Neurotransmission Flashcards
What is sound?
The displacement of air particles following a sinusoidal pattern of compression and rarefacation….
What is the range of human hearing?
Range of human hearing 20Hz-20KhZ
What are the components of the auditory systems?
Outer Ear- air
Middle Ear- air
Inner Ear- fluid
Central Auditory Pathways
What is the outer ear made up of?
Pinna- cartillagenous structure
Formed from pharyngeal arches 1 & 2 ( 6x Hillocks of His)
Forms between 10th and 18th week in utero Directs soundwaves towards ear canal High pitch > Low pitch
Ear Canal- 1/3 cartilage & 2/3 bone
What is the structure of the tympanic membrane in the outer ear?
Posterior fold
Incus
Umbro
Anulus
Pars tens a
Pars flaccida
Anterior fold
Short process of malleus
Manubrium of malleus
Cone of light
What are the components of the middle ear?
Bones
Malleus, Incus & Stapes
Muscles
Tensor Tympani & Stapedius
Tubes Eustachian Tube
What is the structure of the ossicular chain in the middle ear?
Aditus (inlet) to mastoid antrum
Malleus
Incus
Chorda tympani
Tensor tympani
Tendon of stapedius
Tympanic membrane
Facial nerve In facial canal
Prominence of lateral semicircular canal
Prominence of facial canal
Stapes
Promontory
Tympanic plexus
Tympanic nerve
Lesser pterosaurs nerve
Malleus structure?
Head, neck, anterior surface, manubrium of malleus
Short crus of incus
Body of incus
Lenticular process of incus
Anterior crus
Base of stapes
Posterior crus
Long crus of incus
Head of stapes
What is the size of the malleus?
23mg
8-10mm
What is the size of the stapes?
2.5mg
Smallest bone in the body
Footplate - 1.5 x 2.99mm
What is the role of the middle ear?
Acoustic impedance match between air and fluid- filled inner ear
How many energy is lost transferring from air to fluid?
99.9% loss of energy
How does the middle ear carry out its role?
Amplification of the airborne sound vibration = make it louder
Ratio Area TM : Stapes 14:1
Lever action of ossicles - handle of malleus is 1.3 times longer than long process of incus
Total gain 18.3:1 or 20 - 35 dB
How is energy transferred from outer ear to inner ear?
Air -> fluid
Via Ossicular chain
200 fold increase to boost in pressure form TM to inner ear
What are the roles of muscle in the middle ear?
Protection of the inner ear from acoustic trauma Stiffens the ossciular chain
Stapedius stimulated acoustically
Reflex arc: 3 or 4 neurones
6-7 ms reaction time in cats
25 ms in man - thunderclap, not shotgun
Tensor Tympani-voluntary and involuntary control Chewing !
What is the role of the Eustachian tube?
Ventillation of the middle ear space Drainage of secretions
Often dysfunctional in children – causing hearing loss and middle ear infection
In adults, dysfunction causes shiny things to appear in (some) ENT surgeons homes……
What are the vestibulocohclear apparatus in the inner ear?
A set of fluid filled sacs, encased in bone Cochlear- responsible for hearing Labyrinth- responsible for balance Innervation: Vestibulocochlear nerve
What is the cochlea like?
2.5 turns fluid filled bony tube
2 openings- round window & oval window
3 compartments ( Scala Tympani, Scala Media & Scala Vestibuli) 2 Ionic fluids
What are the cochlear fluids like?
Endolymph - High K+
Perilymph
- Like ECF and CSF
- Na+ rich
Gradients maintained by:
Na, K-ATPase
& NKCC1 CIC-K chlorine channels Ion channel abnormalities- deafness.
What is the structure of the cochlea?
What is the structure of the Eustachian tube?
What are the components of the cochlear?
Basilar membrane
- Narrow at base
- Wide at apex
- Stiff at base
- Floppy at apex
- High frequencies detected at base - - Low frequencies at apex
Like Guitar Strings…
What are the mobile aspects of the ear?
Basilar membrane - mobile
Tectorial membrane - fixed
Movement (compression and rareification)
What is the structure of the organ of corti?
What are the roles of hairs?
Hair cells
Inner Hair Cells- Mechanical transduction
Outer Hair Cells- fine tuning
Base attached to basilar membrane Stereocillia anchored to tectorial membrane.
Shearing forces at the stereocillia
What does displacement of the basilar membrane cause?
Displacement of the basilar membrane causes movement of specialized mechanical transducing cells
What is the structure of the inner hair cells?
Endolymph - stereocilium (K+)
Perilymph - Afferent and efferent - blood? (Depolarize here - Ca 2+)
What happens at the inner hair cells?
