Advanced Physiology

Introduction:
Control mechanisms:

Feedback control:

 Negative feedback loop

o Detects change (in any direction), activates mechanisms that opposed it, and
thereby maintains relatively stable internal conditions and keeps controlled
variable close to the set point (target)
o Negative= opposes change
o E.g. get to hot sweat, too cold shivering
o E.g. receptors sense decreased blood vol control centre in hypothalamus
stimulates pituitary gland to release antidiuretic hormone (ADH) kidneys retain
more water
 Positive feedback loop
o Response enhances/exaggerates/amplifies the original stimulus, may exhibit a
cascade or amplifying effect more you have, the stronger the effect
o To be compatible with homeostasis in living orgs, should culminate until some
counter mechanism breaks the loop
o Without break out mechanism it results in death
o E.g. blood clotting- self amplifying cycle leads to greater change in same
direction, feedback loop is repeated- change produces more change
 Break/tear in blood vessel wall platelets adhere to site and release
chemicals released chemicals attract more platelets feedback cycle
ends when platelet plug is formed

Feedforward control:

 Anticipatory mechanisms
 Controls given parameter by means of anticipatory responses to known clues informing
about expected change ahead of actual influence taking place
 Motor control- predicting events, i.e. car coming when crossing street
 Cardiovascular control before physical activity- athletes not completely relaxed before
race, heart and CV system already working
 Regulation of blood pH (acid-base homeostasis)
o Cold blooded animals controlled by feedback loop only don’t have to move to
generate energy, can sit and wait for food
o Mammals controlled by feedback and feedforward mechanisms thus achieving by
order of magnitude smaller fluctuations
o Achieved by sensing changes in bicarbonate buffering system: when acidic
products enter the bloodstream the CO2-carbonic acid equilibrium changes
towards CO2 (buffer being used to neutralise acid)
 o Buffering system coupled with the body’s capacity for respiratory compensation,
production of CO2 in circulation increases ventilation and promote loss of CO2 to
the atmosphere until the excess acid is all exhaled
o Regulation occurs before blood pH changes take place

Language of the neurons:

 Endrocrine system obeys nervous system, but nervous system also obeys endocrine
system

Neuronal excitability:

 Types of potentials
o Resting potential stimulus produced graded potential (cell body) may
produce Action potential (axon) triggers synaptic activity info processing
 Graded potentials
o Chemical stimulus opens chemically gated sodium ion channels
o Removal of chemical stimulus leads to repolarisation
o Different chemical stimulus opens chemically gated potassium channels, causing
hyperpolarisation

o
o 0mV- both sides of cell same charge, resting potential: -70mV polarised
o Depolarisation- making it less polarised (closer to 0), repolarisation- making more
polarised
 Action potential
o Positive feedback loop, all or nothing response, lasts 1 millisecond
o Graded depolarisation brings area of excitable membrane to threshold (-60mV)
o Voltage gated sodium ion channels open and sodium ions move into cell-
transmembrane potential rises to +30mV
o Sodium channels close, voltage gated potassium channels open, and potassium
ions move out of cell- repolarisation begins
o Potassium channels close, both sodium and potassium channels return to normal
states
o During absolute refractory period, the membrane can’t respond to further
stimulation
o During relative refractory period, the membrane can respond only to a larger than
normal stimulus
 o
 Propagation of action potential
o Passive spread of current
 In a bare plasma membrane, without voltage gated channels, as on
dendrite, voltage decays because current leaks across membrane
o Continuous propagation
 In unmyelinated axon, voltage gated Na and K channels regenerate the
action potential at each point along the axon, so voltage doesn’t decay
 Conduction is slow because movements of ions and of the gates of
channel proteins take time and must occur before voltage regeneration
occurs
 Further we are from location, less we feel effect of current if we generate
action potential in body cells, how can we get it to brain?  continuous
propagation
 Voltage gated channels next to action potential activated (become
positive) trigger new action potential in region next to it and so on, so
forth
o Saltatory propagation
 In myelinated axon, myelin keeps current in axons (insulates), voltage
doesn’t decay much
 APs generated only in nodes of Ranvier and appear to jump rapidly from
node to node

Information transfer:

 Action potential and synapses

 o
 Chemical synapse
o Most abundant synapse type
o Specialised site of communication between neuron and another cell which relies
on neurotransmitter release
 Presynaptic cell (before synaptic cleft)- usually a neuron, may have
synaptic knob, has synaptic vesicles that contain neurotransmitters,
presynaptic membrane (where neurotransmitters are released)
 Postsynaptic cell (after synaptic cleft)- can be a neuron or other type of
cell, postsynaptic membrane- bears receptors for neurotransmitters
 Synaptic cleft- narrow space between cells


 How synapse works- propagation of an action potential at a cholinergic synapse
o Synapses which employ acetylcholine (ACh) as neurotransmitter are called
cholinergic
o NT release triggered by depolarisation of synaptic knob when AP arrives
o Depolarisation of synaptic knob opens voltage gated calcium channels influx of
calcium cause exocytosis of ACh from synaptic vesicles
o Released ACh diffuses across synaptic cleft and binds to the receptors of
chemically (ligand) gated Na channels on postsynaptic membrane
 Greater the amount of Ach released, the more receptors/channels respond
and the larger the depolarisation
 If depol great enough, AP will appear in postsynaptic neuron
 o Acetylcholinesterase (AChE- enzyme) breaks down ACh and stops signal within
20 msec
 Postsynaptic potentials
o Graded potentials in postsynaptic cell in response to NT
o Excitatory postsynaptic potential (EPSP)
 Graded depolarisation caused by NT arrival
 Shifts transmembrane potential closer to threshold (facilitated)
o Inhibitory postsynaptic potential (IPSP)
 Graded hyperpolarisation, e.g. opening of chemically gated potassium or
chloride channels
 Shifts transmembrane potential further from threshold (inhibited)
 More inhibition, larger than usual stimulus needed to reach threshold
 Integration potential at level of postsynaptic potential
o One neuron may receive input from numerous neurons forming synapses

o
 Information processing within a neuron
o Temporal summation
 Single synapse stimulated repeatedly
 E.g. before effects of one EPSP can dissipate, another arrives more
ACh release more postsynaptic cell depolarisation
o Spatial summation
 Involves multiple synapses activated simultaneously
 Discovery of neuronal communication code (language)
o Lord Edgar Adrian discovered relationship between number of action potentials
generated for intensity of stimuli
o Build images from electrical impulses encode
o Neurons encode messages to communicate
o Aps represent a digital code
o Digital code can represent any info using discrete (discontinuous) values like
binary digits (0 and 1) widely used in technology yes or no
o Nervous system has used digital code since its origins 550mya during Cambrian
period when first complex animals and nervous system appeared
o Nervous system used digital code in form of very weak short electrical nerve
impulses (is spike/AP or there isn’t)
 Neurons encode info and give commands by means of Aps
o Strength of muscle contraction is encoded in frequency of action potentials sent
by motor neurons high freq, strong contraction
 Plants- different way to generate Aps diff ions, diff time span but principle similar
o E.g. venus fly traps- only closes if insect touches hair twice in certain timespan
 Neurons encode info
o Stimulus intensity may be encoded in freq of generated action potentials
o Stronger the stimulus, more Aps
o Interplay of multiple mechanisms
o Logarithmic compression of afferent response- more interested in difference than
absolute value, i.e. can’t really tell difference between 2kg and 2.05kg
o Number of neurons activated with different thresholds (sensitivities)
o Adaptation
o Control of sensory organ- intrafusal muscle fibres of muscle spindles, pupil in
vision
o How stimulus quality is encoded- labelled line encoding
 Info from a particular receptor travels over particular pathways to particular
parts of the nervous system and activity in the given afferent pathway
would evoke an experience of a special quality or modality
 Nociceptors, pain
 Information encoded by sensory organs
o Discharge rate can encode different things
 Tactile receptors in human skin
o Each human fingertip has 2000 tactile receptors of 4 diff types- vibration, stretch,
pain/temp
 What can a single neuron tell?
o Neuron which on its own is completely indifferent to stimulus quality may become
crucial to determine stimulus quality in a pop of neurons
 Neuronal pop coding of movement direction
o Individual neurons in the arm area of the primate motor cortex are only broadly
tuned to a particular direction in 3D space
o When individual cells were represented as vectors of their preferred direction the
resulting vector sum of all cell vectors (pop vector) was in a direction congruent
with the direction of movement
o By recording activity in relatively small pop of neurons, it is possible to predict
parameters of intended movement

Constructing neural circuits:

Formation of topographic maps:

 Topographic map is like the ordered projection of a sensory surface, i.e. retina, skin, or
an effector system, i.e. musculature, to one or more of the structures of the central
nervous system
 E.g. chemoaffinity hypothesis- topographic maps in optic tectum
o Crushed frogs optic nerve, rotated eye by 180° and waited until axons
regenerated and grew back to original tectal destinations causing inadequate
behaviour shooting tongue in wrong direction, must be mechanism for orderly
connection
 Chemoaffinity operates not by 1-1 or lock and key recognition, but by gradients of
affinities that provide axons and their targets with markers of general position within
system of coordinates (like N and S on a map)
 o Grow towards receptors, i.e. retina, stronger on one side, weak on other
o Cells with highest affinity grow towards region with highest conc of that substance

Competitive interactions and the formation of neuronal connections:

 Adult skeletal muscle fibres are each innervated by a single axon

 Initially during development there is polyneuronal innervation multiple muscle fibres
 Inputs are gradually lost during early postnatal development until only one remains
 Synapse elimination- denotes reduction of axonal inputs from different cells, not the
reduction of overall number of synapses
 Process is completely controlled by activity at the synapse (don’t use it, you lose it)
NT receptors beneath the loser terminal branches disappear before that nerve terminal
is withdrawn, synapses which aren’t activated when muscle contracts are weakened
positive feedback loop only protected if recieved AChR, during contractions are
protected
 AChR antagonist curare acting postsynaptically and Na channel blocker TTX acting
presynaptically both retain polyneuronal innervation and stop synapse elimination
process

Electrophysiology and function of ion channels:

 Ion channels
o Proteins- transmembrane spanning proteins (integral membrane proteins)- goes
across membrane
o Facilitate movement of ions in and out of membranes/cells- no energy required
o Selectively permeable
o Gating- opening and closing
o Very fast (milli secs)
 Membranes form barriers
o Specialised proteins control the transport of molecules across the membrane
barrier
o Hydrophobic and hydrophilic
o Active transporters
 Actively move selected ions against conc gradient
 Create ion conc gradients
 Sodium potassium pumps/ATPase
 3 sodiums out, 2 potassium in- establishes gradient
o Ion channels
 Allow ions to diffuse down conc gradient
 Are selectively permeable to certain ions
 Channel, transporter, pump, carrier or pore?
o Ion channel- selectively moves certain ions across a membrane, doesn’t require
ATP
o Transporter/carrier- moves large substances across membrane, down a conc
gradient, can move more than one substance (co- or counter-transport)
 o Ion pump- active transport against conc gradient that requires energy in form of
ATP
o Pores/toxins- not selective or very weakly selective (larger openings), structurally
different (β-barrels or long α helices)

o
 5% of genes code for ion channels
 Most abundant molecule in orgs- water
o Squids- extracellular conc close to sea water
o Mammalian extracellular conc much lower shows mammals evolved from
intermediate orgs in freshwater
 Properties of ion channels
o Transmembrane spanning
o Selective
o Stimulus induced gating- doesn’t happen without stimulus voltage, ligand
(binding)
o Social- come together in various subunits defines properties of ion channel
o Speedy
o Specialised

