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de 1
1) Sensation and Sensory Processing:
Perceiving the world
2) Pain
Neuroscience

Sean Sweeney

Slide 2

STS: Lecture Overview:
L9: The sensory system: an overview of sensory organisation
for nervous systems
...
Molecular mechanisms of taste and olfaction in mammals and insects
L11: Hearing/Touch/Balance: mechanosensation
...
Organisation and molecular construction and function of the hair cell,
a paradigm for movement sensation in insects, worms and mammals
...
Signal transduction cascades downstream of rhodopsin for invertebrates
and vertebrates
...


Slide 3

Learning Outcomes:
Understand the purpose of the sensory system to an organism
Differentiate between different sensory ‘modalities’
Understand that the sensory system is organised in a logical
manner, tuned to life strategy eg mouse=olfactory
Understand that sensory stimuli are transduced, encoded and
finally perceived

Many of the transduction ‘events’ are mediated by ion channels
(trp receptor)
Understand that ‘pain’ or the sensation of noxious stimuli is
cross modal
Understand the centrality of TRP channels to many modalities

Slide 4

Nervous System Overview: the organisation of behaviour

GLIA!

interneuron
Integrating centre
(brain, ganglion)

Central
nervous
system
(CNS)

efferent neuron

Incoming
stimulus
Peripheral
nervous
system

Output
afferent
neuron

Feedback
control

(PNS)

Effector organs
(muscles, glands)

Sensory receptors

Sensors

Integrating centres

Output pathways

All nervous systems have this basic plan, the
difference is in the distribution of the integrating centre
(CNS or in distributed ganglia)
...
These form
integrating centres
...

Octopus has distributed separated brains, Ganglia
...

All our outputs are essentially muscular
There’s feedback control- deciding which signal
(saliency) is important
...


Questions:
1) How is the stimulus detected? (at a molecular level)
2) How is the stimulus transduced and encoded?
3) How does the CNS perceive the incoming information?touch lightly
for 2) and 3), how is the wiring diagram organised?

4) How can qualitative and quantitative information about
the stimuli be represented?
5) for some modalities, how can location be represented

Slide 6
How many senses do you have?

Hearing, touch, sight, taste, smell & balance

Slide 7

The stimuli
touch
movement
imbalance
sound
temperature
light
pain
taste
smell
moisture

mechanosensation

thermosensation
photosensation
nociception

internal
or
external?

chemosensation
osmosensation (hygrosensation)

Others? (not well understood)
Monitoring the internal environment for homeostatic
regulation

Mechanisms and molecules not understood
...
Deflection
...

Osmosensation- not clear about, may be linked
(transduction) to eg guard cells in plants, mechanical
swelling
...
It’s the response to anything that could be
damaging
...


Slide 8

The anatomy of detection
touch
movement
imbalance
sound
temperature
light
pain
taste
smell
moisture

body surface
body surface, muscle spindles, chordotonal
organs
auditory organ
anatomically coupled
auditory organ
body surface, hypothalamus, gustatory system
eye/photoreceptive organ
body surface, internal pain receptors
integrated w/ the gustatory system (gut?)
olfactory organ, body surface?
body surface? gustatory system?

Dedicated Organs v Dispersed Receptors (somatosensory):
- tuned to life strategy of organism

Animals have related structures
...

Similar structures
...

Hypothalamus- internal temperature measured by
Eye/photoreceptive organ- not just eyes can detect
light, others do relate to circadian rhythm
Olfactory organ- can be anywhere in some organisms
Map in body of sensory system
...


TRP channels work as heteromultimers (different classes of trp
channel) in supramolecular complexes (Channelosome)

Transient receptor potential
...

s
They have 6 transmembrane domains which are
essentially the same in all organisms
...
They are
permeable to cations eg NA/Ca
...

Line theory- when we stimulate a neuron it goes
through the somatic sensory system to the CNS and
will perceive any stimulation as the sense its dedicated
to!
Google Definition: Different qualities of a percept such
as hot versus cold, sweet versus salty are encoded by
separate group of cells
...

