindle function and proprioception.
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What does the Erg3 mutant mouse model demonstrate?
Provides genetic model of MS degeneration after birth, abolishing sensory feedback - basic walking patterns partially preserved (slow) - fine motor control severely impaired ## Footnote This model is valuable for studying the effects of sensory feedback loss on movement.
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Describe & compare the 2 competing theories for rhythmic pattern generation up until end of 19th century
Chain of reflexes - series of reflex, foot periodically touches/muscles periodically stretch -> tactile + proprioceptive reafference ncecessary Central pattern generators (CPGs) - rhythm gernated centrally -> sensory reafference not necessary
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# ``` ``` ``` ``` Experimental demonstration of CPGs
Brown 1911 in decerebrated cats, leg fixed by clamp, dorsal root cut (no sensory reafference) -> rhythmic flexors (TA) & extensor (GN) alternation emerged soon after dorsal root cut Ficitve motor patterns generated in absence of sensory input in tissue ex vivo. Also observed in vivo after neuromuscular blockers (curarized animals)
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Where are CPGs located in humans?
Brainstem (resp, chewing, swallowing) Spinal cord (defecation, ejaculation + locomotion)
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How do CPGs generate rhythmic patterns?
Expression depends on interaction between 2 main factors: 1. Circuitry - connectivity among cells in the network (synapses/gap junctions) 2. Circuit elements - intrinsic dynamics of individual cells within network ## Footnote Rhythm is emergent property of these interactions
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Common principles of CPG circuitry models
- Distinct CPGs are associated with individual limbs (we know single limbs can generate rhythmic patterns) - Limb coordination (e.g. alternation in walking, near-synchrony in gallop) arises from connectivity among CPGs - Left-right coordination achieved by commissural interneurons crossing the spinal cord midline (extra reading in genetics) - In tetrapod animals (e.g. cats, mice) forelimbs-hindlimbs coordination achieved by long propriospinal descending neurons (LPDNs). - - LPDNs connecting cervical and upper thoracic segments with lumbar spine segments
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Half centres CPG model
Rhythm generation via reciprocal inhibition (interaction of excitatory + inhib interneurons) Rhythm provides alternate excitation of extensor + flexor MNs. Downstream interneuron provides reciprocal inhibition of MNs.
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Limitations of Half centres CPG model
Does not account for experimental observations: - complexity of natural + ficitve motor patterns i.e. some activation doesn/t follow strict extensor/flexor alternation - effects of sensory reafference on phase/duration of locomotor patterns
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Multilevel CPG model
Suggests pattern formation (PF) is an intermediate level between rhythm generator (RG) & MNs RG provides rhythm but PF adjusts specific patterns of MN activations - interacts w/ Ia/renshaw interneurons RG level connects to multiple PF levels -> complex sequential muscle activation ## Footnote extensor & flexor phases can be adjusted w/o affecting cycle duration
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Multiple interacting CPGs model
Within each limb there are separate CPGs for each set of synergistic muscles - Interactions amongst CPGs generate complex activation patterns - Debate over multilevel vs multiple models contribution to locomotion
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IV properties of individual cells
Pacemaker - endogenous bursting of V Bistable cells - plateau potentials Half centres (from Brown model) - spike frequency adaptation
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What is locomotion composed of?
2 phases: stance + swing Proprioception controls timing of stance to swing transition. ## Footnote ○ Walking (stance 65%, swing 35%) ○ Running (stance 40%, swing 30%, float 15%)
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Stance to swing transition
Controlled by sensory reafference at spinal cord level. - decerebrated cats can adjust locomotor patter at different speeds on treadmill Stance associated w/ extensor muscle activation. Swing associated w/ flexor muscle activation.
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Describe hindlimb extension during stance to swing transition
Swing initiated when leg extended. Extending hip initiates flexor burst in spinalized cats - effect elicited in MSs in hip flexors
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Describe hindlimb unloading
Swing initiated when leg is unloaded - in decerebrated cats loading of ankle extensors inhibits flexor burst - Mediated by Ib afferents
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What is the mesencephalic locomotor region (MLR)?