Channelomics:

 Study of ion channels

o Function- electrophysiology
o How to study- voltage clamp, patch clamp, planar lipid bilayers, quartz substrates,
silicon chips and population match clamp, physics, maths and modelling
 Voltage clamp
o Squid 400x larger diameter than mammalian
o Clamping at a certain voltage (maintaining membrane potential)- measuring
current

o
 Patch clamp technique
 o Allows recording of single ion channels in cell attached, inside out and outside-
out configuration
o Can control and adjust ion conc on inside and/or outside of channels and can use
drugs that block or modulate channels
o Micropipette sucks onto section of neuron cell membrane with ion channel
 Planar lipid bilayers
o Record single channels
o Reconstitute channels expressed and purified
o Fuse vesicles
o Manipulate both sides of solutions and alter lipid composition
 Quartz substrates for single channel recording- modern
 Electrophysiology- disadvantages
o Slow- low output
o Requires skilled operator
o Expensive equipment
o Patience
o Sophisticated software for recording and analysis
o Electrically shielded rooms
 Latest technology
o Fast through put systems- cabinets with computers and everything in them to do
work for you
o Based on silicon orifice that replaces glass pipettes
o Population patch clamp (PPC) technology- pop recordings, i.e. 6 cells
 Maths and modelling
o Lots of maths, physics, computer programming and modelling involved
o Filtering, signal noise ratios, Markov model of opening and closing, probability
o How do ions move across use nanotubes for modelling
 Studying ion channels- structure
o Nuclear magnetic resonance (NMR), circular dichroism (CD), Xray
crystallography, cyro-electron crystallography, computational modelling and
structure predictions (in silico)
o 3D structure must allow
 Fast nature of ion conduction
 Ion selectivity- where is the selectivity filter?
 Movement to allow opening and closing- rotates and folds
 Ligand binding
 Voltage sensing
o Hard to get clear crystal structures- moving, can only lock in one state, need high
conc in solution need to get in solution
 Hydropathicity plots
o Amino acids hydrophobic or hydrophobic give score to hydrophobicity, i.e.
hydrophobic +ve, hydrophilic –ve diff spikes in diff areas of membrane
o How many membrane spacing domains?
 Integral membrane proteins
 o Type I- single transmembrane span, N-terminus in ectodomain, C-terminus in
cytosol
o Type II- single transmembrane span, C-terminus in ectodomain, N-terminus in
cytosol
o Type III- multiple spans
 What structures can cross the membrane
o Single α helix can’t form an ion channel
 Subunits
o Monomers
o Multimers- trimer, tetrameter, pentameter
o Composition- homo-mers, heteromers diff composition gives diff function
 Studying structure-function
o Site directed mutagenesis
o Transfections, overexpression, deletion
o Fluorescent labelling and microscopy
o Use of drugs and blockers
o Animal and disease models
 Classification of ion channels
o Based on structure
o Based in type of ion selectivity- Na, K, Ca, H, Cl
o Based on mechanism of gating- voltage gated, ligand gated (respond to
extracellular or intracellular ligands chemical binds on extra/intracellular side
and opens gate), mechano-sensitive (stretch, pressure, heat etc.), light gated
(artificial)
 Evolution of ion channels- common ancestor of ion channel that developed in pK system
 Channel diversity
o Gene duplication & divergence
o Alternative mRNA splicing
o Hetermultimeric assembly of different α subunits
o Heteromultimeric assembly of α and auxillary (β,, δ) subunits
o Association with other modifying proteins
 Where do we find ion channels- everywhere
o All membranes (inside [organelles] and out), all cells, all organs, all life forms
(animals, plants, fungi, bacteria, viruses)
 Function of ion channels
o Osmotic changes- particularly plants, marine animals
o Calcium signalling- synapses, muscle contractions
o Excitable cells- nerves, muscles
o Sensory signals
o Role in cell cycle  cancer
o For all physiological responses in animals

Voltage dependent potassium channels:

 Large diversity- electrical characteristics, amino acid composition

 Selectivity filter
 Venoms contain ion channel inhibitors
o Tarantula neurotoxins bind to voltage sensor of KvAP
o Scorpion neurotoxins bind with high affinity to the pore of KvAP
o Some pore forming proteins

Ligand gated channels:

 Bind to something to open channel

Glutamate receptors:

 Glutamate receptor subunits

o 3 families- tetrameters from 4 homologous subunits- NMDA, AMPA, Kainate
o NDMA receptors
 Permeable to K, Na, Ca ions
 High conductance
 Activate slowly
 Desensitise slowly & incompletely  prolonged Ca ion influx in face of
sustained glutamate release
 Voltage dependent block with Mg
 Activated during intense synaptic activity
 Mediates synaptic Ca entry
 Physiological model for memory formation and storage (memory and
learning)
 LT penetration- stimulation induced, persistent increase in synaptic
efficiency

Post-translational modifications:

 Time domains and modes of ion channel regulation

o Biophysicalpost-translational trafficking/recycling expression/assembly
o Shorter longer
 Phosphorylation
o Many ion channels are phosphorylated and in some this has been shown to
regulate the activity of the ion channel
o SoPIP2 water channel from spinach is gated and de-phosphorylation of Ser115
and 274 reduces the diameter of the channel opening
 Other PTMs- protein methylation (e.g. cardiac sodium channel), glycosylation,
ubiquitination, sumoylation, others to be discovered

Channelopathies:

 What if channels don’t work properly?

 Diseases involving ion channel function
o Cystic fibrosis, hypertension, diarrhea, cancer, incontinence, MS, epilepsy,
deafness, migraine, kidney stones, tinnitus, osteoporosis
 Autism spectrum disorder- linked to defects in voltage gated calcium signalling
 Epilepsy- K channelepsy
 Brain development- role for glycine receptors

Drug targets:

 Drugs can affect open probability, single channel conductance, gating, selectivity
 Ion channel drugs for medicine- e.g. epilepsy, hypertension
 Lots of research for new drugs/applications

Pores/toxins:

 Anthrax
o Virulence factor secreted by Bacillus anthracis
o Protective antigen ultimately forms a channel
o PA forms heptameters (7) and octameters (8) pore larger with octameters (8
subunits ring)
o The mean pore diameter of the octameter pre-channel is ~10% larger than the
heptamer
 Viroporins
o Viral proteins that form pores or ion channels
o Essential for replication of viruses
o First one described was NB and M2 from influenza viruses
o Drug targets of current anti-influenza drugs
o Many more proteins from a variety of viruses followed

Sensory Systems:
 Primary receptors- neuron, e.g. olfactory receptors
 Secondary receptors- not a neuron, e.g. receptors in gustatory, equilibrium and auditory
systems

Somatic sensory system- touch and proprioception:

 Tactile receptors in the human glabrous skin of the hand

o Each fingertip has 2000 tactile receptors of 4 diff types which are innervated by
afferents reflecting properties of respective receptor type
 Meissner corpuscle- mechanical transients, high freq vibration, Fast
Adapting Type I (FAI) very sensitive
 Pacinian corpuscle- mechanical transients, vibration at moderate freq
range, Fast Adapting Type II (FAII)
 Ruffuni organ- stretch, slowly adapting type II (SAII)
 Merkel disks- pressure, slowly adapting type I (SAI)
 Free nerve endings- pain, temp
o Fast adapting- immediate (vibrations), slow adapting- forces etc.
o Different afferent types respond to the same stimulus differently
 Tactile sensory control of object manipulation
o Overshoot phenomenon overestimate weight of something, i.e. picking up
bottle
 Tactile receptors in different parts of the body
 o Diff regions have diff tactile receptor types in diff proportions
o No Pacinian corpuscles in facial skin
o Glaborous skin of foot in innervated predominately by Meissner afferents (FAI)
o Hairy skin on arms
 Fast adapting afferents
 No Meissner afferents, instead Field units- very sensitive fast
adapting afferents with relatively larger receptive field
 Hair follicle afferents (fast adapting) innervate about 10-30
individual hairs
 Slowly adapting afferents- there are Merkel (SAI) afferents and numerous
SAII
 C-tactile afferents- unmyelinated, mediate pleasantness of touch,
activation felt subconsciously, possible involvement in modulation of pain
sensation
 Dermatomes- territory innervated by each spinal nerve
o Dermatomal maps vary among individuals
o Dermatomes overlap in regard to tactile sensation, less for pain and temp
testing pain provides more precise assessment of segmental nerve injury
o 2 pt discrimination threshold- fingers are more sensitive than arms with callipers
 Mouth sensitive as well speech, chewing complex
 Proprioception
o Sense of relative position of neighbouring parts of body, position of limbs and
other parts in space, strength of effort being employed in movement
o To provide this info proprioception has to be integrated with highly specialised
vestibular sensory system (considered separately)
o Specialised mechanoreceptors- proprioceptors (receptors for self) muscle
spindles, Golgi tendon organs, joint receptors
o Skin (cutaneous) mechanoreceptors- may provide proprioceptive info to signal
body part location by sensing pattern of skin stretch
o Visual system contributes (helps calibrate)
o Muscle spindles
 Extrafusal muscle fibres- true force producing fibres
 Intrafusal muscle fibres- part of the sensory organ muscle spindles, keep
sensory elements stretched to maintain sensitivity in changes in stretch
regardless of overall muscle length
 Primary endings (group I afferents)- show rapidly adapting responses to
changes in muscle length, provide info about velocity of the movement
 Secondary endings (group Ia afferents)- produce sustained response to
muscle length, thus largely provide info about the extent of muscle stretch
 ɤ motor neurons- activate intrafusal muscle fibres and by changing tension
significantly impact on sensitivity of muscle spindles
 α motor neurons- activate extrafusal (force producing) muscle fibres
o Highest density of muscle spindles is in extraocular muscles, intrinsic muscles of
the hand and muscles of the neck; not present in ear muscles
o Golgi tendon organs
  Formed by branches of group Ib afferents distributed among collagen
fibres that form the tendons- provide info about muscle tension
 Arranged in series with small no. (10-20) extrafusal muscle fibres- pops of
afferents provide accurate sample of tension which exists in a whole
muscle
o Joint receptors
 Several types, resemble receptors in Ruffini endings, Pacinian corpuscles
and Golgi tendon organs
 Function debatable- may contribute to fine representation of finger
position, however in most joints it seems they play a protective role in
signalling positions that lie near limits of normal joint range of motion
 Ppl with artificial joints exhibit only minor deficits in judging the position or
motion of limbs
 Anaesthesia of knee joint has no detectable effect on judging joints
position or movement
 Thalamic and cortical projections
o Info supplied by different somatosensory receptors remains segregated in its
passage to cortical circuits
o Primary somatic cortex SI (postcentral gyrus) consists of Brodman’s areas 3a, 3b,
1, 2
 Each cortical area contains a separate and complete representation of the
body- somatotopic maps
 Area 3b- 1st step in cortical processing, lesions result in deficits in tactile
sensation
 Area 1&2 lesions result in partial deficit and inability to use tactile info to
discriminate texture (1) and size/shape of object (2)
 Area 3a- receives input from proprioceptors
o Secondary somatosensory cortex SII- tactile learning and memory
o Parietal areas 5&7 involved in sensory and motor function recognition
 Plasticity in adult somatosensory cortex
o Amputation or nerve damage removing sensory input from one digit causes
changes in somatotopic maps (functional remapping)- takes place at multiple
levels of processing, in brainstem, thalamus and cortex. Central representation of
healthy digits expands to take over the cortical territory that has lost its main input
o If 2 fingers always receive the same concurrent sensory input, their borders fuse
and their representation becomes inseparable
o Short term deprivation of sensory input by local anaesthetics reversibly
reorganise receptive fields of cortical neurons, instead responding to the
stimulation of skin surrounding the anaesthetised region