Movement of the sterocillia Rapid response required
Mechanically gated K+ channels opened causing depolarization ( K+ rich endolymph)
Depolarization results in opening of voltage gated Calcium channels
Release of neurotransmitter- Glutamate (plus others)
Repolarization through K+ efflux ( into K+ poor perilymph)
What is the relation between tonotopy and the role of the outer hair cell?
Each nerve responds maximally at a specific frequency.
But our ability to discriminate different frequencies is not fully explained by this theory.
Outer Hair Cells can alter the stiffness of the basilar membrane to ensure maximal stimulation at one site and dampened response at another.
Increased resolution
How is sound information encoded?
Sound analysed to encode in formation for neural transmission
FREQUENCY (PITCH) Encoded in nerves by location along the basilar membrane INTENSITY (LOUDNESS) Encoded in nerves by numbers responding and by firing rate SOUND TRANSDUCTION Inner Hair Cells (and OHCs)
AMPLIFICATION Outer Hair Cells
What is the pathway in the ear?
Auditory fibre – spiral ganglion.
Spiral Ganglion to Cochlear nerve ( VIII) Central auditory pathway
What is the central auditory pathway?
Cochlea -> 8th nerve
-> 2. cochlear nucleus
-> 3. superior Oliver’s complex
-> 4. lateral leminiscus
- 5. inferior colliculus
-> medial geniculate body
-> auditory cortex
Numbered - unsure of order - check!!!!
What does the brainstem do?
Sound Localization…
How do we localize sound?
Sound source
Sound wave
Rough estimate of ITD
Left, right ear arrival time
Perceived azimuth in this case
What are interaural time differences?
MSO neurons are coincident detectors responding to only when excitatory signals arrive simultaneously
Anatomically differences in connectivity allow each MSO neuoron to be sensitive to sound source from particular location
- Sound reaches left ear first
- Action potential begins travelling toward MSO
- Sound reach right ear a little later (at right ear)
- Action potential from right ear begins travelling toward MSO (at right ear)
- Action potentials converge on an MSO neuron that responds most strongly of their arrival is coincident (middle)
What is the path of the central auditory pathway?
Eighth Nerve Cochlear Nucleus Olive
Lateral Leminiscus Inferior Colliculus
What is conductive vs sensorineural hearing loss?
Defective outer/middle ear
=CONDUCTIVE HEARING LOSS
Defective Inner Ear
= SENSORINEURAL HEARING LOSS
How do you treat conductiv hearing loss?
Treatment depends on the cause…Improve conduction
Improve amplification - hearing aids
How do you treat sensorineural hearing loss?
Stimulate e.g. auditory brainstem implant - stimulus cochlear nucleus
What are the CNS cell types?
Neurones and glia
Differentiated glia:
- oligodendrocytes
- microglia
- Astrocytes
Others e.g. glial stem cells, oligodendrocytes precursors, ependymal cells
What are neurones?
Specialised for electrical signalling
• Inputs via dendrites
• Action potentials propagate along the axon from the axon hillock
• Mainly formed during development
What can tissue section be stained with?
Tissue sections can be stained with histological stains
• e.g. H&E:
- Haemotoxylin, stains nucleic acids blue
- Eosin – stains proteins red
How do neurones communicate?
Neurons communicate via synapses - 2 types
• Chemical – majority – via neurotransmitters (glutamate, GABA, dopamine, serotonin,
etc.)
• Electrical – less abundant – via direct flow of ions
- enable synchronized electrical activity, e.g. brainstem (breathing) & hypothalamus (hormone secretion)
What occurs in chemical synaptic transmission?
Neurons communicate via synapses - 2 types
• Chemical – majority – via neurotransmitters (glutamate, GABA, dopamine, serotonin,
etc.)
• Electrical – less abundant – via direct flow of ions
- enable synchronized electrical activity, e.g. brainstem (breathing) & hypothalamus (hormone secretion)
What is the structure of an electrical/chemical synapse?
Where are excitatory synapses often concentrated?
On dendritic spines
ER in spines - some proteins are made in spine
What is neural plasticity?
Neural plasticity
- changes in neuronal/synaptic structure and function in response to neural activity - basis of learning and memory
• Spines are dynamic structures – number, size, composition
• Spine remodelling linked to neural activity
• Relevant to disease – e.g. schizophrenia & Alzheimer’s - ↓spine density
What is neuronal heterogeneity?
Neurons differ in their:
• Size
• Morphology
• Neurotransmitter content
• Electrical properties
• E.g. neocortex (right)
What is an example of neuronal heterogeneity that is vulnerable in MND and huntingtons?
Betz cells = upper motor neurons – large, excitatory (glutamatergic,) long projections, pyramidal cells
• Vulnerable in MND
Medium spiny neurons = striatal interneurons – small, inhibitory (GABAergic)
• Vulnerable in Huntington’s disease
What is the aborisation of axons and dendrites?