A brain region discovered by Shik, Severin, and Qrlovskij in 1966, involved in locomotion control Low intesnity stim -> walking High intensity stim -> running
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What determines the initiation and speed of locomotion in MLR?
MLR firing rates. - Optogenetic stim at 20Hz evokes locomotion vs lower freq at 10Hz is not effective - Firing rates of individual neurons approx prop to locomotion speed
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What must be accounted for to understand the cellular basis of locomotion control in MLR?
Anatomical and cellular diversity
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What two main regions compose the heterogeneous MLR?
Pedunculopontine nucleus (PPN) and cuneiform nucleus (CnF)
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What types of neurons are expressed in both the PPN and CnF?
Excitatory glutamatergic and inhibitory GABAergic neurons Only PPN expresses cholinergic neurons.
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What is the role of glutamatergic neurons in MLR?
Initiate and drive locomotion
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What is the role of GABAergic neurons in MLR?
Terminate locomotion
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What is the role of cholinergic neurons in MLR?
Modulate locomotion
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What does optogenetic stimulation of glutamatergic neurons reveal about speed behaviours of CnF vs PPN?
CnF evokes a full range of speed from slow to fast locomotion -> firing rate of CnF neurons linearly related to speed PPN only evokes slow locomotion -> firing rate of PPN neurons have complex relationship w/ speed
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What other roles does PPN have beyond controlling locomotion speed?
PPN populations of glutamatergic neurons selectively active in non locomotor behaviours: - rearing, project to spinal cord - grooming & handling , project to basal ganglia Also control posture via body extension ## Footnote Extended posture associated w/ both execution of rearing & locomotion *Body extension is 1st principal component of mouse posture
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What do MRF neurons project to in the spinal cord?
CPGs via reticulospinal tract
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What system is crucial for balance control during locomotion?
Vestibular system
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What are the two types of linear head accelerations sensed by hair cells in otoliths?
* Horizontal * Vertical ## Footnote Sensed by hair cells in otoliths -> utricle & saccule
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Which vestibular nuclei receive information from the internal ear?
* Medial * Lateral * Superior * Inferior
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What types of information do cells in vestibular nuclei integrate?
* Vestibular * Proprioceptive * Motor * Inputs from cerebellum ## Footnote Some vestibular nuclei project to spinal cord via vestibulospinal tracts
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What is the effect of vestibular disorders on patients?
* Postural instability * Reduced ability to respond to unexpected perturbations * Increased variability in locomotor pattern (especially at low velocity)
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What type of accelerations are sensed by hair cells in semicircular canals?
* Yaw * Pitch * Roll ## Footnote Semicircular canacls inc PC, SC & HC
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What does the lateral vestibular nucleus (LVN) control?
Tone of extensor (antigravity) muscles for posture control. LVN neurons project to spinal cord via lateral vestibulospinal tract.
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What is decerebrated rigidity?
Extended & stiff limbs in decerebrated cats. Rigidity reduced after lesioning of LVN
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When do LVN neurons fire more, during locomotion or at rest?
During locomotion ## Footnote Highest during extensor muscle contraction
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Response of LVN to balance perturbations
- Fast EMG response in extensor muscle ~20ms latency - Slower EM co-activation of both flexors + extensors ~50ms latency ## Footnote Effects above are mediated by cell pop in LVN w/ direct projection to spinal cord via vestibulospinal tracts.
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What occurs when there is an ablation of LVN cells?
* Abolishes EMG fast + slow response * Increases postural instability
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What is the role of vestibular reflexes in maintaining balance?
Oppose movements to maintain stable balance
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How can vestibular reflexes be modified for locomotion?