Pain:

 Protective mechanism essential for preservation and survival of an individual

o Can’t live without pain (exceptions- congenital insensitivity to pain [CIP])- protects
us, otherwise bite tongue, roll ankles etc.
 o Unpleasant sensory and emotional experience associated with actual or potential
tissue damage, or described in terms of such damage
o Function to warn bodily harm form trauma and injury, but also signals the
presence of unhealthy conditions or inflammation in tissues of the body
o Sensation triggers a cascade of events that are essential for preventing further
damage and promoting healing
o A complex somatic distress signal, is a multidimensional phenomenon that
includes sensory-discriminative, affective-motivation, motor, autonomic
components
 Nociceptors
o Nerve cell endings that initiate the sensation of pain
o Nociceptors involves specialised receptors, not simply greater discharge from
afferents that respond to normal (innocuous) stimulus intensifies
 Types of pain
o Chronic- long time (2-12mths), pain that extends beyond expected period of
healing’=
o Acute- resolves quickly
o Nociceptive pain- caused by stimulation of peripheral nerve fibres (nociceptors)
o Neuropathic pain- originates in nervous system peripheral or central (brain)
o Psychogenic pain- physical pain caused/increased/prolonged by mental,
emotional or behavioural factors complains of pain that doesn’t match
symptoms
o 1st pain- sharp pain mediated by Aδ nociceptive fibres
 Type I Aδ nociceptive fibres respond to dangerously intense mechanical
and chemical stimuli
 Type II Aδ nociceptive fibres respond to dangerous heat levels
nd
o 2 pain- more delayed, diffuse, dull longer lasting pain mediated by C
nociceptive fibres
 Subgroup of afferents preferentially sensitive to either heat/chemical
stimulation or mechanical stimulation
 Molecular receptors
o TRPV1- found in Aδ and C fibres, confers sensitivity to heat and capsaicin
(chilli birds not sensitive to capsaicin, don’t have TRPV1 digestion not as
strong, can spread seeds). Member of transient receptor potential (TRP) channel
family. V1- vanilloid type 1 sensitive to endovanilloids (produced in peripheral
tissues in reponse to injury)
o TRPA1- sensitive to chemical irritants, menthol and noxious cold (<10°C),
caffeine suppresses TRPA1 activity. Snakes- in heat sensitive Loreal pit organs,
it detects infrared radiation
o ASIC3- acid sensing ion channel, responsible for muscle and cardiac pain
resulting from changes in pH associated with ischemia
o TRPV3 and TRPV4- mediate innocuous warm temp sensation (20-40°C), also
reacts to carvacol (oregano, tequila), eugenol (clove oil, nutmeg, cinnamon, basil)
o TRPM8- cold and menthol receptor, menthol shifts activation of cold responsive
fibres to warmer temps. Receptor involved in pain sensation, required for sensing
innocuous ambient cold temp
 Central pathways
o Anterolateral system- main neural pathway that conveys pain and innocuous
temp information to higher centres, capable of mediating non-discriminative touch
(unable to identify objects)
o Lissauer’s or dorsolateral tract- path of ascending and descending collaterals
travelling up and down +/- 2 segments
o Special dorsal column pathway for visceral pain- located closest to midline of
spinal cord. Midline myelotomy (surgical transection of axons in pathway) may be
used to relieve debilitating pain from visceral cancers
 Referred pain
o Pain perceived at a particular location other than its actual source
o Relatively few neurons in the spinal cord specialised solely for the transmission of
visceral (internal) pain
o Partly conveyed by neurons signalling cutaneous pain
o E.g. heart pain pain in arm
 Sensitisation
o Hyperalgesia- increased sensitivity to pain, slightly painful stimuli perceived as
significantly stronger and more painful
o Allodynia- pain induced by normally innocuous stimuli
o Peripheral sensitisation- usually results from the interaction of nociceptors with
substances released when tissue is damaged. Sensitising substances are
released from activated nociceptors themselves, produced as result of tissue
damage, or released from non-neuronal cells like immune system cells residing
within or migrating to injured area
o Central sensitisation- activity dependent increase in the excitability of neurons
following high levels of activity in nociceptive afferents
 Pain modulation mechanisms
o Explain subjective variability in painful stimuli and the striking dependence of pain
perception on the context of experience
o Gate theory of pain- both thin nociceptive and large diameter tactile nerve fibres
carry info from the site of injury and in the dorsal horn of the spinal cord, and
large fibre activity relative to the thin fibre activity inhibit signals transmitted via C
nociceptive fibres
o Endogenous opioid system- 3 opioid peptide groups with somewhat different
distribution within CNS enkephalins, endorphins, dynorphins. Explains
analgesic effects of opium derivatives like morphine
o Endocannaboids- supress nociceptive neurons in dorsal horn of spinal cord
without altering the activity of non-nociceptive neurons. Also act as
neurotransmitters all over the CNS and have various functions. Decrease release
of NTs like GABA and glutamate. Found in cannabis

Visual system:

 The eye
o Retina- layer containing photoreceptors
 o Choroid- composed of rich capillary bed, has high concentration of light absorbing
(non-sensory) pigment melanin
o Ciliary body- extending from choroid, muscular component, vascular component
(ciliary processes) produces fluid
o Sclera- tough white fibrous tissue, at front of eye is transformed into cornea
 Cataract- opacitiy of lens, 50% of worldwide blindess, caused by UV
exposure
o Aqueous humour- produced in posterior chamber and flows into anterior chamber
through pupil. Drained by specialised cells at junction of iris and cornea
 Glaucoma- failure to adequately drain aqueous humour, intraocular
pressure can reduce blood supply and thus damage neurons
o Vitreous humour- contains phagocytic that remove blood and other debris.
 Floaters- collection of debris, often arise in ageing vitreous membrane
when it pulls away from the retina, especially in myopic individuals
o Cornea- contributes most of necessary refraction, underwater its refraction is
eliminated
o Lens- considerably less refractive power, however its adjustable
 Accommodation- dynamic changes in refractive power of the lens

o
 Retina
o Outer layer ganglion cells amacrine cells bipolar cells and horizontal
cells rods/cones
o Rods- light
o Cones- colour red, blue and green light sensitive types
o Fovea- most sensitive part, all cones no rods use peripheral vision to see at
night
o Hard to distinguish green and red light similar wavelengths
 Light sensitivity
o Photopigment contains
 Retinal- aldehyde of Vit A
 Opsin- diff opsins tune the molecules absorption of light to a particular
region of the spectrum
o Rhodopsin- photopigment of rods
  Unlike most sensory cells, light causes cells to hyperpolarise rather than
depolarise
 Photoreceptor cells are neurons, but don’t generate action potentials and
in retina signal processing is achieved by means of graded potentials
(analog encoding)- possible due to small distance between cells
 Absorption of single light photon by rhodopsin results in the closure of 200
ion channels (2% of all channels). >100 photons required to produce a
comparable response in a cone
o Scotopic vision- rod mediated perception poor central resolution, poor
spatial/temporal, no colour info
o Mesopic- twilight vision when both rods and cones contribute
o Photopic- only cones contribute
 In a daylight condition rod contribution to vision drops out almost entirely
because their response saturates (reaches max level)
 Photoreceptor current in cones recovers about 4x faster than in rods
 Perception of light intensity and contours
o Optical illusions- light intensity perception based on overall brightness contrast or
brightness contrast after object segregation
o Brain/eyes analyse visual cues and give us colour not all that we see is real
o Identify object perception based on properties brain trying to recognise/group
object when it may not be there
 Central projections of retinal ganglion cells
o Visual field deficits resulting from damage along primary visual pathway
 Stereopsis
o Neurons in lateral geniculate nucleus of thalamus are strictly monocular, driven
by L or R eye
o Genticulate neurons terminate in alternating eye specific ocular dominance
columns within cortical layer 4
o Beyond layer 4 signals from 2 eyes converge and are called binocular
 Neurons in other layers which are located exactly over the centre of layer 4
ocular dominance column receive input mostly from one eye, while those
that lie over the borders between ocular dominance columns respond
equally well to simulation of other eye
o Stereopsis- sensation of depth that arises from viewing objects with 2 eyes. 2
eyes look at slightly different angles, objects that lie in front or behind the plane of
fixation project to non-corresponding on the 2 retinas
o Binocular neurons- receptive fields driven by 2 eyes are slightly offset so that cell
is maximally activated by stimuli that fall on non-corresponding parts of the retina
 Far cells- discharge to retinal disparities arising from points in front of
plane of fixation
 Near cells- discharge to retinal disparities arising from points in front of
plane fixation
 Tuned zero- respond to plane of fixation
 Tuning properties of neurons in striate complex
o Instead of concentric on-off receptive fields in retina and thalamus, neurons in
cortex respond vigorously to light-dark bars or edges
 o Neurons are tuned to their preferred orientation
o Visual scene is encoded in activity of distinct pop of orientation-selective neurons
o Responds less as stimulus goes horizontal, analyse visual scene by orientation of
lines
o Neurons arranged in vertical columns have receptive fields that are cantered on
the same region of visual space and exhibit similar orientation preference
o Map of orientation preference exhbiits smooth progressive change which is
interrupted periodically by point discontinuities where neurons with disparate
orientation preferences lie close to each other in a pattern resembling a child’s
pinwheel
o Each point in visual space lies in the receptive fields of a large pop of neurons hat
collectively occupy several mm of cortical SA, an area that contains neurons
having the full range of orientation preferences
 Processing of object properties and movement
o Layers of cells in lateral geniculate nucleus of thalamus are distinguished on the
basis of cell size (large neurons- magnocellular, small neurons- parvocellular)
o Both layers receive inputs from distinct pops of ganglion cells that exhibit
corresponding differences in cell size
o P ganglion cell- cells of parvocellular layers high spatial resolution (shape,
size, colour)
o M ganglion cell- cells of magnocellular layers high temporal resolution (location,
speed direction of moving objects)
o Cells of koniocellular layers- show minor role in low-acuity colour vision related to
evolutionary older (blue) system
 Ventral and dorsal streams of extrastriate cortex
o 25 areas involved in vision (know function not names)
o V4- contains neurons responding selectively to colour of visual stimulus without
regard to its direction of movement, part of ventral stream  damage causes
inability to see colour
o Middle temporal (MT) area- contains neurons responding selectively) to the
direction of movement change without regard to its colour, part of dorsal stream
damage results in inability to appreciate (see) movement of objects, difficulty
judging movement of approaching car or ppl, difficulty pouring tea because fluid
seems to be frozen
o Regardless of specialisation, info at diff stages at least partly converge, function
of higher visual areas involves integration of info from diff pathays
 Ocular asynchrony
o Strabismus
o Cats  cells in all layers