E.g. cerebellar purkinje cell
What are oligodendrocytes?
Myelinating cells of the CNS
• Unique to vertebrates
• Myelin insulates axon segments, enables rapid nerve conduction
• Myelin sheath segments interrupted by nodes of Ranvier – saltatory conduction
• Provide metabolic support for axons
What is the myelin sheath like?
Formed by wrapping of axons by oligodendrocyte processes (membranes)
• Highly compacted – 70% lipid, 30% protein
• Myelin specific proteins, e.g. myelin basic protein (MBP) can be used as “markers”
What are microglia?
Resident immune cells of the CNS
• Originate from yolk sac progenitors
that migrate into the CNS
• “Resting” state, highly ramified, motile processes survey environment (2-3 μm/min)
• Upon activation (e.g. by ATP), retract processes, become “amoeboid” & motile
• Proliferate at sites of injury - phagocytic
What are the functions of microglia?
Immune surveillance
• Phagocytosis – debris/microbes
• Synaptic plasticity – pruning of spines
• “Bad” (M1) & “good” (M2) microglia
What are astrocytes?
Star-like cells”
• Most numerous glial
cells in the CNS
• Highly heterogeneous – not all star-shaped
• Common “marker” glial fibrillary acidic protein (GFAP)
How do astrocytes contribute to the blood-brain barrier?
Anti-GFAP immunostaining for astrocytes – cell bodies & processes coating capillaries
Dual immunostaining with second astrocyte marker AQP4 reveals more of the vascular network:
GFAP
Aquaporin 4 (water channel – necessary due to the blood- brain barrier – see later)
What are take functions of astrocytes?
Structural - define brain micro-architecture
• Envelope synapses – “tripartite synapse” – buffer K+, glutamate, etc.
• Metabolic support – e.g. Glutamate-Glutamine shuttle
• Neurovascular coupling – changes in cerebral blood flow in response to neural activity
• Proliferate in disease = gliosis or astrocytosis
What are some specialised astrocytes?
Radial glia – important for brain development
Bergmann glia (cerebellum) - green
Muller cells (retina)
What is MND and multiple sclerosis?
Motor neurone disease – adult-onset neurodegenerative disease characterised by loss of upper (motor cortex) and lower (spinal cord) motor neurones
• Multiple sclerosis – autoimmune demyelinating disease where immune cells attack the myelin sheath of oligodendrocytes
25
MND spinal cord shows pathological changes in:
A. Motorneurons B. Microglia
C. Astrocytes
D. Alloftheabove
MND symptoms are due to loss of:
A. Motor neurons
B. Microglia
C. Astrocytes
D. All of the above
AcutesymptomsinMSreflectdysfunctionof:
A. Neurons
B. Oligodendrocytes
C. Tlymphocytes
D. Blymphocytes
Pathological CNS lesions in MS involve:
A. Neurons
B. Oligodendrocytes
C. Tlymphocytes
D. Alloftheabove
What are nuclei, tracts, commissures, grey matter and white matter? (CNS terminology)
Abundance of neuronal cell bodies in nuclei
• Axons gathered into tracts
• Tracts that cross midline = commissures
• Grey matter abundant in neural cell bodies & processes – neuropil contains few cell bodies
• White matter contains abundance of myelinated tracts & commissures
What are ganglia, nerves, Schwann cells? (PNS terminology)
Cell bodies & supporting cells located in ganglia – e.g. dorsal root ganglia (DRGs)
• Axons bundled into nerves
• Many PNS axons are enveloped by Schwann cells (myelinating cells
of the PNS – neural crest derived c.f. oligodendrocytes, derived from CNS- resident neural progenitors)
What is the blood brain barrier?
• Dyes injected into blood penetrate most tissues, but not the brain
• Dyes injected into CSF – brain stains → specialised blood-brain barrier
• Formed by endothelial cell tight junctions, basement membrane (few fenestrations), astrocyte end feet & pericytes (contractile, aid blood flow)
• Sensitive to inflammation, hypertension, trauma, ischaemia
• Problem for drug delivery!
Where does CSF drain into?
CSF also drains via perineural routes and via meningeal lymphatics
What are ependymal cells?
Epithelial-like, line ventricles & central canal of spinal cord
• Functions - CSF production, flow & absorption
• Ciliated – facilitates flow
• Allow solute exchange between nervous tissue & CSF
What is the choroid plexus?
Frond-like projections in ventricles
• Formed from modified ependymal cells - villi form around network of capillaries
→ highly vascularised with a large surface area
• Main site CSF production by plasma filtration driven by solute secretion
• Gap junctions between ependymal cells form blood- CSF barrier
What are neurones?