They are transiently downregulated during initiation & termination of locomotion
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Serial model for motor control
Internal/external stimuli forms a goal. Motor cortex plans how to achieve goal + signals to brain stem/spinal cord to induce muscle effectors Disproved by cortical lesions in cats -> still able tom move about well (clumsy) , Bjursten ## Footnote Evolution - lamprey (common ancestor of jawed & jawless vertebrates) analogous to cat experiment, not evolved cerebral cortex vs mammals but still had functioning movements
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Parallel model for motor control
Cerebral cortex evolved + enlarged forming parallel system to existing brain features (brain stem) Both cerebral cortex & brainstem capable of independent muscle stimulation. - cortex can also signal brainstem via corticobulbar tract
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What did Lawrence and Kuypers study? ## Footnote 1968
Looked at reaching/grasping in monkeys after bilateral pyramidotomy (cut CST) After 5 months rehab: Intact: running, walking, whole hand grasping Impaired: independent finger movements to retrieve pellets -> CST signals for distal movement + motor control
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What 2 ways can the corticospinal tract innervate spinal cord neurons? ## Footnote CST - corticospinal tract
- Synapse directly into LMNs -> special to primates (evolution of manual dexterity) - Indirect connections to LMNs via interneurons
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Function of lateral & ventromedial descending pathways
Both groups had bilateral CST lesion. If lateral cut -> whole hand grasping, dexterity lost - basic system for posture + locomotion If ventromedial cut -> impaired locomotion + posture - controls extermities (esp hand)
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Function of the CST
- Mediate control similar to brainstem pathways - Additional capacity for independent finger movement
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Implications for human recovery after major motor system damage
Monkeys 2 months after incomplete lesion of right pyramid: - affected left hand - skilled food retrieval, intact finger movements ## Footnote Resiliency of parallel model
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Functions of the brainstem
Control of trunk & limbs for posture, locomotion, orienting towards salient obects, reaching/grasping. Also has circuits for orofacial behaviours -> breathing, swallowing, whisking (mice/rats)
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What is the main structure for saccadic eye movements/orientation?
Superior colliculus - provides input from retina to visual layer & outputs to brainstem from motor layer
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Describe the circuit basis of orienting eyes
Receptive fields on retina sensitive to visual stimuli - microtimulation in motor layer causes saccade to correpsonding RF location -> SC has motor map, activated by an RF lcoation -> innervates PPRF
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How is eye orientation carried out (effectors)?
Brainstem has premotor neurons (gaze centres). PPRF (paramedian pontine reticular formation) innervated by SC & frontal eye fields, activates LMNs LMNs: nuclei of cranial nerves III, IV, VI for eye movement.
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Use of iDREADDS to inhibit prey capture ## Footnote Inhbitory designer receptors exclusively activated by designer drugs
iDREADDs expressed in NF neurons of superior colliculus in mice. Agonist CNO injected - binds receptor -> K+ channels open inhibitg NF neurons (40% decrease firing rate) - slow orientation
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How are whisking rhythms generated?
Sensory feedback (reflex) OR Central pattern generator in absence of sensory input: small network of neurons whose activity generates more specific movements w/ correct timing & sequences Whisking persists after frontal cortex lesion -> CPG in brainstem (EMG)
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Which part of brain generates different rhythm?
Retrograde tracing - studied inputs to facial nucleus -> vIRT as whisking candidate CPG LMNs: Cranial nerve V - trigeminal Cranial nerve VII - facial Cranial nerve XII - hypoglossal Nucelus ambiguous - airway muscles ## Footnote Vibrissa Intermediate Reticular Formation
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How did Moore et al (2019) determine vIRT as whisking CPG?
EMG -> positive vIRT firing during whisking Is vIRT sufficient? - kaiante injected in vIRT -> whisking rhythm Is vIRT necessary? - electrolytic lesion in vIRT on one side of brainstem -> whisking stopped on corresponding side ## Footnote SO brainstem has premotor CPG that projects to LMNs
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Reflexes, rhythms & voluntary movements
Reflexes - stereotyped responses to specific stimuli (automatic) Rhythms - voluntarily controlled, largely autonomous Voluntary movements - under conscious control, intentional, involve choice, learnable -> primary & premotor cortex located in posterior forntal lobe
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Cytoarchitecture of motor cortex
Nissl stain generated Brodmann areas Area 3b: granular, primary somatosensory cortex Area 4: agranular, includes very large Betz cells, primary motor cortex ## Footnote Motor cortex discovered by Fritz & Hitzig by electrical stimulation of dog forntal lobe -> elicits movement
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What is the primary motor cortex (M1)?