Auditory system:

 External ear
o Vertical asymmetrical convolutions of pinna are shaped so external ear transmits
more high freq components from an elevated source than from the same source
at sea level, function related to sound localisation
 o Human auditory meatus boosts sound pressure up to 100x for frequencies 3kHz
 Middle ear
o When sound travels from a low-impedance medium like air to higher impedance
medium, like water, almost all (99.9%) of acoustic energy is reflected. Overcome
by:
 Larger tympanic membrane transmits all energy to smaller diameter oval
window
 Lever action of middle ear bones/ossicles
o Middle ear muscles tensor tympani and stapedius reduces amount of sound
energy transmitted
o Hyperacusis- overly sensitive to moderate intensity sounds due to flaccid
paralyses of these muscles
o Weber test uses tuning fork placed against scalp to determine whether hearing
loss is due to conductive problems
o Tympanic membrane ossicles (malleusincusstapes) oval window
 Inner ear
o Semi-circular canals, round window, cochlea, organ of corti
o Bekesy travelling wave
 Counterintuitively basilar membrane is narrow and stiff at the basal end
near stapes at the oval window, and wider and more flexible at the apical
end
 Tonotopic place encoding- labelled line coding mechanism. Our perception
of sound depends on where each component frequency produces
vibrations along the basilar membrane
o Mechanoelectrical transduction- can detect movement, converts displacement
into electrical potential
 Electrical properties of hair cells
o Hair cell has resting potential -45mV relative to perilymph and -125mV relative to
endolymph
o K+ serves both- to depolarise and repolarise the cell
o Endolymph is high in K so opening mechanically gated K channels let K stream in
from endolymph into the cell and depolarise it, this also causes Ca voltage gated
ion channels and release neurotransmitter
o Perilymph is poor in K and rich in Na. Depolarisation of the cells opens voltage
gated K channels, and Ca dependent K channels at the base of the cell to open
allowing K flow out from the cell into the perilymph
o Tight junctions seal apical surfaces of hair cells ensuring that endolymph
selectively bathes the hair bundle and is separate from basal proportion
surrounded by perilymph
o Stria vascularis plays central role regulating ion composition of endolymph
 o
 The cochlear amplifier
o Inner hair cells are sensory receptors innervated by afferent fibres
o Outer hair cells are innervated by efferent nerve fibres
o Evidence of cochlear amplifier
 Tuning is too sharp to be explained by passive mechanisms alone
 At very low sound intensities basilar membrane vibrates 100x more than
expected
 Ear can actively generate sound- otoacoustic emissions either
spontaneously or in response to stimuli. Otoacoustic emissions are
clinically important because they are the basis of a simple, non-invasive,
test for hearing defects in newborn babies and in children who are too
young to cooperate in conventional hearing tests
o Tinnitus (ringing in ears) while majority of cases has central origin, it may result
from activity of outer hair cells
o Blocking outer hair cells eliminated ability to distinguish close freq sounds
o Outer hair cells change their shape (contract/expand) in response to small
electrical currents outer hair cells are cochlear amplifiers- can contract and pull
basilar membrane up at their resonant frequencies
 Binaural hearing, sound localisation
o For sound localisation humans use several mechanisms
o For localisation in horizontal plane:
 Interaural time differences (sound onset and phase shift)
 Longest interaural time distance is 700 (distance between ears
divided by speed of sound), psychophysics experiments have
shown that we can detect differences as small as 10μs, we can
localise sound up to 1° precision
 Interaural intensity differences
o For detection of sound elevation, the spectral filtering mediated by external
pinnae and thus spectral cues are used
o Interaural time distance
 Neural circuitry computing interaural time difference is located in medial
superior olive MSO (brainstem nucleus)
  In humans computation performed by delay lines and coincidence
detectors
 Works only within freq range when phase locking of spikes is possible-
<3kHz
o Interaural intensity difference
 Neural circuitry computing interaural intensity difference is located in
lateral superior olive MSO (brainstem nucleus)
 In humans computation performed by excitatory/inhibitory interaction
 Sound processing
o Nuclei of lateral lemniscus (brainstem)- encodes onset of sound regardless of
freq or intensity, encodes sound duration
o Inferior colliculus (brainstem)
 Contains auditory space map in 3D
 Responds to components of biologically relevant sounds- neurons may
respond to specific freq modulated sounds or sounds of specific duration
 Filters self-effected sounds from vocalisation, chewing or respiration
activities
o Auditory thalamus- medial geniculate complex in humans likely involved in
speech sound analyses
o Auditory cortex
 Primary auditory complex A1
 Contains longitudinally arranged tonotopic maps
 Combination sensitive neurons sensitive to combination of tones
 Orthogonally there are stripes of neurons either excited by input
from 2 ears (EE) or excited from 1 ear and inhibited from another
ear (EI cells) reminiscent of visual dominance columns
 Secondary auditory cortex or ‘belt areas’

Vestibular system:

 Provides info about orientation of head in respect to gravity and head motion
 Sensory receptor cells located in semicircular canals of inner ear and otolith organs-
utricle (orientated close to horizontal plane) and saccule (vertical plane)
 Vestibular input controls
o Ocular reflexes- e.g. compensate for head movement and stabilise visual scene
o Postural adjustments
o Perception of spatial orientation
o Navigation through environment
 Vestibular processing is inherently multisensory- input from all the vestibular organs is
integrated with input from the visual and somatic sensory systems (proprioceptive input)
to provide perception of body position and orientation in space
 Otolith organs
o Considerable spontaneous activity in nerve fibres to be able to encode changes
in any direction
 o Head tilt can produce displacement similar to acceleration, however, blindfolded
subjects can distinguish between those 2 stimuli, by integrating info from
semicircular canals
o In most natural circumstances hair bundle displacement will occur transiently in
response to linear acceleration and tonically in response to tilting of head

o
 Semicircular canals
o Ampulla- bulbous expansion at base of each semicircular canal
o Crista- sensory epithelium containing hair cells
o Cupula- gelatinous mass

o
 Ocular reflexes
o Vestibule-ocular reflex (VOR)- mechanism for producing eye movements that
counter head movements thus permitting the gaze to remain fixed on a point
(fixation pt)
 Compensatory eye movements extremely rapid within 5ms
 Physiological nystagmus eyes move slowly to counteract the head
movement, when it reaches its far limit, eye jumps back to another
extreme by fast saccade. Reflex described in terms of direction of slow
and fast eye movement
 Spontaneous nystagmus- when eyes move rhythmically from side to side
in absence of head movement there is dysfunction on one of the sides
 Oscillopsia (bouncing vision)- loss of VOR
 Clinical evaluation fo vestibular system
o VOR mediated by excitatory and inhibitory inputs from 2 sides of the body
o With lesion to the medial longitudinal fasciculus MLF lateral movement is
observed only on less active side

Chemical senses:

 Olfactory system
 o Humans can detect ozone reliably 10 molecules per billion in room, Citrus smell
(D-limonene)- 15 mols per bil, Ethanol- 2000 mol per bil
o Perceived smell may change with odorant conc
o Anosmia- failure to identify one or more common odours
o Zink salts are toxic to olfactory system and irreversibly damage olfactory
receptors and stem cells
o Rats, dogs etc. have much larger olfactory bulb than humans
o Odorant receptors
 About 3-5% of genome devoted to encoding odorant receptors
 Humans- 950-1000 apparent odorant receptor genes from which some are
so called pseudogenes and only 400 are transcribed
 Each receptor cell expresses only one gene and one allele from each gene
 Olfactory neurons are constantly renewed (rodents- all neurons are
renewed every 6-8wks)
 Olfactory ensheathing cells are glia cells believed to support growth of new
axons in mature nervous system. Some experimental therapies attempted
to use them for repair of CNS damage like spinal cord injuires
 Taste/gustatory system
o 5 perpetually distinct categories of tastants- salt, sour, sweet, bitter and unami
(savoury, monosodium glutamate)
o Some parts of tongue may be marginally more sensitive to one or another taste,
but no functional specialisation
o Artificial sweeteners (mostly amino acid derivatives)
 Saccharin- 300-500x sweeter than sugar, bitter aftertaste
 Aspartam- derived from AAs aspartic acid and phenylalanine
 Neotame- 7000-13,000x sweeter than sugar
o Miraculin- taste buds exposed to miraculin, ordinary sour foods (citrus) are
perceived as sweet, effect lasts up to an hour

Motor control mechanisms:

 Neural centres responsible for movement control
o Lower motor neurons (α motor neurons)- neurons which send their axons directly
to skeletal muscles
o Local circuit neurons- located in spinal cord or in brainstem cranial nerve motor
nuclei activate α-motor neurons
o Upper motor neurons- control local circuit neurons and α-motor neurons
o Complex circuits- regulate activity of upper motor neurons without direct access
to either local circuit neurons or lower motor neurons instead

Lower motor neuron circuits:

 Lower motor neurons send their axons directly to skeletal muscles

o Usually mean α-motor neurons however γ-motor are also LM neurons
o Axons travel via the ventral roots and peripheral nerves or cranial nerves (in case
of brainstem cranial nerve motor nuclei)
 o All commands for movement (reflective or voluntary) are ultimately conveyed to
muscles only by lower motor neurons
o ‘final common path’- no other cells have direct access to muscles, has to go via
LM neurons
 Local circuit neurons
o Activate α-motor neurons
o Located close to where corresponding α-motor neurons are (in spinal cord or
brainstem cranial nerve motor nuclei)
o Receive input from sensory neurons
o Receive descending projections from higher centres
o Mediate sensory motor reflexes
o Maintain interconnections for rhythmical and stereotyped behaviour
o Even without inputs from brain can control involuntary highly coordinated limb
movements like walking (demonstrated in animals, but not humans)
 Upper motor neurons
o Cell bodies located in cerebral cortex or brain stem
o Axons synapse with local circuit neurons and rare cases (mostly for distal
muscles) directly with lower motor neurons
o Essential for initiation for voluntary movement
o Essential for complex spatiotemporal sequences of skilled movements
o Upper motor neurons in brainstem regulate muscle tone, and orientation of eyes,
head, body with respect to vestibular, auditory visual and somatic sensory inputs
 Complex circuits
o Need direct access to either local circuit neurons or lower motor neurons
o Regulate activity of upper motor neurons
o Cerebellum
 Largest subsystem detecting and attenuating the difference between
expected and actual movement- ‘motor error’
 Mediates real time ongoing error correction (feedback control)
 Responsible for LT reduction of errors (motor learning)
o Basal ganglia
 Suppress unwanted movements
 Prepare upper motor neuron circuits for initiation of movement
 Malfunction can lead to Parkinson’s and Huntington’s disease

 Motor neuron-muscle relationship
o Each lower motor neuron innervates muscle fibres within a single muscle
o Each muscle fibre is innervated only by one single α-motor neuron
o All motor neurons innervating a single muscle (motor neuron pool for that muscle)
are grouped together in one cluster
o Motor neuron pools that innervate distal parts of the extremities (fingers/toes) lie
farthest from the midline (lateral motor neuron pool)

o
 Motor unit
o Made up of a motor neuron and skeletal muscle fibres innervated by that axon
o Individual motor axons branch within muscles to synapse on many muscle fibres
o Fibres are typically distributed over a relatively wide area within the muscle
 To ensure contractile force is spread evenly
 To ensure local damage to motor neurons or their axons will not have
significant effect on muscle contraction
o Action potential generated in the axon bring to threshold all muscle fibres
innervated
o Motor unit is the smallest unit of force that can be activated to produce movement
 Types of motor units
o Vary in size- in regard to cell body size of motor neuron and no. of fibres it
innervates
o Small α-motor neurons innervate relatively few muscle fibres to form motor units
that generate small forces
o Large motor neurons innervate larger, more powerful motor units
o Small units have lowest activation thresholds and thus are first to be recruited
o Motor units differ in types of muscle fibres that they innervate
o 3 major types
 Slow (S) motor units
o Small cell bodies, small number of muscle fibres
 o Resistant to fatigue- muscle fibres rich in myoglobin, mitochondria, dense
capillary network
o Important for activities that require sustained muscular contraction, e.g. posture,
o Low activation threshold
o Capable of low firing rates
 Fast fatigue resistant (FR) motor units
o Intermediate size
o Generate 2x the force of a slow motor unit
o Fatigue resistant
 Fast fatigable (FF) motor units
o Largest motor units consisting of pale muscle fibres
o Generate highest level of force
o Sparse mitochondria therefore easily fatigable
o High activation threshold
o Important for brief exertions that require large forces such as running or jumping
o Capable of high firing rates

o
 Types of motor units
o Soleus muscle involved in postural control has predominately small motor units
and avg innervation ratio is 180 muscle fibres per motor neuron
o Gastrocnemius muscle innervation ratio is 1000-2000 muscle fibres per motor
neuron and can generate forces needed for sudden changes in body position
o Extraocular muscles have avg innvervation ratio of 3 fibres per unit
 Use dependent motor unit plasticity
o Pattern of neural activity in a motor nerve provides instructive signal can influence
expression of muscle fibre phenotype. The relative role and extent of genetic
predetermination is not fully clear
o Implications for FES (functional electrical stimulation) in paralysed patients
 Chronic electrical stimulation in cats fibre types change to slow
 Use dependent motor unit changes
o Exercise regimes can ‘slow’ the contractile properties of motor units while
increasing the endurance and strength of muscle fibres
o Neural contributions to exercise induced changes in performance aren’t limited to
alterations of motor unit phenotype
o Increase in strength achieved in the early phases of resistance training often
exceeds what can be attributable to phenotype changes indicating central neural
mechanisms that mediate adaptation to training regime
o Training one arm has shown appreciable gains in the non-exercised limb
o Gains in muscle strength could be achieved by even imagined exercise
 Regulation of muscle force
o Muscle force could be increased by increasing discharge rate (no. of spikes per
unit time) or no. of active motor units
o Gradual increase in muscle tension results from recruitment of motor units fixed
in order according to their size
 Weak synaptic stimulation activates only low threshold S motor units
 As synaptic activity driving a motor neuron pool increases, FR units are
recruited and finally at the highest levels of activity FF units are recruited
o Systematic relationship known as the size principle
 Effects of stimulation on muscle tension
o Under normal conditions the max firing rate of motor neurons is less than that
required for fused tetanus
o Asynchronous firing at different lower motor neurons provides a steady level of
input to the muscle, which averages out the changes in tension due to
contractions and relaxations of individual motor units and achieves apparently
smooth overall muscle contraction
 Muscle stretch reflex
o Stretch reflex (myostatic/knee jerk/patellar reflex) is a monosynaptic reflex with
biological function to maintain muscle length at a desired value
o From control pt of view it is feedback control mechanism
 Deviation from the desired length are detected by the muscle spindles,
since increases or decreases in the stretch of muscle spindles alter the
level of activity in the sensory afferents, which directly translates into
excitation of α-motor neurons regulating strength of muscle contraction
 Induced muscle contraction will return its length to desired position
restoring muscle spindle activity to background level
o During neurological testing input is mostly from Ia muscle spindle afferents
o Normally muscles are always under some degree of stretch, this reflex circuit
mediated by group II muscle spindle afferents is responsible for steady level of
muscle tension muscle tone
 Gain of the stretch reflex
o Depends on excitability of α-motor neurons and sensitivity of muscle spindles
regulated by γ-motor neurons
o Level of γ-motor neuron activity referred to as γ bias or gain and ca be adjusted
by upper motor neuron pathways as well by local circuitry
o Gain of the myotatic reflex refers to the amount of muscle force generated in
response to a given stretch of the muscle spindle
Under various demands of voluntary and involuntary movement α and γ motor
neurons are often coactivated by higher centres to prevent muscle spindles from
being unloaded or overstretched/overactivated
o Γ motor neuron activity can be modulated independently of α-motor neuron
activity if the context of movement requires it
o In general γ motor neuron activity is high if movement is relatively difficult and
demands rapid and precise execution
 ‘Viscous cycle’ theory of muscle pain
 o Demonstrated in anaesthetised cats that activation of muscle nociceptors (group
III and IV afferents) via γ-motor neurons can increase muscle tone and stiffness
causing further ischemia and accumulation of muscle metabolites increasingly
stimulating nociceptors and so on viscous cycle theory/ Johansson-Sojka
hypothesis
o Example of positive feedback loop
o While painful muscles do become stiffer, no evidence supporting increased
muscle spindle activity in humans- suggested that anaesthesia used in cat
experiments may increase excitability of spinal cord circuits
 Coactivation and α and γ motor neurons
 Negative feedback system to regulate muscle tension
o Golgi tendon organ circuit is a negative feedback system to regulate muscle
tension- contracts Ib inhibitory interneurons in local circuits
o Golgi tendon organ circuit counteracts small changes in muscle tension by
increasing or decreasing the inhibition of α-motor neurons
o Golgi tendon organ control system tends to maintain a steady level of force,
counteracting effects that diminish muscle force, i.e. fatigue
o Protective role at large forces
o Ib inhibitory interneurons receive inputs from various sources including upper
motor neurons, joint receptors, muscle spindles and cutaneous receptors
 Flexion reflex pathways
o Triggered by cutaneous nociceptors (Aδ myelinated fibres)
o Polysynaptic pathway
o Excitation of ipsilateral flexors and inhibition of extensors
o Inhibition of contralateral flexors and excitation of extensors, thus providing
postural support during withdrawal
o Following damage to descending pathways other types of stimuli can trigger
flexion reflex
o Descending pathways also able to suppress reflex
 Summary
o Muscle spindle system is feedback control system that monitors and maintains
muscle length and thus keeps limbs in desired position
o Golgi tendon organ system is a feedback control system that monitors and
maintains muscle force
 Spinal cord circuitry and locomotion
o Central pattern generators (CPGs) are biological neural networks that produce
rhythmic patterned outputs
o Fully capable of controlling the timing and coordination of complex patterns of
movement and adjusting them in response to altered circumstances
o In other words CPGs don’t require sensory input to be initiated, but their activity
could be modified by sensory feedback
o Cats after transection of spinal cord at thoracic level can walk on treadmill making
coordinated locomotor movements with their hindlimbs
o Speed of locomotor movements is determined by the speed of the treadmill,
suggesting that movement is reflexive response to stretching the limb muscles
 o When dorsal roots are also transected and thus there is no sensory input,
locomotion can be induced by intravenous injection of L-DOPA (dopamine
precursor)
o In humans CPGs have not been successfully activated
 Lower motor neuron syndrome
o Paralyses- loss of movement
o Paresis- weakness of muscles
o Areflexia- loss of reflexes
o Muscle atrophy due to denervation and diuse
o Fibrillations- spontaneous twitches of single denervated muscle fibres
o Fasciculations- spontaneous twitches of single motor units

Upper motor neuron circuits:

 Descending motor control

o
 Motor cortex
o Primary motor cortex and premotor cortex
o Mediates planning and initiation of complex temporal sequences of voluntary
movements
o Cortical areas receive regulatory inputs from basal ganglia and cerebellum via
relays in the ventrolateral thalamus
o Upper motor neurons of primary motor cortex have stronger direct effect over α-
motor neurons than premotor cortex
 Primary motor cortex
o Primary motor cortex layer 5 pyramidal cells are upper motor neurons
o Betz cells are largest neurons (by soma size) in body, but constitute only 5%of
pyramidal cell projections to the spinal cord
o Betz pyramidal neurons are primary responsible for skill movements of hands and
fingers
o Corticobulbar (to brainstem) and corticospinal tracts, axons pass through internal
capsule
o 90% of pyramidal tract neurons cross midline (decussate)
o 10% form anterior corticospinal tract and terminate ipsilaterally of bilaterally,
mostly control axial and proximal limb muscles
 o Only limited number of axons has privilege to synapse directly with α-motor
neurons limited to forearm and hand
o Some elements of corticobulbar and corticospinal tracts originate from
somatosensory cortex and terminate in dorsal horn- likely to be involved in
modulation of proprioceptive signals
o Animals with larger repertoire of skilled movements have predominately more
connections to motor circuits in ventral horn
o Electrical stimulation of motor cortex elicits contraction of muscles on
contralateral side
o Observations in progression of epileptic seizures motor cortex contains
organised spatial representation/map of the body’s musculature
o Cortical homunculus is a visual representation of the concept of the ‘body within
the brain’
o Finer organisation assessed by cortical microstimulation and spike triggered EMG
averaging revealed that maps are rather different to what was believed before
o Even smallest currents capable to illicit response excited several muscles and
simultaneously inhibited others suggesting that organised movements rather than
individual muscles are represented in the map
o Peripheral group referred to as muscle field
o Within same body parts a particular movement could be elicited by stimulation of
widely separated sites supporting argument that neurons are connected in
patterns to create specific movement patterns
o In behaving animals, force generated by contracting muscles correlated with firing
rate of upper motor neurons even prior to execution of expected movement
o Activity of upper motor neurons in cortex controls movements rather than
individual muscles
o Such organisation represents dynamic and flexible means for encoding higher
order movement parameters that entails the coordinated activation of multiple
muscle groups across several joints to perform behaviourally useful actions
o Experiment- varying microstimulation time in monkeys to resemble volitional
movements (hundreds of ms to several secs)
 Resulting movements sequentially distributed across multiple joints and
were strikingly purposeful and target orientated
 Output encoded not simply the trajectory of arm motion, but also final
position of the hand- hand to mouth as if to feed, hand to central space as
if to inspect object
 Encoding of movement direction
o Recordings during visually guided movements
o Neuronal population vector- discharges in individual upper motor can’t specify the
direction of an arm movement simply because they are tuned too broadly, thus
each arm movement must be encoded by concurrent discharges of a large pop of
such neurons
 Premotor cortex
o Receives extensive multisensory input
o Receives signals related to motivation and intension from prefrontal cortex
 o Influences motor behaviour indirectly via reciprocal primary motor cortex output
constitutes 30% of fibres in corticospinal tract
o Recent view on premotor cortex function is that its main function is to select
movements appropriate to the context of the action and select movement based
on external events
o Cells fire at appearance of visual cue well before monkey receives signal to
actually make the movement encodes intension
o Patients with frontal lobe damage may have difficulty learning to select a
particular movement to be performed in response to a visual cue, even though
they understand the instruction and can perform the movements
o Medial premotor cortex initiates movements based on internal cues rather than
external- lesion to this area in animals reduces no. of self-initiated ‘spontaneous’
movements while ability to execute movements in response to external cues
remains largely intact
o Normally cells in medial premotor cortex begins to discharge 1-2 secs before
onset of self-initiated movement
o Individuals with lesions in premotor cortex may also have difficulties performing
movements in response to verbal commands
o Broca’s area is critical for production of speech
 Mirror motor neurons
o Typically fires both when animal acts and when animal observes the same action
performed by someone else
o Neural activity pattern of those neurons ‘mirror’ the external (observed)
behaviour, as they would themselves control the execution of this action
o Those neurons fire even when view of action is obstructed or there are only some
other cues like sound available
o Mirror neurons subserve imitation learning
 Motor control centres in the brainstem
o Vestibulospinal tract
 Direct projections from vestibular nuclei to the spinal cord ensure a rapid
compensatory feedback response to any postural instability detected by
vestibular apparatus
o Reticular formation
 Relevant neurons in the reticular formation initiate feedforward
adjustments that stabilise posture during ongoing movements
 Feedforward mechanism predicts the resulting disturbance in body stability
and generates an appropriate stabilising response

o
Exercise Physiology:
 Control of movement and exercise- ‘motor control’ perspective
o Neuromuscular system- brainspinal cordskeletal muscles and peripheral
nerves
 Broader perspective
o Lungs, neuromuscular and metabolism, heart and blood vessels, skin
o Cardiovascular system- always working, closed
o Skin- muscles and skin should cook under heat produced from exercise but don’t
 Essential physiology of movement
o Brain controls muscles and our movement and this involves feedback from
muscles, tendons and joints (neuromuscular)
o Muscles need energy released from the metabolism of foodstuff (glycogen) and
its metabolism are controlled mainly by the liver, adipose tissue and GI tract, as
well as muscles themselves
o O2 requirements of the brain and muscles are supported by breathing
(respiratory) and circulation (CV)
o Heat generated by muscles must be lost to avoid heat related injury and death
(thermoreg)
o Exercise depends on integrated muscle control of all these fundamental
processes
 Physiological control of movement and exercise
o Some regions of brain control of few systems- i.e. thermoreg, muscular, CV
vasodilation etc.

o
Muscle and energetics:

 Force, motor unit recruitment and fibre type

o Motor unit pool- All α-motor neurons which project to a given muscle
o Force controlled by CNS via its effects on no. of Mus recruited and firing
frequency of Mus
o Max force of a muscle can only be generated by recruiting 100% of the MU pool
 Very few ppl able to recruit 100% of Mus- most ppl 90-95% train to
increase
o Graded variations in force, velocity (speed) or power (force x velocity) depend on
graded variations in MU recruitment
o The type of MUs and muscle fibres involved in exercise depends on the force or
power (intensity) of the task
 o Muscles contract at submaximal forces during common activities (walk, run)
o i.e. need to increase tetanic force by 20% (run), need to recruit 50% of motor
units

o
 Muscle shortening, power and ATP hydrolysis
o Power (watts)= force x velocity
o Myosin, actin, myosin heads comparative
o Faster the cycle, faster the shortening how quickly ATP broken down and
reconstituted enzymes- catalyst myosin head/myosin ATPase- breaks down
own fuel
o Hence function of myosin ATPase activity
o Calcium released by cytoplasmic reticulum

o
 Energy, metabolism and exercise
o 3 pathways all contribute to energy supply to resynthesise ATP at rate its being
used
o Creatine phosphate- enough for few seconds of intense exercise anaerobic
o CHO- too much broken down lactate anaerobic
o Heat by product of all
o Amount of ATP in muscle cells generally stay constant during exercise very
efficient
o Graph
 Short, intense exercise (5secs)- all energy from anaerobic
 60mins of exercise- nearly all from aerobic
 In between- starts to shift more towards aerobic
 o Action and relaxation consumes energy- most energy goes into action

o
 Mechanical power and efficiency
o Efficiency (%)= mechanical power/metabolic power x 100%
o E.g. on bike 100 J/s mechanical power/ 400 J/s metabolic power = 25% efficiency
 Remaining (75%) lost as heat need to dissipate heat thermoreg
important

o
 Summary
o Muscle force is increased through neural control of MU recruitment and firing
frequency
o Force applied as muscle shortens generates muscle and mechanical power
o ATP hydrolysis is required for muscle force and power production, and fuel
metabolism supports the demand for the continued supply of ATP
o Contributions of aerobic and anaerobic metabolism to ATP supply during exercise
depend on the intensity and duration
o Efficiency of developing mechanical power is ~20-25% and most of the energy
liberated by fuel metabolism is in form of heat

Oxygen uptake:

 Basic concept underlying measurement of pulmonary O2 uptake

o O2 uptake= O2 inspired – O2 expired

o
 V dot- rate of oxygen uptake
o Inhale air- 21% of which is oxygen, exhale air- 18% oxygen at rest during
exercise 14-15%
 Difference absorbed into blood stream
 Max, stepwise and graded exercise
o Common type of exercise protocol
 o Assessment of anaerobic threshold and VO2 max
o Various modes of exercise
o Energy/oxygen demand is proportional to power output
 Continuous response of O2 uptake during stepwise, graded exercise

o
o Stepwise, graded- every 3 mins increase in workload
 Not steplike increase in oxygen uptake, exponential rise in oxygen
uptake dynamic response/curve
 Working towards steady state harder to reach steady stake as
exercising for longer/harder
 Overall- linear curve, then plateaus
 Resting and exercise O2 uptake in humans

o
 Oxygen deficit and anaerobic metabolism during submaximal exercise

o
 Lactate (anaerobic) threshold
o Lower workloads, lactate doesn’t change much as all
o Work for longer, passes threshold and lactate increases
 o Heart can use lactate as fuel, just like glucose
o Lactate threshold- rate of lactate uptake exceeds lactate removal at this point

o
 EPOC: excess post-exercise O2 consumption
o As soon as you stop exercise, doesn’t go back to resting straight away, stays
elevated
o Energy needed to remove waste products, cool down etc.

o
 Which consume more oxygen during exercise?
o Splanchnic- liver, GIT, spleen
o Blue bars- VO2 max, white- resting
o Heart and skeletal muscle consume the most during exercise

o
 Mitochondria consume more O2 and support increased ATP synthesis during exercise
o Sit below sacrolema and between myofibrils- very well positioned to support ATP
resynthesis
 o
 Summary
o During maximal graded exercise, oxygen uptake increases in proportion to
exercise intensity until it begins to plateau (and might plateau) near the end of
exercise
o At each stage of exercise, oxygen uptake rises towards a steady state value at a
rate which depends on exercise intensity
o During a period of adjustment to a new intensity an oxygen deficit (anaerobic
metabolism) is incurred that is inversely proportional to the speed of adjustment
of oxygen uptake
o Blood lactate begins to rise at higher intensities (LT) and is a function of the rates
at which lactate is released into the circulation from contracting muscles and
taken from the circulation by other tissues
o After exercise, oxygen uptake returns to resting levels following an exponential
time course, but remains higher than resting levels for a period proportional to the
intensity and duration of exercise
o This excess post-exercise consumption (EPOC) contributes to the total oxygen
consumed and energy liberated in performing exercise

Fick equation- oxygen supply and utilisation:

 Increasing O2 uptake depends on raising O2 delivery and control of circulation and

breathing
o Like cogs in a machine, muscle work stimulates O2 consumption and
cardiorespiratory systems respond to increase O2 delivery from the atmosphere
to the contracting tissues
o Raise oxygen consumption, must raise O2 delivery in coordinated manner
o Cogs- muscle interconnected with circulation, interconnected with ventilation
 Muscle- O2 consumption, CO2 production
 Circulation- CO2 flow, O2 flow
 Ventilation- inspired and expired feedforward and feedback mechanisms

o
 Fick, O2 uptake and cardiac output
o Dashed arrow= oxygen flow into circulation  because the amount of oxygen
stored in body tissues is low and relatively constant, is equal to oxygen uptake
o q2 = oxygen uptake
o q1= oxygen flow in blood returning to the lungs
o q3= oxygen flow in blood leaving the lungs  q2= q3-q1 (difference equals
oxygen uptake)
o Two flows are equal to the product of blood flow (Q dot) and conc of oxygen (C 02)
in the pulmonary arteries (to lungs, Q•Cpa02) and pulmonary veins (Cpv02)
o Fick eqn: V•O2 = Q• x (Cpv02 – CpaO2)
 Q• (Q dot)= cardiac output (blood flow into or out of lungs)

o
 O2 consumption in heart and skeletal muscles is matched by O2 flows to them
o Thick arrows- O2 flow
o O2 flows (mL•min-1) from atmosphere into the pulmonary circulation and to
mitochondria in all respiring cells via the systemic circulation
o Increased consumption of O2 by contracting tissues stimulating an increased O2
flow from atmosphere to the mitochondria in contracting cells
o Higher O2 flow to contracting tissues; lower O2 flow from these tissues back to
the heart and lungs