Neurons are highly specialised, heterogeneous cells which are supported by glia
• Patient symptoms typically reflect loss of neuronal function
How are glia important in health and disease?
• Glia are important in health and disease:
- initiation of disease (e.g. multiple sclerosis)
- progression of neurodegenerative diseases (e.g. MND) - research as alternative target for therapy
What are the responses to diff stimuli?
Cognitive analyses - frontal cortex - response suppression
Context - hippocampus and septum - amygdala - conditional emotional responses
Complex neutral stimuli - sensory cortex - amygdala - conditional emotional responses
Neutral stimuli - thalamus - amygdala - conditional emotional responses
Species specific threat stimuli - midbrain and hypothalamus - species specific responses (freeze/flight/fight)
Sudden distal stimuli - hindbrain - startle response
Noxious or contact stimuli - spinal cord - reflexive withdrawal
All stimuli - sensory input - leave as a motor, autonomic and endocrine output
What does the CNS involve?
Brain, spinal cord (skull?)
What is the somatic NS like?
Somatic nerves system - interacts with the external environment:
Skin muscles, joints, eyes, ears etc (Afferent nerves - sensory signal)-> CNS
Opposite way = efferent nerves (motor command) - from CNS
What is the autonomic NS like?
Autonomic nervous system (unconscious/automatic):
Internal organs -(afferent)—> CNS
Opposite - efferent
Regulates body’s internal environment
What does the PNS involves?
Division located outside of skull and spine
What is teh spinal cord divided into?
Cervical region - head and neck, diaphragm and arms and hands
Thoracic region - chest muscles, breathing and abdominal muscles
Lumbar region - legs and feet
Sacral region - bowel bladder control, sexual functions
What are the spinal cord roots?
Dorsal RootAfferent (affected by the world)
Ventral Root RootEfferent (having an effect on the world)
[MOTOR]
What is the first subdivision of the brain?
Forebrain - telencephalon and diencephalon
Midbrain - mesoncephalon
Hindbrain - metencephalon and myelencephalon
What is the telencephalon and diencephalon made up of?
Telencephalon - Cerebral cortex, basal ganglia and limbic system
Diencephalon - thalamus and hypothalamus
What is the mesoncephalon made up of?
Tegmentum and tectum
What is the metencephalon and myelencephalon made up of?
Metencephalon (pons, cerebellum)
Myelencephalon (medulla)
What is the myelencephalons medulla like?
Old brain, involved in autonomic and low level sensorimotor control
Medulla (myelencephalon):
Contains tracts carrying signals between the rest of the brain and the body.
Contain caudal part of the reticular
formation (“little net”):
low level sensorimotor control –
e.g. balance
Involved in variety of vital functions:
Sleep/Wakefulness
Motor Plant: movement, maintenance of muscle tone
Various cardiac, circulatory, respiratory, excretory
reflexes
What is the pons like?
- Relay from cortex and midbrain to the cerebellum
- Contains millions of neuronal fibers
- Pontine reticular formation (pattern generators) – e.g. for walking
What is the cerebellum like?
Smaller than the brain but contains as many neurons as all the rest of the CNS.
“Motor errors” between intended movement and actual movement – adjusts synaptic weights to eliminate error.
Online correction can take place during the movement : motor learning.
Thought exclusive for motor coordin-ation – recently implicated in cognitive and affective/emotional function.
[‘hijacked’ for its computational power??]
What is tectum like?
Tectum – visual/spatial and auditory frequency maps
Also called: colliculi (“little hills”)
Superior Colliculus - Sensitive to sensory change – orienting/defensive movements
Inferior Colliculus - Similar, but for auditory events
What is the tegmentum like?
Three colourful structures
- The Periaqueductal Gray
- red nucleus
- Substantia nigra
What is the peraqueductal grey like?
Role in defensive behavior
Role in pain (ascending and descending signals)
Role in reproduction
From tegmentum
What is the red nucleus like?
- target of cortex and cerebellum projects to spinal cord
- Role in pre-cortical motor control (especially arms and legs)
From tegementum
What is the substantia nigra?
- Substantia nigra pars compacta (Dopamine cells) – basal ganglia, Input…Parkinson’s disease
- Substantia nigra pars reticulata – basal ganglia output
part of basal ganglia)
What is the thalamus like?
Relay structure from diencephalon
Specific nuclei : relay signals to cortex/limbic system for all sensations (but smell…).
Non-specific nuclei : Role in regulating state of sleep and wakefulness and levels of arousal
Important relays from basal ganglia and cerebellum back to cortex
What is the hypothalamus like?
From diencephalon
- Regulates the pituitary gland which regulates hormonal secretion: interface between brain and hormones
► Role in hormonal control of motivated behavior …including hunger, thirst, temperature, pain,
What is the cerebral cortex like?
