Neur 241- Exam Three

Clinical features of PD (2)

Postural instability

Brachycardia

Postural instability in PD; cause, timing

Loss of postural reflexes results in a stooped posture

Typically occurs late in PD, so can be useful in distinguishing alternative forms of PD in which it is an early feature

Pathological features of PD (2)

Lewy bodies

Loss of DA neurons in the substantia nigra

Lewy body definition

Abnormal aggregation of proteins found intracellularly

Lewy body relationship to PD

High coincidence, although can have LB w/out PD and vice versa (for example, found in frontotemporal dementia)

Unclear if they cause PD or if they are a downstream effect

Lewy bodies and a-synuclein

The most abundant protein found in lewy bodies

Normally is non-folded and soluble, present at the synapse

When folded into filaments, stimulates the misfolding of other a-synuclein (simular to prion model)

a-synuclein and mitochondrial breakdown

Body attempts to breakdown a-synuclein filaments; however, components of the mitochondrial breakdown are especially toxic

Loss of DA neurons in the substantia nigra relationship to PD

All individuals w/ PD experience loss of DA neurons in the SN (that project up to the striatum in the nigrostriatal pathway)

DA neurons and neural structures (+ functions) impacted

Dopamine producing areas (substantia nigra and ventral tegmental) found in the midbrain

SN is important for motor control

Basal ganglia (where SN projects to) is important for smooth, continuous movement

Plasticity and manifestation of PD

Brain’s plasticity allows for some coping after loss of DA neurons

After 50% lost, individuals become symptomatic

Reasons for vulnerability of DA neurons

1. Highly branched, long axons (perhaps millions of branches for one axon), presenting mitochondrial burden (high delivery and energy expense)

2. Tonic pacemaker cells (fire constantly even without excitatory stimuli, at rate of 2-10 times per second)

3. Calcium load (voltage-gated Ca²⁺ channels used for pacemaker oscillations transport calcium, otherwise found in low intracellular concentrations, putting burden on mitochondria to uptake excess Ca²⁺)

PD and edge-tipper theory

DA neurons in SN function on the edge of what is possible for neurons

Presence of genetic or environmental factors tips them over the edge

Paraquat

Toxin that specifically kills DA neurons by killing mitochondria

Often used to model PD in mice/rats

(Other environmental toxins — NPTP — etc. have similar effects)

PINK1 and PRKN

Recessive genes that code for proteins important for mitochondrial control through mitophogy

Implicated in spontaneous and familial PD

Breakdown occurs over time — importance of age as a risk factor

Mitophogy

Engulfing of defective mitochondria

PINK1 and PRKN disrupt this process such that DA neurons die

Dominant and recessive PD genes

Dominant mutation that favors misfolding of a-synuclein (familial PD)

Recessive mutations that disrupts mitochondrial control, PINK1 and PRKN (familial and spontaneous PD)

“Vicious Cycle” theory of PD

A self-amplifying pathological feedback loop between mitochondrial dysfunction and a-synuclein aggregation:

1. Mitochondrial impairment & oxidative stress: (damaged mitochondria promote the misfolding and aggregation of a-synuclein)

2. a-Synuclein toxicity (resulting from misfolding) disrupts motochondria structure

3. Progressive neurodegeneration (dysfunctional mitochondria drives additional a-synuclein misfolding)

Types of treatment options for PD (3)

1. Boost DA signaling

2. Deep brain stimulation

3. Generate DA neurons

Boosting DA signaling as PD treatment

Use L-DOPA to ensure whatever DA neurons are left (likely 50% already gone) have all the DA precusors

Useful for easing symptoms, but doesn’t prevent progression or cell death

Deep brain stimulation as PD treatment

Attempt to replicate input of pacemaker cells with electrode placed in basal ganglia

Can temporarily aliviate motor symptoms, but doesn’t stop disease progression

Generating DA neurons as PD treatment

Pluripotent skin stem cells (treated with neurotrophic factors used to induce pluripotence) are injected into basal ganglia to see if they can become DA neurons

Individuals with ALS usually die from ______

Respiratory failure (when diaphragm is paralyzed)

____% of ALS cases are sporadic, compared to early-onset familial

90%

ALS definition

Progressive paralytic disorder characterized by degeneration of motor neurons in the brain and spinal cord

ALS prognosis

Typically 3-5 years

Relationship between brain/spinal cord and motor system in ALS

Not technically innervating muscles, but considered motor neurons because they are part of the circuitry

Pyramidal neurons, definition and disease connection

Neurons found in the motor cortex; implicated in upper motor neuron ALS

“True” motor neurons, definition and disease connection

Motor neurons located in the spinal cord gray matter; implicated in lower motor neuron ALS

Symptoms of upper motor neuron ALS (clinical and pathological)

Muscle stiffness and/or spasticity

Thinning of white matter in spinal cord (“sclerosis”)

Symptoms of lower motor neuron ALS (clinical and pathological)