o
 Graded exercise, Fick variables and cardiac output
o Graph: arterial (pa)- systemic arterial blood (equal to pulmonary venous blood),
venous (pv)- blood draining tissues and returning to lungs(equal to pulmonary
arterial blood)
o Data from study of well-trained cyclists
o O2 uptake increases in a (roughly) linear manner and then plateaus
 o CO (Q•) increases 4-5x and plateaus earlier than O2 uptake- linked to
cardiovascular control
o CaO2 (arterial O2 conc) is stable, although it might rise slightly due to
haemoconcentration or even fall dramatically in elite athletes linked to
respiratory control and O2 supply and the matching of ventilation to CO
o CvO2 declines in an exponential manner and linked to O 2 utilisation and control of
metabolism within contracting tissues
o a-vO2 increases in an exponential manner- reflects the interaction between O2
supply and utilisation

o
 Normal CV responses during graded exercise
o Dashed lines- responses in endurance trained individuals
o MAP- mean arterial pressure
o TPR- total peripheral resistance

o
 Cardiac output and its distribution during exercise
 o
 Ventilatory response to exercise
o Training delays onset of threshold
o Ventilation increases as a function of exercise intensity and O2 uptake
o At mild to moderate intensities, ventilation increases in proportion to the increase
in O2 uptake- a linear response
o At higher intensities, V increases disproportionately more than the increase in O2
uptake
o Transition between these 2 responses (linear and nonlinear)  Owle’s Point 
has been termed the ‘anaerobic threshold’, ‘ventilatory threshold’ or ‘gas
exchange threshold’
o Training, which increases VO2 max, shifts threshold to right to a higher minute
ventilation and O2 uptake
o The rise in minute ventilation is a function of a rise in tidal volume and breathing
frequency
o Not clear how breathing response is controlled physiologically

o
 Summary
o Fick eqn for oxygen focuses attention on the 3 variables which comprise it and
physiology related to them
o CO (Q dot) is, quantitatively, the most important variable of the Fick eqn which
influences oxygen uptake
o Examining the behaviour of CO during exercise focuses attention on the control
of circulation in its entirety, because the heart operates within a closed system of
 blood vessels (i.e. the vasculature) and thus both influences and is influenced by
the vasculature
o E.g. disease which directly affect the heart (coronary heart disease) or vsculature
in the lower limbs (peripheral arterial disease) will impair the rise in CO during
graded output
o Oxygen conc in systemic arterial blood, which is equal to that in pulmonary
venous blood draining the lungs, is influenced by breathing and the effectiveness
of gas exchange between the lungs and circulation
o E.g. chronic constructive pulmonary diseases reduce the Vol of air within alveoli
and the rate of oxygen diffusion to the circulation, resulting in a low arterial
oxygen concentration (hypoxaemia)
o Together, CO and arterial oxygen conc influence the rate of oxygen delivery to
contracting muscles
o The oxygen conc in systemic (mixed) venous blood, which is equal to that in
pulmonary arterial blood, is influenced by the utilisation of oxygen by contracting
muscles relative to the supply of oxygen by circulation
o E.g. metabolic defects in muscles (i.e. McArdle’s disease) can restrict rate of fuel
metabolism and oxygen consumption within contracting muscles, resulting in an
increased oxygen conc in the blood (venous) leaving these muscles

Case studies (integration):

 Central cardiovascular limitations- heart failure

o Heart failure limits stroke volume and the rise in CO
o Early stages, walls of heart enlarges, chamber volume reduced (hence SV
reduced) high BP thickens walls to withstand higher BP
o Heart muscle weaker, SV falls
o Healthy patients able to elevate CO much higher than heart failure patients
decreased SV

o
 Peripheral vascular limitations
o Peripheral arterial disease restricts limb blood flow and limits the rise in heart rate
o i.e. stroke, arthrosclerosis- pain in lower limbs when walking
 o PADs can’t walk as long as controls, much lower HR fatigue too early because
of blood flow restriction and muscle ability

o
 Pulmonary limitations
o Pulmonary gas exchange, CaO2 and the Fick eqn for O2 uptake


o Low arterial O2 conc in the elite athlete limits VO2 max
o Oxygen saturation
o Pulmonary arterial blood pulmonary venous blood (graph)
o no effect in untrained
o elite athletes desaturate huge CO, CV adapts, lungs don’t adapt much not
enough time for oxygen to saturate blood during travelling through alveoli

o
 Continuous line- minimal O2 desaturation in untrained subjects under
normal anoxia
 Dotted line- large O2 desaturation in endurance trained subjects under
normoxia
 Dashed line- hyperoxia has no affect on %SaO2 in untrained, but reduces
hypoxaemia in trained
 Maximum O2 uptake not affected by hyperoxia, but increased in trained
 Metabolic limitations
 o Affect the utilisation of O2 and result in an increased CvO2 limit oxygen
utilisation
o mCardles disease- no glucosphosphyorlyase
o PFK defieincy- can’t metabolise glucose from muscles or liver
o Substantially reduced VO2 max, CO not affected, peripheral circulation not
affected
o Low a-vO2 difference caused by high venous O2
o O2 uptake controlled and limited by a number of steps- not usually one single
limiting factor

o
 Max pulmonary O2 uptake for healthy subjects vs. two muscle metabolic
diseases (McArdle’s and PFK deficiency)
 Diseases limit muscles ability to utilize O2
 Q dot (CO) in these diseases is normal, but a-vO2 very low
 a-vO2 is low because venous O2 is high, reflecting impaired ability to
utilise the available O2
 a-vO2 in healthy subjects is a high fraction of the theoretical max value,
indicating a high level of extraction of O2 from the blood
 Highlights how the control of O2 uptake can sometimes rely heavily on a
single ‘limiting’ factor

Adaptation to the environment: temp, food sources &

altitude:
Adaptation to environment- shrinking in the tropics, slimming gluttons/hot Eskimos,
gassy mountain dwellers and moving to a mixed up world:

 Adaptation
o How does is happen, why?  reproduction maximising fitness
o Fitness- measure of success with which your genome is propagated in future
generations
o Adaptations evolve as those most adapted to their environment and hence have
some fitness advantage, become more frequent in a pop are selected for
o If diff pops have different selection pressures and adapt to them, then in the
future if they become reproductively isolated from each other they become a new
species
o Adaptation can lead to speciation, but species can exhibit localised adaptation
(when there is restricted gene flow) if diff pops have diff selection pressures
Difference between Asian and European ear wax and why they are different:

 Earwax- cerumen
o Wet- European races, G
o Dry- east Asian races, A
o A is recessive- hence in a mixed (het) pop >25% have dry ear wax selection
 ABCC11- ATP binding cassette, subfamily C, member 11
o Transmembrane transport channel
o Single nucleotide substitution- a single nucleotide polymorphism (SNP)- non-
synonymous mutation (missense)
o DNA polymorphism at a site in the coding sequence of ATCC11 causes amino
acid polymorphism that determines ear wax type
 Wet type associated with warmer climates (humidity) and dry with cooler climates
o AA means ABCC11 not very functional
 Selection pressure
o ABCC11 associated with apocrine glands (skin-sweat) and mammary glands
o Dry earwax- less sweat, also less incidence of breast cancer, less breast milk
 Current theories
o Cooler climate- need to conserve heat, sweat increases heat loss therefore
reduced ability to sweat retain heat
o Suggestion involved with attraction, European girls like sweaty men?

Adaptation to temperature- shrinking in the tropics:

 Poikilothermic- changeable temperature

 Homothermic- same temperature (only birds and mammals), i.e. deep sea animals won’t
experience any temp variation in their enviro (2-4°C) and are temp conformers, so
technically not homothermic
 Heterothermic- different temps, can regulate (mainly behaviourally) their temp but will
conform when faced with extremes
 Ectothermic- external sources to regulate body temp
 Endothermic- maintain body temp through metabolic activity (internal heat)


o E.g. lizard a ectothermic heterotherm and poikilotherm, marine fish a poikilotherm

Explain the principles of heat transfer between orgs and their environment:
 Conduction
o Heat diffusion (from a region of high to low kinetic energy), i.e. solid to solid

o
 Q= heat transferred in time (t)
 k= thermal conductivity of the barrier
 A= area
 T= temp
 d= thickness of barrier
 Convection
o Heat transfer through macroscopic motion of substances (solid vs. air/water)
o Convection always more efficient than conduction (but runs both ways)
o q= k A dT
 q = heat transferred per unit time
 (W)A = heat transfer area of the surface
2 2
 (mo)k = convective heat transfer coefficient of the process (W/m K or W/m °C)
 dT = temperature difference between the surface and the bulk fluid (K or °C)
 Radiation
o Invisible and visible heat transfer
o Fire/sun includes visible (shorter) and invisible (longer) wavelengths, we see and
feel the heat
o But everything emits invisible (infrared) wavelengths, we can feel but can’t see it
o Intensity of radiation is proportional to the fourth power of its temp, i.e. the hotter
the smaller wavelengths it emits blue flames hotter than orange
o F= σT4
 F= energy flux, σ= Stefan-Boltzman constant, T= temp in Kelvins
o Absorptivity- measure of how much radiation an object can absorb, i.e.
black=100%
o Emissivity- same as absorptivity but measure of how much radiation an object
emits
o Radiation from living objects (except fireflies) is infrared (heat), not in the visible
range, which means we all lose heat at the same rate irrespective of our colour
(same is true for fur etc.)
o Colour can affect how much heat we gain from visible energy source (sun)
o Net heat transfer: Q= C (T2 – T1)
 C= conductance, T= temp
o Anything above absolute zero (-273.15°C) emits thermal radiation
 Exploiting water- evaporation, an effective mechanism of heat loss
o Takes 100 cal to raise 1 g of water from 0°C to 100°C
o Takes 580 calories to convert 1g of liquid water at 35°C (human skin temp) to 1g
of water vapour at 20°C (enthalpy of vaporisation)
o Heat loss- radiation (heat waves) 60%, evaporation of sweat 22%, conduction to
air setting up air currents (conduction) 15%, conduction to objects 3%
 Heat balance
o Htot= ± Hc ±Hr ±He (sum = Hother) ± Hs
 Htot= rate of metabolic heat production (always +ve)
 Hc = rate of conductive/convective heat exchange (+ve for loss)
 Hr = rate of net radiation heat exchange (+ve for loss)
  He = rate of evaporative heat loss (+ve for loss)
 Hs = rate of storage of heat in the body
o Under normal circumstances Hs = 0, if Htot > Hother then body gains heat (i.e. Hs
+ve), if Htot < Hother then body loses heat (Hs –ve)
o To regulate core temp in the face of environmental temps, depending on their
level of organisation, orgs may be able to adjust Htot, Hc, Hr and He
 Homeostasis
o Constancy of internal environment, coordinated physiological process which
maintains the most constant state in the org
o Regulation- costs energy but permits cells to function in steady conditions
independent of external variation
o Conformity- energetically cheap (trade off), cell functionality is determined by
external variation, e.g. if cold you slow down/stop
o As a rule, complexity/specialisation will drive the necessity for homeostasis, but
there are alternatives (antitheses of homeostasis)
o Homeostasis definition- the maintenance of constant internal conditions in the
face of a varying external environment