Frontal area where electrical stimulation elicits somatotopically organised movements at low stimulation intensities, located in precentral gyrus.
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Do individual neurons in M1 control discrete muscles?
Neuron doctrine (Cajal) - individual neurons control individual muscles Spike triggered averging EMG for moneky hand muscles -> each neuron activates several muscles SO M1 not precise muscle map as Leyton & Sherrington proposed (1917) -> many M1 neurons contribute to control of each muscle + each neurons contributes to control of several muscles ## Footnote So NO
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Who hypothesised M1 as an ethological action map?
Graziano - long duration macrostimulation to one part of M1 -> coordinated behaviours (hand to mouth action) M1 has zones associated w/ function
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Why do M1 neurons need to operate on a collective basis?
M1-LMN connections are 100-200uV BUT depolarisation required to evoke AP is ~15mV. Individual neurons cannot cause contraction alone. -> population coding
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Population coding vector scheme in M1
Each M1 neuron has preferred direction (PD). Firing rate of each MN contributes to an average of many different neurons PD -> population vector Vectors decoded in monkeys, pop vectors closely matched reaching direction. - explains how precise reaching possible despite imprecise individual neurons
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What is a brain-machine interface (BMI)?
Medical device that measures/alters electrophysiological activity of at neuronal population level. Types of BMI function: restore lost sensory & motor abilities, also regulates pathological neural activity + restores lost brain processing capabilities.
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How do cochlear implants function? ## Footnote Restores lost sensory ability
Bypasses damaged sensory hair cells by direct stimulation of neurons to auditory nerve. They have microphone, sound analyser (frequency decomposition) & a cochlear stimulator electrode array (stimulates each location on cochlear w/ matching component)
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What is the function of a regular basilar membrane?
Frequency decomposition - each part is selective to different sound frequency - base tuned for high freq - apex tuned for low freq Sound makes mem vibrate - max vibration depends on tone frequency
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Summarise the perfomance and utiity of cochlear implants
40-55% monosyllabic words & 70-90% sentences - due to context? - Most widespread and successful BMI - 2008: 120,000 cochlear implants (worldwide) - Many implantees: >90% on tests of sentence intelligibility (quiet conditions)
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Tetraplegia & ALS
Tetraplegia - paralysis of arms & legs Amyotrophic lateral sclerosis Symptoms inc: paralysis, dysarthria & dysphagia Similar to C1 & C7 spinal cord injuries ## Footnote Dysarthria - breathing difficulties Dysphagia - eating difficulties
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BMI schematic for tetraplegia & ALS ## Footnote Restore lost motor ability
Electrode array, decoding algorithm & actuator.
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Work of Moran & Schwartz for motor BMI ## Footnote 1999
Complex movements (spiral) can be decoded from motor cortex activity in monkeys. M1 neurons were recorded & pop vector decoding predicted movements 100ms ahead - potential implications for spinal cord damage tretaments
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Work of Serruya for motor BMI ## Footnote 2002
Monkey M1 recorder w/ utah array - allows recording electrical activity across larger section of the brain joystick task - linear filter used to decode hand movement from M1 activity neural control used to track target -> proof of principle
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Work of Hochberg for motor BMI and its strengths/limitations ## Footnote 2006
Patient w/ spinal cord transect C3-C4 (complete tetraplegia) impanted w/ utah array in M1 arm area. Asked to make imagined movements - algorthm trained to decode imagined M1 activity (Serruya method) Neural control tested - some neurons directionally controlled ~80% accruacy +: 1st demonstration of neural control in humans, perfromance increase 70-90% -: limited complexity, unknown level of practical use
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Work of Wilson for motor BMI & strengths/limitations ## Footnote 2021
Pateints C4 spinal injury, 2 utah arrays implanted in M1 hand area. Imagined handwriting -> asked to handrwite complete sentences, activity recorded + ouput given in real time Algorithm trained to decode characters -> 90 characters per min, 5% error rate (no backspace) +: addresses degrees of freedom limitation, achieve peer typing speed (comparable to texting) -: one participant, needs deciated lab
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Brainstem and cortical control of speech
Brainstem: Facial muscles innervated by many peripheral nerves (facial VII, hypoglossal XII, trigeminal V & laryngeal). LMNs & premotor nuclei located in brainstem Cortical: M1 face area lesion -> pseudobulbar palsy, loss of voluntary control over speech Broca's areas (44-45) involved but not sufficient - Broca's aphasia impaired ability to produce language
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Work of Moses for communication BMIs in ALS ## Footnote 2021
ECoG array implanted over left sesnorimotor cortex in patient w/ stroke in Pons age 20. Word & sentence task -> decoded by deep learning algorithm to classify words from neural signals Isolated words 47% correct, sentence decoding had 61% error rate & 26% w/ language modelling - 15 words per min ## Footnote Language model reduced error rate
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What is electrocorticography (ECoG)?