Subcortical (under the cortex) portions:
Basal Ganglia
Limbic system
What is the basal ganglia like?
- group of structures
- loop organization
These structures thought to be involved in motor function since involved in movement disorders
What is the limbic system like?
Group of structures
These structures involved in emotion, motivation and emotional association with memory
limbic system influences the formation of memory by integrating emotional states with stored memories of physical sensations
What is the limbic system made up of?
Amygdala
Hippocampus
Fornix
Cingulate gyrus
Septum
Mammillary body
What is the limbic system made up of?
Amygdala
Hippocampus
Fornix
Cingulate gyrus
Septum
Mammillary body
What is the amygdala and hippocampus involved in?
Amygdala (“Almond”): Involved in associating sensory
stimuli with emotional impact
Hippocampus (“Sea Horse”): Involved in memory (long term) / Involved in spatial memory
What is the mammillary body and fornix involved?
Mammillary body: Breast shaped Important for the formation of recollective memory – amnesia
Fornix: C-shaped bundle of fibers, Carries signals from the hippocam-pus to the mammillary bodies and septal nucleus
What is the mammillary body and fornix involved?
Mammillary body: Breast shaped Important for the formation of recollective memory – amnesia
Fornix: C-shaped bundle of fibers, Carries signals from the hippocam-pus to the mammillary bodies and septal nucleus
What are the cingulate gyrus and septum involved in?
Cingulate gyrus (Limbic cortex) - Linking behavioural outcomes to motivation and autonomic control – atrophied in schizophrenia
Septum:”something that encloses”
Involved in defense and aggression
Wha are the lobes of the forebrain?
Frontal lobe, parietal, temporal, occipital
Pre and post central gyrus around the central sulcus
What is the cerebral cortexes cortical lobes made up of?
Gray matter (6 layers) : cell bodies
White matter: fibers / axons
Biggest part of the brain in Primates
What is the frontal lobe like?
Contain the precentral gyrus from which motor instructions (particularly for fine motor control) that are sent to muscles controlling hands and feet.
Primary motor cortex: contains many of the cells giving origin to the descending motor pathways - it is involved in the initiation of voluntary movements.
Premotor and supplementary motor areas: higher level motor plans and initiation of voluntary movements.
What is the frontal lobe like?
•Involved in - i.e. lesions disrupt….
•“Executive” planning – generating models of the consequences of actions
• Judgmental roles
• Emotional modulation
•Working memory: short-term information (rather than long-term factual data)
•Control of behavior that depends upon context or setting
•Prefrontal cortex: generating sophisticated behavioural options that are mindful of consequences
What is the parietal lobe like?
Contains the post central gyrus which receives sensation from the rest of the body
Primary somatosensory cortex:
Maintains representations of the body’s and of the head’s position in space.
•Permits complicated spatio-temporal predictions – e.g. catching something when you are moving
What is the temporal lobe like?
Contains the primary auditory cortex
Inferotemporal cortex recognition faces and objects
Plays an important role in integrating sensory information from various parts of the body
Interface between cortex and limbic system - association of affect/emotion with things
What is the occipital lobe like?
Contains visual cortices
Dorsal stream
Vision for movement - where (is it in relation to us - note path towards motor areas)
Ventral stream
Vision for identification
What [does it mean to us – note path towards temporal/limbic areas]
How does the Brain control behaviour?
Therefore all our actions will engage a bit of cortex interacting with a bit of basal ganglia, cerebellum and hippocampus…all directing the brainstem on what to do
How many neurones are there?
Approximately 100 billion (109) neurons in the ‘average’ brain
•But, 0.15 quadrillion (1015) connections between them (synapses)
What is the neruone?
Basic cellular unit of the nervous system
•Huge range - specialised for different functions
•All have same basic components
•Dendrites
•Cell body/soma
•Axon
•Presynaptic terminals
What are the basic neurone types?
Multipolar, bipolar, pseudo-unipolar and unipolar
E.g. Different Types of Neurons. A. Purkinje cell B. Granule cell C. Motor neuron D. Tripolar neuron E. Pyramidal Cell F. Chandelier cell G. Spindle neuron H. Stellate cell (Credit: Ferris Jabr; based on reconstructions and drawings by Cajal)
What are the basic neurone types?
Multipolar, bipolar, pseudo-unipolar and unipolar
E.g. Different Types of Neurons. A. Purkinje cell B. Granule cell C. Motor neuron D. Tripolar neuron E. Pyramidal Cell F. Chandelier cell G. Spindle neuron H. Stellate cell (Credit: Ferris Jabr; based on reconstructions and drawings by Cajal)
What are the connections between neurones?
Transmission of information from location A to location B – Axonal transmission
• Integration/processing of information and transmission between neurons – synaptic transmission
What is the nueurones resting potential
At rest – the inside of the neuron has a negative electric charge…why is this ?