Outline latitudinal rules associated with morphological changes in orgs and physiological
rationale behind such changes:

 Bergmann’s rule
o Within the same species of warm blooded animals, pops having smaller
individuals tend to be found in warm climates near the equator
o Those with greater bulk/mass are found further from the equator in colder regions
o i.e. mass proportional to latitude
o E.g. cougars, larger in north USA, south S.America (Argentina, Chile), smaller
around the equator
o Body size and height in humans- larger found in far Nth/Sth Americas, smaller
around the equator
o Cranial module and face size in humans- same patterns in Americas
o Even ectotherms follow Bergmann’s rule, i.e. ants- longer body length at higher
latitudes
o Tropics need to dissipate more heat
 Surface hypothesis- the metabolic rate of birds and mammals maintaining a steady body
temp is roughly proportional to their body surface area
 Rubner’s surface law- maintenance of body temp vs. mass

o
o SA proportional to square of lengths and volume to the cube of lengths
o Therefore, as Vol increases SA only increases by 2/3 power of the volume= 0.67
 Rubner’s law based on 4 hypotheses:
o Mammals (idea based on studies of mammals) maintain a body temp higher than
that of the enviro
 o Heat loss occurs at surface (skin) and hence the rate of heat loss is proportional
to the SA
o Small mammals have a greater SA:Vol than large mammals and hence must lose
heat faster
o As an endotherm, if you lose heat you must replace it via metabolism
 The SA:Vol decreases as an org gets larger
o Larger orgs lose less heat smaller SA:Vol
o Smaller orgs lose more heat larger SA:Vol
 Additions too and variants on Bergmann’s rule- temp and morphology
o Hesse’s rule (Heart weight rule)
 Species inhabiting colder climates have a larger heart in relation to body
weight than closely related species inhabiting warmer climates
 Colder- need to pump more blood, deliver heat to extremities, less
pumping freq
 Extra metabolic work is required (hence larger heart) to keep orgs warmer
in colder climates
 Expanded by Mayr- within a species (birds) an individual which breeds in a
colder part of the area of distribution is likey to lay a larger clutch than one
breeding in a warmer part, have larger wings, a larger digestive system
and more developed migratory instinct
o Allen’s rule (proportional rule)
 Endotherms from colder climates usually have shorter limbs (or
appendages/extremities) than equivalent animals from warmer climates
 E.g. snowhares short legs, toucans large, hollow beaks
 Dissipate more heat in tropics
 Short and squat retain heat vs. long and thin lose heat proportionally
more SA exposed to environment i.e. Eskimos short and squat, Africans
tall and thin
 Bergmann’s rule has been criticised and there are many exceptions/deviations from it
o Latitudinal variation in Net Primary Production (NPP)- move from poles to tropics
the NPP decreases due to reduction of available soil nutrients (fires and rainfall-
leaching) which is reflected in reduced body size etc.
o Migration ability hypothesis- only large orgs can migrate well from the cradle
(tropics) to the poles and hence self-propagate (see opposite with Allen’s rule)
o Starvation resistance/environmental variability- in variable enviros larger size
reduces extinction risk- temperate climates are much more variable than tropical
climates
 Bergmann’s rule and climate change
o Animals should get smaller as it gets warmer
o Studies have shown direct measurable effects of CC on body size

Define the heat balance equation and how its component can be altered to
increase/decrease body temp of an org:

 Affecting heat balance (adapt to environment) other than alter morphology and sweat
more/less
 Htot= ± Hc ±Hr ±He (sum = Hother) ± Hs
 Surface/skin colour
o Gloger’s rule- within a species of endotherms, more heavily pigmented forms
(birds) tend to be found in more humid environments, i.e. near the equator
o Humans- Africans, Indians, Aborigines, but Intuits dark as well?
o Skin colour won’t affect emissivity, but darker means more absorptivity
o Protection from the sun- i.e. Tibetans- high altitude high UV
o White ppl- need to absorb sunlight to make Vit D
o Intuits get plenty of Vit D from diets (meat)
 Heat balance
o Under normal circumstances Hs = 0, if Htot > Hother then body gains heat (i.e. Hs
+ve), if Htot < Hother then body loses heat (Hs –ve)
o To regulate core temp in the face of environmental temps, depending on their
level of organisation, orgs may be able to adjust Htot, Hc, Hr and He
 Modifying (increasing)
o Htot = rate of heat production
 Eating more, switching (up or down) our metabolism (i.e. by eating more)
o Hs = rate of storage of heat in body
 Insulating primary/core organs
 Used to believe that ppl from colder climates had more fat, but there is no
pattern, Artic races appear to be leaner
 Different for marine orgs water conductivity
 Water can be <0°C but still maintain body temp >36°C
 Water extremely effective conductor- high specific heat capacity
 Want surface to be close to enviro temp to minimise heat loss
thick layer of blubber
 Human babies have highest fat % of other mammals at birth high brain
metabolism need fat for metabolism to meet energy demands of brain
(not really for insulation)
 Increased cerebral development/capacity, offset for enviro
variability tool use, adapting/exploiting enviro

Explain what BAT is and how it is responsible for thermogenesis:

 How can fat (adipose tissue) up regulate metabolism BAT (brown adipose tissue)
 Non-shivering thermogenesis (NIS): regulating metabolism (heat generation)
o 34 ATP’s produced in oxidative phosphorylation for every glucose molecule
o Chemiosmosis- intermembrane [H+] > matrix [H+] so ion gradient can be used to
drive ATP synthesis via ATP synthase (secondary active transport)
o Pumping of protons through the respiratory chain is tightly coupled with the
production of ATP synthase
o Uncoupling proteins (UCPs)- leaky proton channels in inner mitochondrial
membrane
 Thermogenesis- BAT
o How to make heat when cold decouple pathways and increase cellular
metabolism, i.e. UCP1
 o Leaky proton channels mean respiratory chain is no longer coupled to ATP
synthase so respiratory chain is free to pump protons heat production
o Presence of UCP1 (lets protons back in) means the respiratory chain is free of
proton coupling (conc gradient) determined by the rate of ATP synthase
production and hence can pump protons out as fast as they enter through
UCP1 more work more heat
 BAT and babies
o Increased BAT works for babies
o In humans, lost when 26wks old- how do Intuits stay warm, especially as they
aren’t fat eating more

Detail how diet of an org can affect BAT expression and the consequences of this:

 Adaptations to food sources- slimming gluttons and hot Eskimos

 Intuits- metabolism up, calories consumed might be slightly more and eat lots of fat and
protein (much more than other races)
o We eat that much fat and protein obese, but Intuits aren’t fat
o Specific dynamic action (SDA) NO
 Rise in metabolic rate after eating (energy produced through digestion
etc.)- temporary effect
o Increase metabolism to make more heat?
 Dietary induced thermogenesis (DIT)
o Newborn mammals have BAT which ups rate of metabolism through leaky proton
channels (UCPs) for non-shivering thermogenesis
o Could we achieve same thing through diet and hence explain why Eskimo’s don’t
get cold and have an increased metabolism
o Feed lab animals with excess calories (high fat and/or high carbs) rats get
fatter increased metabolism
o Some appeared to be obesity resistant
 Obesity has genetic determinant and for metabolism it seems that food can up-regulate
it, but what in food is affecting BAT production and what about noradrenaline?
o Host of other factors affect BAT expression
 Eskimos- in part diet, but also due to cold acclimation BAT unregulated by T3 and T4

o
o Lean, cold exposure production of brown fat
o Overweight, cold exposure produce some brown fat, but not much
o Therefore, genetically determined
Outline how humans can be physiologically adapted to live at high altitudes, including the
differences between races (convergent evolution):

 Adaptation to altitude- gassy mountain dwellers

 Living at high altitudes (>2000m) problems
 Composition of air
o O2=21%, CO2= 0 (negligible), nitrogen (inert gases)=79%
o Argon (0.93%) important for fish swim bladders
o At 3000m, composition is still 21% O2 and 79% nitrogen, same as 3000m below
sea level (in a balloon)
 Concentration (molarity) and pressure
o Ideal (universal) gas law: PV=nRT
 P= pressure, V=volume, n= no. of moles, R=universal gas constant, T=temp
o Dalton’s Law of partial pressure
 Pressure of a mixture of gases is equal to the sum of the pressures of all
the constituent gases alone
 Pressuretotal= Pressure1 + pressure2 …
 If pressure doubles, partial pressure doubles  oxygen toxic above
1.6atm
 i.e. at 1atm- partial pressure O2=0.2, N=0.8
 Altering total pressure has no effect on relative conc of gas
 PP increases as we dive underwater and decreases as we climb up
mountains
 Pressure increases by approx. 1atm for every 10m water depth
o Fick’s law of diffusion
∆𝑝
 R= D x A x
𝑑
 ∆p= difference in partial pressures, or conc difference difference
in pp of O2 or Co2 in the environment minus that of the org
 Low pp means we can’t get enough oxygen across our lungs into our
blood
 At extremes suffocation
 At medium levels and unable to acclimate eventual death due to
pulmonary or cerebral oedema
 HACE- High Altitude Cerebral Edema  life threatening form of Acute
mountain sickness, build up of fluid in brain severe headache, vomiting,
lethargy, coma
 HAPE- High Altitude Pulmonary Edema- life threatening build up of fluid
from lungs that prevents proper transfer of oxygen from air to bloodstream
 Caused by increased BP in lungs due to lungs constricting from low
O2 pressure
o Problem- initial inefficient response to low O2 pressure
o Solutions- increase lung Vol, increase HGN, increase vascular system and
capacity, increase amount of DPG in blood, increase heart and breathing rate
beginning of successful acclimation to low oxygen pressure
 However, never get to be as good as we were
  But can exploit- enhanced fitness level for a short after returning to low
altitude athletes altitude training
 Altitude and birth weight
o Some ethnicities maintain a high birth rate
o Selection/adaptation- acclimatisation (minutes, days) developmental (years)
genetic (generations)
 Tibetan adaptation (25,000ya)
o Retained higher VRs, normal HGN conc, much more vascularisation compared to
Andeans, arterial O2 conc very low compared to Andeans, NO high (higher
pulmonary blood flow), O2 conc saturation same as Andean’
 Andean adaptation (11,000ya)
o Normal VR (sea level), increased HGN conc, normal vascularisation, arterial O2
conc very high compared to Tibetans, NO normal, O2 conc not markedly
different to Tibetans
 Ethiopian adaptation
o No apparent adaptation, but they must have
o We know there are genetic differences (have ID’d candidate loci) but don’t really
know what they do except they are involved with HGN (also seen in Tibetan and
Andean pops)