Electrodes placed directly on brain surface, more invasive but more reliable/recordable signals - cover boths sections of motor cortex
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Describe an example of a BMI for locked in syndrome (ALS) ## Footnote Chaudhary (2022)
Only limited eye movement remains, can worsen to no movement at all (completely locked in syndrome) Coupled neural recording system to a speaker: measured AP firing rate + mapped it to tone generator (high/low freq sound) - Tasked w/ matching target tone, so had to learn to control firing rate - Provided analogous communication to blinking/yes or no Binary communication translated into word generation via matching tone frequency to letters sequentially -> form sentences. - Intelligible output on 44/107 days Very slow speed, 1.08 characters/minute
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Successes of neural control BMIS
- provides insights into neural coding - novel treatments of severe paralysis - proof-of-principle established - progress in refining methods
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Limitations of neural control BMIs
- studies ar eof single participants - systems cannot be used independently by caregivers - comercialisation required
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What are the 5 types of eye movements?
Saccades Smooth pursuit Vergence Vestibulo-occulomotor movements Optokinetic ## Footnote 6th fixation system holds eyes still during intent gaze
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Describe saccadic eye movevements
Fovea shift rapidly to peripheral target - variable distance, rapid, both eyes move together. Up to 900 degrees/second - stereotypical waveform w/ smooth increase + decrease in eye velocity. - distance moved determines velocity -> cannot voluntarily change velocity of saccades (only direction + amplitude). - saccades also made to auditory + tactile stimuli.
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Describe smooth pursuit eye movements
Requires moving target to drive it, much slower than saccades max velocity of 100 degrees/second. - Calculates how fast moving target is + adjusts accordingly. Very different control system to saccades - Eye moves away from target before saccade as latency of pursuit system shorter than that of saccade ## Footnote Pursuit movements begin adjustments earlier
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Describe vergence eye movements
Eye moved in oppsoite directions so image positioned on both fovea. Smooth but disconjugate: - eyes rotate inwards (converge) if object comes closer - eyes rotate outwards (diverge) if object moves further away
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What 3 axis of rotation define eye orientation?
Horizontal: adduction (away from nose) & abduction (towards nose) Vertical: elevation & depression Torsional: intorsion (top of cornea towards nose), extorsion (top of onrea away from nose)
263
What 6 muscles are attached to each eye?
4 rectus & 2 oblique: Medial rectus adducts eye, lateral rectus abducts eye. Superior/inferior rectus/oblique muscles control vertical & torsional movements
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What 3 cranial nerves control extraocular muscles?
Abducens (VI), Oculomotor (III) & Trochlear (IV) ## Footnote Nuclei in brainstem
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What can cause diplopia?
Damage to crainial or extraocular muscles/nerves. Causes fixed image to no longer fall on same locations of both retina. -> double vision
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What results from damage to the 3 cranial nerves that control exraocular muscles?
- Damage to abducens nerve -> damage to lateral rectus, loss of abduction beyond midline, causing diplopia - Damage to oculomotor nerve -> loss of eye movements medially or upward from mid-position, leads to drooping eyelid, mydriasis & downward + lateral gaze - Damage to trochlear nerve -> skew deviation (eyes at different vertical positions in orbit), leads to deficits in intorsion/extorsion, elevation/depression + torsional deficit.