Spontaneous muscle twitching and then muscle degeneration after long period without input (“amyotrophic”)

Thinning of ventral roots exiting the spinal cord

Bulbar neurons; definition, disease connection, and symptoms

Motor neurons found in the medulla that innervate cranial nerves

Can be implicated in both upper and lower ALS

Difficulty chewing, speaking, or swallowing

Genetic mutations associated with ALS (3)

1. C9ORF72

2. SOD1

3. TDP-43

ALS genes involved in protein aggregation into inclusion bodies (misfolding)

SOD1

TDP-43

ALS genes involved in defective RNA processing and granule aggregation

C9ORF72

TDP-43

RNA processing defects in ALS; definition and reason for toxicity

When DNA repeats during replication gets copied into RNA during transcription, RNA also shows the repeat and aggregates

Dual toxicity: loss of regular splicing function of the RNA, and addition of RNA globules/abnormal proteins

Symptom management in ALS

No cure.

Feeding support — nasogastic feeding, eventually insertion of a direct gastronomy tube

Ventilation support — noninvasive support, eventually a tracheostomy

Sound definition and hearing definition

Vibrations in the ear

Detection of oscillations

Encoding volume and pitch

Increased amplitude (which causes larger change in pressure pressure) for louder sounds

Increased frequency of oscillations for higher-pitched sounds

Pure tones vs. harmonic tones

Sounds with a single frequency vs. multiples of a tone (440-880 Hz)

Timbre

How many harmonics are present

Structures of the outer ear

1. Pinnae

2. Ear canal

Pinnae, definition and function

External portion of the ear

Funnels sound into the ear canal

Purpose of the shape of pinnae

Helps provide cues about direction and distance of sound

Ear canal, definition and function

Tunnel between outer ear and tympanic membrane (eardrum)

Channels sound to vibrate tympanic membrane

Parts of the middle ear, definition

Cavity between tympanic membrane and cochlea

Tympanic membrane (eardrum)

Ossicles (malleus, incus, stapes)

Tensor tympani muscle

Stapedius muscle

Oval window

Round window

Ossicles, definition and function

Series of three bones (malleus, incus, stapes)

Concentrates sound from tympanic membrane to oval window

____ pushes on the oval window

Stapes (stirrup)

Oval window, definition and function

Membrane-covered opening that channels vibrations to cochlea

Vibrates to cause movements in cochlear fluid, participating in first step of transduction

Tympanic membrane (eardrum), definition and function

Membrane that seals the end of the ear canal

Transmits sound from outside to the ossicles

Tensor tympani muscle and stapedius muscle, connection points and functions

Tensor tympani connects to malleus, stapedius connects to stapes

Contract to dampen amplitude (perceived loudness) before body makes a sound, such as coughing (FAST)

Parts of the inner ear

Cochlea (inc. vestibular canal, middle canal, and tympanic canal)

Basilar membrane

Organ of corti

Cochlea, definition, function, and parts

Long rolled-up tube w/ three parallel canals

Converts vibrations into neural activity

Includes vestibular canal, middle canal, and tympanic canal

Structures connecting middle ear to inner ear

Oval window pushes into vestibular canal, which has continuous fluid with the tympanic canal

Basilar membrane, location and function

Between middle and tympanic canal

Ripples/deflects

Organ of corti, location, parts, and function

Sits atop basilar membrane

Includes tectorial membrane, outer hair cells, and inner hair cells

Receptor system that transduces

Hair cells, location, makeup, and function

Connect basilar and tectorial membranes

Made up of stereocilia

Transduce basiliar membrane movement into electrical signals

Mechanosensitive ion channels in ear

Ca²⁺ channels within hair cells that bend and open in response to touching by sterocilia, releasing neurotransmitter

There are no specialized hearing neurons (T/F)

True!

Bases of hair cells connect to _______

Vestibulochoclear nerve

Location of IHC compared to OHC

IHC are closer to the central access of the cochlea, found in a single row down the organ of corti

OHC (efferent) function

Change stiffness of basilar membrane, in order to affect perception of frequency

OHC modify the length of stereocilia, which affect BM stiffness when made longer

IHC function (afferent and efferent)

Afferent encode sound info to brain (direct perception of sound)

Efferent have postsynaptic regulatory role on IHC (can synapse onto afferent fibers to “turn down” responsiveness)

OHC (afferent) function

Send info to the brain about mechanical activity (so that it can be modified/adjusted)

Basilar membrane and encoding frequency

Encodes different pitches by place coding; low frequencies show largest deflection at the end, and high frequencies show largest deflection at the base

Where there is greatest deflection, higher number of hair cells get bent, opening more ions channels and increasing frequency of action potentials

Neurotransmitter of IHC and OHC

IHC use acetylcholine

OHC use glutamate

Relationship between frequency of tone stimuli and threshold in dB

V shaped curve, with lowest thresholds at the preferred frequency of particular neurons

Information post-transduction (hearing)