Why is the neurone resting potential -ve?
Neuronal cell membrane - semi-permeable
Some substances which are electrically charged (+ve or –ve) cross readily – potassium (K+) and chloride (Cl-)
•Some cross with difficulty – sodium (Na+)
•Some not at all – large organic proteins (-ve charge)
What forces determine the distribution of charged ions?
Diffusion – the force driving molecules to move to areas of lower concentration
Electrostatic attraction/repulsion: Electrostatic pressure - ions (like magnets) move according to charge – Like ions repel and unlike attract
Ions:
A- (anions - protein)
Na+ (sodium ions)
K+ (potassium ions)
Cl- (chlorine ions)
How does forces that determine ion distribution relate?
Diffusion + electrostatic pressure
Ions
A- (anions - protein) - restricted to inside of cell
Na+ (sodium ions) - mostly outside neuron
K+ (potassium ions) - mostly inside neuron
Cl- (chlorine ions) - mostly outside neuron
What other factor determines ion distribution?
Sodium-potassium pump
•Active process to transport Na+ ions out of neuron & K+ in
•Three Na+ for every two K+
•Require energy supplied by ATP
What is the final resting potential of neurones?
Final resting potential –70mV
•Result is NA+ high concentration outside but with both forces pushing in
•Membrane and pump resists Na+ inward movement
•K+ & Cl- can move backward and forward across membrane so reach steady state determined by opposing forces of diffusion and electrostatic pressure
•Some sodium leaks back in but is expelled by the pump
What is the action potential?
The Action Potential
•Neuron fires – a sudden pulse where the negative resting potential is temporarily reversed
•Transmits information i.e. the message [digitally / all or none / 0 or 1]
•Events within the action potential
–Depolarization & threshold
–Reversal of membrane potential
–Repolarisation to resting potential
–Refractory period
What triggers an AP?
The membrane potential remains in this resting ‘stable’ state until something disturbs the balance:
Neurotransmitters initiate such changes at the dendrites of neurons
•Neurotransmitters activate receptors on dendrites / soma
•Receptors open ion channels
•Ions cross plasma membrane, changing the membrane potential
•The potential changes spread through the cell
•If the potential changes felt at the axon hillock are positive (+mV), and large enough, an action potential is triggered
What occurs in depolarisation/hyperpolarisation?
The membrane potential:
Depolarisation more +ve V than -70
Polariser at -70mV = RMP
Hyperpolarised more -ve V than -70
Excitatory neurotransmitters depolarise the cell membrane
- increases probability of AP being elicited
-cause an excitatory post synaptic potential (EPSP)
Inhibitory neurotransmitters hyperpolarise the cell membrane
- decreases probability of an action potential being elicited
- cause an inhibitory post synaptic potential (IPSP)
An action potential will be elicited if the membrane potential is depolarised beyond the threshold of excitation
What are postsynaptic potentials?
EPSP
Temporal/spatial summation
What AP?
EPSPs begin to depolarise cell membrane
•Threshold ~ -60mV
–When reached Na+ channels open (Na+ rushes in) and polarity reverses to +30 inside
•Membrane potential reverses with the inside
What are voltage gated channels in the cell membrane like?
The voltage changes are caused by the opening or closing of ion channels
•In the cell membrane there are channels which are opened by voltage changes…thus
voltage changes control the ion channels which control the voltage changes……….
The action potential is therefore self perpetuating
How is the AP initiated and propagated?
What is the speed of depolarisation like?
depolarisation of each and every segment of the axon in turn is SLOW, need faster conduction than this…
How does speed of conduction change?
Myelination greatly speeds up axonal conduction
Myelin comes from oligodendrocytes in the CNS and from Schwann cells in the PNS
How does speed of conduction change?
Myelination greatly speeds up axonal conduction
Myelin comes from oligodendrocytes in the CNS and from Schwann cells in the PNS
Describe the propagation of the AP?
Signal loss due to lack of insulation –could be overcome by continual opening of next ion channel
•But SLOW due to time to activate each channel.
•Mainly short axon interneurons
Saltatory conduction
What occurs in saltatory conduction?
Saltatory Conduction
•Decremental conduction between nodes (but ‘re-boosted’ each time)
•But very fast along axon.
•Most CNS neurons.
What can axonal transmission failure cause?
Axonal transmission failure:
Multiple Sclerosis
Most common disease of NS in young adults
What are the symptoms of multiple sclerosis?
Symptoms:
•Eye movements – uncontrolled, seeing double
•Speech – slurred
•Paralysis – partial/complete, any part of body
•Tremor
•Co-ordination – lost
•Weakness – tired
•Sensory – numbness, prickling, pain
What is the prognosis of multiple sclerosis?