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Step pulse response of oculomotor neurons
Extraocular MNs signal eye position & velocity. Firing rate of MNs increse during saccade in pulse of activity (0->900degree/sec) Baseline MN firing rate changed to reflect new position at end of movement -> step change in intensity ## Footnote height of step = size of saccade height of pulse = speed of saccade
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Vertical vs horizontal saccade generation
Horizontal - generated by MNs in pontine reticular formation Vertical - generated by MNs in mesencephalic reticular foration (midbrain)
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Which neurons are involved in activating pulse generation? ## Footnote For horizontal movements
Medium-lead burst - direct connections to oculomotor neurons Long lead burst - drive medium-lead burst cells & receive inputs from higher centres
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Which neurons are involved with inhibition/regulation of pulse generation?
Omnipause cells fire continuously, except around time of saccaden - GABergic & inhibit medium-lead burst neurons Inhibitory burst - driven by medium-lead burst cells & suppress contralateral abducens neurons ## Footnote Saccadic movement needs both omnipause cells to pause firing & excitation of long-lead burst cells -> stability
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What neurons control the step response in oculomotor neurons?
Neurons in medial vestibular nucleus & the nucleus prepositus hypoglossi. ## Footnote -> lesions cause drifting of eyes back to central position
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Saccadic control by superior colliculus (SC)
Motor signals provided by pontine & mesencephalic burst cells BUT their output controlled by SC SC is a layered, multi-sensory structure on dorsal surface of midbrain -> upper layer receives visual signals from retina + lower layers process multiple signals from other regions of brain. ## Footnote Also called optic tectum, highly conserved & relatively smaller in size as forebrain enlarges in more complex animals
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Neurons for smooth pursuit
Found in vetsibular nucleus, nucleus prepositus hypoglossi & the pons. - all receive inputs from cerebellum which correlate w/ speed of tracked object Receives major input from visual areas + frontal eye fileds (FEFs)
274
Describe the layered structure of the superior colliculus (SC)
Superficial layers - more visual, largely sensory Intermediate & deep layers exhibit more sensory-motor control
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Describe the sensory inputs to the superficial SC
Primarily visual, main target of retina. >90% of all RGCs project to SC in mice. Supplemented by extensive projection from visual cortex. Notable retinotopic order of inout & processing centres
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# ``` ``` Summarise the extensive inputs to intermediate/deep SC
- Visual (FEF, lateral interparietal cortex) - Auditory/somatosensory (trigeminal complex, barrel cortex, inferior colliculus, nucleus of the brachium of the inferior colliculus) - Recent experience (FEF, M2) - Target value (Substantia nigra) - Saccade control (FEF, cerebellum)
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Map alignment in the SC & its functional benefits
Different layers in SC have mutually aligned maps of space for each sensory modality. Benefits: - allows multi-sensory facilitation -> different inputs dirve one enhanced response (detect biologically relevant events) - simpler transformation from sensory cues to motor commands (e.g. orientation)
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Superior colliculus functions due to diverse inputs/outputs ## Footnote Very extensive outputs of SC
- Receive, process & integrate sensory info AND register it spatially - Direct appropriate behaviour e.g. distinct SC stimulation -> orientation & defensive behaviours
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Does the SC control eye movements?
Yes - superficial layer neurons code for oculomotor acitivity ~1/2 increases activity if animals going to make saccade to stimulus in its receptive field
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SC features for eye movement
Distinct movement-related cells in SC fire prior to saccades of specific size & direction. - Movement related neurons in SC have movement fields - Actual eye movements encoded by population code - individual movement cells have large overlapping fields - Most rostral portion of SC is fixation zone -> maintains fixation/focus. ## Footnote Can command saccade generators in brainstem
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Which areas of the brain stem are saccade generators?
Mesencephalic & pontine reticular formations - receive commands from SC
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Describe the relationship between excitatory and inhibitory projections to the SC?