1. Cranial nerve eight (vestibulochoclear)

2. Brainstem, specifically cochlear nucleus (between pons and medulla)

3. Synapse w/ interneurons at cochlear nucleus

4. Cross midline at cochlear nucleus (most do, some don’t, which is useful for detecting source of stimulus)

5. Project to superior olivary nucleus of pons

6. Inferior colliculus of midbrain

7. Medial geniculate nucleus of thalamus

8. Auditory cortex (located in the temporal lobe)

First projection in hearing system to receive binaural inputs, importance

Superior olivary nucleus

Brain compares strength from the sides to determine source

External noise vs. speech activation in temporal lobe

(Using f-MRI scans) Pure tones/noise activate the primary auditory area

Speech sounds activate the primary auditory area, as well as other auditory cortical regions

Types of deafness (3)

1. Conduction

2. Sensorineural

3. Central

Conduction deafness, problem and solution(s)

Sound vibrations fail to make it to the cochlea, usually due to a middle ear problem

Ossicle implants

Sensorineural deafness, problem and solution(s)

Sound vibrations are not converted into neural activity that can be projected to the brain, often due to problems with the cochlea

Damage to hair cells of cochlea results in retracted stereocilia that are no longer embedded in the tectum

Damage to the basilar membrane corresponds to the pitch that damaged it

Cochlear implants

Cochlear implants

Coiled electrode placed in the cochlea, controlled by a microphone on the outside of the head

Useful in children especially, because neural circuits will eventually atrophy if not used

Central deafness, problem

Damage to auditory structures in the brain

Safe level of noise (in dB)

Below 90 dB

Three axes of the semicircular canals

Pitch (forward/backward)

Yaw (upright left/right)

Roll (laterally left/right)

Mechanism of balance

Fluid in semicircular canals resists movement except in the same plane that head moves in

As fluid moves, hair cells in ampullae at the base of the canals excite the vestibulcochlear nerve

Ampulla, location and function

Found at the base of each semicircular canal

Contain hair cells that project up the the cupula, which bend and open ion channels

(Conceptually simlar to the organ of corti)

Utricle and saccule, location, anatomy, and function

Found at base of semicircular canals, below ampulla/cupula

Contain odolythic membrane, made up of calcium carbonate crystals

Use mass to deflect nearby hair cells, thereby encoding movement and directionality

Projections of utricle and saccule

Use vestibulocochlear nerve, but end point is the vestibular nuclei

Motion sickness

Caused by passive movements that are either unnatural or disconnected (between visual and vestibular inputs)

Sensory-conflict hypothesis

Conflict between visual and vestibular inputs as the cause of motion sickness

Potentially an evolutionary response to help get rid of ingested poison

Likely explains some, but not all, of motion sickness

False-climb effect

Vestibular system experiences climb and acceleration in the same way, posing a danger for pilots (think they’re climbing, actually just accelerating)

Papillae

Big bumps on tongue (containing taste buds) that serve to increase surface area of the tongue

Taste buds, location and anatomy

Line the sides of papilla

Made up of taste receptor cells that contact tastants in saliva

Microvilli

Fine projections in taste receptor cells that contact tastants in saliva

Each ____ encodes for a single taste

Receptor cell

Each taste bud has ALL five tastes (although it can vary somewhat)

Taste receptor cells respond to _____

Tastants (not neurotransmitters)

Taste cells mediate between neurons and tastants (not neurons directly)

Encoding salty taste

Uses Na⁺ channels, as well as others (often the combined activity of multiple receptors)

Cl^- is also important, but no Cl^- channels are present directly

Encoding sour taste

Detection of acidity (in the form of H⁺ protons)

Specifically uses OTOP1 proton channel to depolarize cell

Encoding sweet taste

Uses T1R2 and T1R3 heterodimer

Encoding umami taste

Uses T1R1 and T1R3 heterodimer to respond to dietary amino acids

Also uses a mGluR (metabotrophic) to detect glutamate

MSG

(Monosodium glutamate)

Often used in Asian cuisine and so-called “Chinese Restaurant Syndrome”, despite being the same compound as sodium

Encoding bitter taste

Uses T2R (class a) monomers, which have at least 30 members

Often responding to toxicity

Class C GCPRs

Class of receptors important for taste that heterodimerize

See T1R receptors (in contrast to T2R receptors, which monomerize)

Taste myths (4)

1. Bumps on tongue are taste buds

2. Different regions of tongue are for different tastes

3. MSG causes sickness

4. Individuals who can’t taste certain bitter substances have fewer papillae

Taste receptors are only found in the mouth (T/F)

False, actually found in several other parts of the body, although function is still unknown

Differences in # of papillae between individuals

Number does vary by individual, but not in ways that affect ability to taste bitter compounds (this ability is genetically determined)

Taste pathway

1. Taste receptor cells on tongue

2. Vagus nerve, glossopharyngeal nerve, and facial nerve

3. Solitary tract and its nucleus (of brainstem)

4. Thalamus

5. Gustatory cortex (insular/frontal cortex)