Prognosis:
•Initial symptoms – slight with remission…
•….becoming more numerous, frequent and severe
•Difficult to diagnose:
•Early symptoms slight – person doesn’t go to doctor
•Other diseases have similar symptoms
•No definitive test: repeated presentation of symptoms combined with MRI
Who gets MS?
•Who gets MS ?
•Young adults 20-40
•Slightly more women than men
•Temperate zones
•Areas with high standards of sanitation
What happens when the action potential reaches the terminal button?
Transmission of information from location A to location B – Axonal transmission
• Integration/processing of information – synaptic transmission
What does novichok do?
Disrupts normal synaptic neurotransmission for the neurotransmitter acetylcholine
What occurs when the AP reaches the terminal buttons?
Ca2+ channels
Exocytosus
Postsynaptic membrane
Chemical synapse
Synaptic cleft
What breaks down Ach?
Acetylcholinesterase is the name of the enzyme that breaks down the neurotransmitter acetylcholine
What happens to the neurotransmitter???
Would remain active in synapse if it wasn’t for:
1.Enzymatic Degradation
2.Reuptake
AChE inhibitor - novichok
How does novichok act?
Inhibiting breakdown of a neurotransmitter means it will stay active in the synapse
•So it will continue to have whatever effects it has, long after these would normally be terminated
What does Ach do?
It is the key neurotransmitter at the neuromuscular junction – it activates muscles
•Not just skeletal muscles (for voluntary movement), also heart, respiratory muscles, gastrointestinal tract, eye muscles, muscles around blood vessels………
What are the symptoms of nerve agents that targets ACh system (e.g. novichok)?
Excessive activation of muscles (convulsions) initially
•Subsequent paralysis as muscle cannot continually contract
•Failure of heart muscles (heart failure)
•Failure of muscles controlling respiration (asphyxsiation/drowning)
•Failure of muscles in eye (pupils constricted / paralysis)
•Failure of skeletal muscles (paralysis)
•Failure of muscles of digestive tract (vomiting/diarrhoea)
What is the treatement for novichok and other nerve agents that target the ACh system?
Atropine is an ACh receptor blocker – but doses needed to be effective very high (side effects)
•Drugs which can re-activate AChE may also be administered
•Usually intensive life-support required (due to cardiovascular effects)
•Long-term damage of neuromuscular function probable
What occurs in synaptic transmission?
Neurotransmitter release
–Calcium ion channels open when action potential reaches pre-synaptic terminal
–Ca++ ions cause vesicles to move to release sites – fuse with the cell membrane – and discharge their contents
–Transmitter substance diffuses across synaptic cleft
–Attach to receptor sites on post-synaptic membrane
What are the 5 fundamental processes of synaptic transmission?
Important to know because almost all the drugs that act on the brain – do so by interacting with one or more of these 5 processes
1.Manufacture – intracellular biochemical processes
2.Storage – vesicles
3.Release – by action potential
4.Interact with post-synaptic receptors – diffusion across the synapse
5.Inactivation – break down or re-uptake
How does the 5 fundamanetal processes of synaptic transmission apply to ACh?
How does the 5 fundamanetal processes of synaptic transmission apply to ACh?
What are some common neurotransmitters?
Fast neurotransmitters – short lasting effects
–Acetylcholine (ACh)
–Glutamate (GLU)
–Gamma-aminobutyric acid (GABA)
•Neuromodulators – slower timescale
–Dopamine (DA)
–Noradrenalin (NA) (norepenephrine)
–Serotonin (5HT) (5-hydroxytryptamine)
How do local anaesthetics work?
E.g. procaine and ligocaine
Na+ channels blockers - particularly well absorbed through mucous membranes
Blocks progress of action potential
Used in medicine and dentistr
What is ACh affected by?
Transmitter at the neuromuscular junction, also used widely in brain and spinal cord
–Affected by:
•Cigarettes (nicotine - agonist)
•Poison arrows (curare - antagonist)
•Spider toxins (black widow - release)
•Nerve gas (WW-I – blocks break-down)
What is noradrenaline (NA) affected by?
Transmitter in peripheral (heart) and central nervous systems
–Affected by:
•Antidepressant drugs (Imipramine – blocks re-uptake)
•Antidepressant drugs (MAO inhibitors – block break-down)
•Stimulants (Amphetamine – increases release and blocks re-uptake)
What is dopamine (DA) affected by?
Important transmitter in basal ganglia
–Affected by:
•Antipsychotic drugs (Chlorpromazine – receptor blocker)
•Stimulants (Amphetamine/cocaine – increase release and block re-uptake)
•Anti-Parkinson drugs (L-DOPA increases manufacture
What is serotonin (5-HT) affected by?