Frontal eye fields (FEF) & lateral intraperietal area (LIP) send provide excitatory projections. Inhib projections form substantia nigra - BUT suppressed by caudate nucleus (excited by FEF) ## Footnote FEF dircetly excites SC + indirectly releases it from suppression bu sub. nigra
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Tetanus neurotoxin for studying oritentng responses by SC | TeNT
TeNT silences all neurons in SC -> increased time taken to attack & capture prey in mice SC involvement in orientation
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What is chemogenetics?
Technique that uses genetically engineered receptors to modulate neural activity by binding to specific, otherwise inert, small molecule drugs -> allowing for precise and reversible control of cell populations and neural circuits
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Chemogenetics to study orientation by SC
Gi coupled GPCR activated by CNO -> decrease in neuronal firing (les cAMP, less Ca2+, K+ efflux) Silenced WF neurons - prey detection & approach initiation was disrupted but orienting still intact i.e. took long time to notice cricket. Silenced NF neurons - no impact on distant approach, impaired orientation + interception -> increased capture time | WF - wide field, NF- near field, PV - parvalbumin ## Footnote CNO - Clozapine N-oxide, selectie silencing
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How is the SC involved in defensive reponses?
Fleeing - SC encodes loop stimuli response in layer specific way - Cells in superior layer fire more than dorsal/deep layers which are far more specific in response - Strong habituation in deep layers (reflected in behaviour)
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Optogenetic inhibition of SC to study fleeing
Light can activate iChloC, inhibiting firing Expressd in medial SC -> no fleeing response, glutamatergic dmSC inhibition reduces escape prob Expressed in dPAG -> threat detected but animals freeze, PAG may initiate escape behaviour - prominent output of SC (61% of innervation) | iChloC - specific Cl channel dPAG - dorsal periaqueductal grey
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What are the LPTN and PBGN?
Outputs of the SC: LPTN - lateral posterior thalamic nucleus PBGN - parabigeminal nucelus (projects to PAG) BOTH innervated by PV neurons from SC
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Optogenetic activation of PV neurons to study fleeing
PV neurons activated + drive opposite motor responses - LPTN activation stops movement (freezing behaviour) - PBGN activations induced fleeing response So their output pathway interaction determines behvaioural motor responses to same stimuli
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What is the vestibular system?
Determines which way is up/down & direction of movement 5 organs of vestib labyrinth independently measure linear + angular acceleration of head. Output of organs flows to vestibular nuclei in brainstem -> control of posture & balance
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What are the 5 organs of the vestibular system?
Utricle (horizontal) and saccule (vertical) transduce linear accelerations of head 3 semi-circular canals transduce angular accelerations of the head. - Combination measures angular and linear accelerations along any axis ## Footnote Semi-circular: anterior vertical, horizontal, posterior vertical
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What is the role of epithelial cells in vestibular organs?
Produce endolymph via ion pump action - extracellular fluid that washes over apical surfaces, rich in K+, poor in Ca2+/Na+
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Hair cell structure & conformation in vestbular system
5 clusters (1 per organ) -> flask shaped, array of cilia at apical ends & kinocilium at end of array Tip link connects end of stereocilium to side of adjacent, longer stereocilium - physically connected to ion channel at 1 end
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Mechanoelectrical transduction by hair cells
Deflecting/moving cilia stretch the tip link -> cation channel opens - Stereocilia deflected towards kinocilium -> ion channels open -> depolarisation -> increased transmitter release. - Stereocilia deflected away from kinocilium -> ion channels close -> hyperpolarisation -> reduced transmitter release.
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Can hair cells send action potentials?
No, they only release NT to underlying neurons (increasing firing rate) Some APS may be fired in resting state due to leakage
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Inputs and outputs of vestibular system
Inputs: brain stem affects sensitivity to perturbations -> hair cells are strain gauges, tip link is a mechanical spring protein Outputs: 8th cranial nerve has ~20,000 myelinated axons, most hair cells fire tonically & phasically - encode info about abrupt & sustained accelerations & translations of the head ## Footnote CN VIII is vestibulocochlear nerve
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Structure of otolithic organs
Utricle & saccule have macula that contains hair cells. Stereocilia at apex of hair cells extend into endolymphatic space + attached to gelatinous sheet (otolithic membrane) -> covers entire macular. Octoconia embedded in + lie on otolithic membrane -> fill endolymphatic cavities of utricle & saccule Detect linear acclerations ## Footnote utricle has ~ 30,000 hair cells vs ~16,000 in saccule
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What are ocotonia?
Fine, dense calcium carbonate particles - embedded in + lie on otolithic membrane. - These fill endolymphatic cavities of utricle & saccule
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What happens when the head undergoes linear accleration?
Membranous labyrinth moves (its fixed to skull) SO otolithic membrane free to move within saccule/utricle -> inertia causes it to lag behnd head movement Otolithic membrane shifts relative to underlying epithelium.
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Transduction of horizontal accelerations and utricle orientation
Movement deflect hair bundles -> electrical response, NT released. Macula of each utricle oriented to lie in horizontal plane - axes of greatest mechnosensitivity lie in all planes SO acceleration acitvates one group of cells & suppresses oppositely oriented cells (intermediate ones not affected) -> output from each utricle is rich, complex + redundant representation of any acceleration in horizontal plane. ## Footnote Redundancy of otolithic organs (many different orientations)
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Saccule orientation
Vertically, very sensitive to vertical accelerations (gravity changes). Some saccular hair cells attuned to horizontal acceleration in A-P axis (redundancy)
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Can head tilting activate utricle hair cells?
YES - determination of what happened depends on angular acceleration signal by semi-circular canals
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What is angular acceleration and what detects it?
When object alters rate of rotation around axis. Detected by 3 semi-cricular canals -> closed tubes filled w/ endolymph, extnd from otolithic organs - also detect acceleration via endolymph motion
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Semi-cricular canals structure
Use endolymph mass to generate response. Felatinous diaphragm (capula) spreads across canal in widest region (ampulla) Capula attached to epithelium except at ampulla crista -> where its penetrated by stereocilia of~7,000 hair cells
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How is angular acceleration detected?
Acc moves endolymph -> presses against capula, bowing movements Bowing stimulates embedded hair cells, oriented in same direction. Angular acc in one direction excites but opposite direction inhibits
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# ``` ``` How are all type of angular accelerations detected?
-> 3 canals almost precisely perpendicular to each other SO represent angular accelerations about 3 mutually orthogonal axes Canals act mainly in pairs e.g. head movement left/right detected by left + right horizontal canals. e.g. head turns left, left horizontal canal hairs activated/right are inhibited ## Footnote A-P combination in right & left ears allows complex detection
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What causes dizziness?
Fluid rotates at same speed as rotation, so continue pushing hair cells when rotations has stopped
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Vertigo ## Footnote Spinning sensation
Damage to either labyrinth - conflicitng info from 2 ears worse than 1 set of signals -> disorientation CNS associates specific motor behaviour w/ each vestib pattern so unsual vestib responses causes protective/erroneous reflex
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Menieres disease
Receptor cells of vestib labyrinth affected - sproadic, relapsing vertigo (associated w/ tinnitus & distorted hearing) Cause unknown. Possible poor endolymph drainage (oedema) -> epithelial damage. - normally drains via endolymphatic duct before reabsorption into spinal fluid ## Footnote Surgical implant shunts bypass drainage port - can work
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Name 2 vestibular reflexes
Vestibulo-ocular - keep images on eyes still when head moves Vestibulospinal - enables skeletomotor system to compensate for head movements Vestib reflexes compensate for head movements & motion perception in space
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What are the 4 nuclei in the vestibular complex?
Main inputs from vestib labyrinth, located in medulla, project to cerebellum, basal ganglia & spinal cord. 4 nuclei: medial, lateral, superior & descending -> send outputs reticular & spinal centres for skeletal movements, vestib regions of cerebellum & oculomotor nuclei
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Superior & medial nuclei
Inputs mainly from semi-circular canals. Outputs to spinal cord & occulomotor centres. Medial nuclei - excitatory neurons Superior nuclei - inhib neurons - Both help generate gaze reflexes
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Lateral nucleus
Inputs from semi-circ canals & otolith organs. Outputs mainly to lateral vestibulospinal tract. - Involved in postural reflexes
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