Diverging projections in the brain – innervating many structures
–Affected by:
•Antidepressant drugs (Prozac – serotonin re-uptake inhibitor – SSRI)
•Hallucinogens (LSD, psilocybin –5HT receptor agonist)
•Ecstasy (MDMA, increase release, reduce reuptake)
How do hallucinogenic drugs work?
Hallucinogenic drugs include LSD, Magic Mushrooms, Ketamine
•They mimic serotonin, and can activate numerous different serotonin receptor subtypes
•But the hallucinogenic effect itself appears to be specifically related to the way they target the serotonin ‘2a’ receptor (5-HT2a)
What is Gamma-aminobutyric acid affected by (GABA)?
Main inhibitory transmitter
–Affected by:
•Anti-anxiety drugs (benzodiazepines - valium – inhibitory effect at GABA receptors
•Anticonvulsant drugs (benzodiazepines – see above)
•Anaesthetics (Barbiturates – potentiate the effect of GABA
What are some problems for drug design?
A region of the brain engaged in a particular function uses several neurotransmission systems e.g. basal ganglia
–Glutamate
–GABA
–Dopamine
–Acetylcholine
–Substance P
–Enkephalin
•Regions of the brain engaged in different functions use the same neurotransmission systems
–Glutamate
–GABA
–Acetylcholine
–Serotonin
–Dopamine/Noradrenalin
What are some side effects?
GABA agonists
–Anti-anxiety
–Anti-convulsant
–Anaesthetic
•L-DOPA
–Anti-parkinson
–Causes psychosis at high doses
•Dopamine blockers
–Anti-psychotic
–Causes Parkinson-symptoms at high doses
How does the resting potential generate EPSPs, IPSPs and action potentials?
resting potential is established and perturbed to generate EPSPs, IPSPs and action potentials
What do the parasympathetic vs sympathetic NS involve?
PARSYMPATHETIC in simple terms:
- The VAGUS Nerve (X) to Thorax & Abdomen
- Cranial nerves to Head, Thorax & Abdomen
- Sacral outflow to Pelvic organs
Sympathetic:
- The Sympathetic Chain
- Other Ganglia
- Post Ganglionic fibres
- cranial nerves to eye
How do somatic motor neurone and an automatic motor neurone differ?
Difference between somatic and autonomic NS?
Voluntary
Involuntary
What are the functions of the Automatic NS?
Thermoregulation, Exercise, Digestion, Competition, Sexual Function
Mictrurition?
What are outputs of the CNS?
PARASYMPATHETIC
- CRANIAL OUTFLOW
- SACRAL OUTFLOW
- SYMPATHETIC Adrenal amplification
- ‘ENTERIC N.S.’
What are the parasympathetic and sympathetic NS like?
hitches a ride’
on cranial nerves 3,7, 9, 10
- Apart from sacral outflow,
S1, 2
Symp:
- White & Grey Rami communicates, Sympathetic chain
- Splanchnic nerves to large thoraco-abdominal plexi
What are the neural connection of the sympathetic trunk?
Rami communicantes
What is the role for the adrenal medulla?
What are the anatomical differences between sympathetic and parasympathetic?
What is the cranial outflow of the parasympathetic NS?
Cranial outflow:
Preganglionic fibers run via:
• Oculomotor nerve (III)
• Facial nerve (VII)
• Glossopharyngeal nerve (IX)
• Vagus nerve (X)
• Cell bodies located in cranial nerve nuclei in the
brain stem
What is the enteric NS?
Enteric system can work independently from ANS
Coordinates GI function
What is the enteric NS?
Enteric system can work independently from ANS
Coordinates GI function
What are the neurotransmitters of the ANS?
Symp - ACh, nicotine receptors, adrenergic receptors, NE
Para: ACh, , nicotinic and muscarinic receptors
What are the neurotransmitters of the ANS?
Symp - ACh, nicotine receptors, adrenergic receptors, NE
Para: ACh, , nicotinic and muscarinic receptors
What are the sympathetic receptor sub types?
Nordarenaline
ALPHA: alpha1, alpha2
BETA: beta 1, 2, 3
What is the ANS input?
Carotid receptors
What is the Carotid Baro-Receptor Reflex pathway?
How does high BP develop and is maintained?
What is the Vaso-vagal or ‘Reflex’ Syncope?
How do you test the ANS in cardio?
Heart Rate and Blood Pressure, preferably beat-by-beat
Radial artery
HUT - head up tilt test
(Arterial) Baro-reflex testing- By Phenylephrine test - - Measure R-R interval after iv pressor agent Phenylephrine- (PE)
What are some non CVS ANS measurements?
Pupillometry
•Sweat measurement
•Skin blood flow, thermoregulation
•Gastric acid secretion
•Sexual function