Can poke eye, but perceive light, stimulate neurons
physically but still makes them send AP which we can
online perceive as light
...

Can work with different classes of channels
...

Some (gustus/tastus) show multiple TRP channels
...
TRP channels
are characterised by a conserved TRP domain

TRPML not found in neurons, expressed globally and
localized in lysosomes
...
Mutations
give rise to the childhood neurodegenerative disease,
Mucopolysaccharidosis IV (MPS IV) where the
lysosomes do not function well and start to ‘store’ undegraded material
...
These domains often bind to
other proteins to generate a ‘channelosome’ complex

that can be important to function
...

Can see original trp (trpC) conserved across in
different animals
TRPN touch in different species
TRP A thermo/mechanosensitive
TRP mL found in lysosomes in all cells
...
Not necessary for any actual senses
TRP Y osmosensation in yeast (which doesn’t have a
NS), has sensory response and stimulus
...
7
DAG
TRPC3
1
...
8(heat)
Heat (43oC), vanilloids
9
...
6
PUFAs, menthol, compounds
from oregano, cloves, thyme
TRP channels can be gated by many endogenous and
exogenous ligands, conformational change and Ca2+ status

PUFAs: poly-unsaturated fatty acids: will become
important for lecture on vision
...

Don’t learn list!
Point Trp C is nearly non selective between
calcium and sodium but theres different things
they gate
...

Allacin- garlic
EtOH- ethanol
Thyme
All these are cool

Slide 13

TRP channels can be gated by three broad mechanisms:
- conformational change (temperature, mechanical)

Ligand gated- Other chemicals generated from
plants/arachnids can affect the channels

- ligand gated (endogenous, exogenous)

- Ca2+ store depletion (acts as a store operated Ca2+ channel)
(see Sangeeta’s lecture on signal transduction)

As an example, we will look at the TRPV1 channel in mammals
and the various means by which it can be gated during the
process of nociception

Slide 14

Sensation of pain: Nociception (latin: ‘nocere’ - to hurt)
Role: to alert to impending injury or to trigger appropriate
protective response
Transduction of noxious stimuli (thermoceptive pain,
mechanoreceptive pain, chemoreceptive pain) BUT ALSO
cognitive and emotional processing

PNS: peripheral nervous system
CNS: Central nervous system eg headaches
ANS: autonomic nervous system- not a sharp pain,
tends to be more diffused
...

(Sherrington, C
...
The Integrative Action of the Nervous
System (Scribner, New York, 1906)
Hyperalgesia: increased sensitivity to pain, usually
associated with post injury

Slide 15

The circuitry in the periphery:
primary sensory neurons
in the DRG project dendrites
to peripheral tissue
...
20m/s

C Fibres: ca
...

Autonomic NS dispersed, diffused
Hyperalgesia- Therefore normally fine stimuli is painful
...
A Delta fibres which are
lightly myelinated and therefore faster comparatively
...
They both express TRPV1
receptors
...

C fibres TRPCA receptors
Diagram at bottom shows initial response (first steep
spike) and after (slower shallower spike)
--C-fibres and A-delta fibres express the vanilloid
receptor (VR1 or TRPV1)
...
They
also respond to extracellular acidification (due to tissue
damage)
...
i
...
pain has two initial components, the
fast pain and slow pain
...

A-beta and A-alpha – large diameter, myelinated
neurons – responsive to non-nociceptive stimuli, v
...
Both A-delta and C-fibres much slower in
response compared to these
...

Other C-fibres: ultra-slow histamine selective fibres:
convey ‘itch’ (pruritogenesis)
tactile C-fibres: low threshold fibres responding to
sensual touch, CT fibres found in hairy skin and Cmechano- or metabo-receptors: muscle cramp and
fatigue
...

Approximates to
‘labeled line
specificity’

Pathways carrying
sensory information
are specific for one
stimulus
(alternative:
‘Pattern theory’)

Label line specificity, can only perceive as pain
...

Pattern theory- sensory system=labelled line but once
in interrogatory sources, theres cross talk in the
interneurons, filtering/perception, computational
processing sends up spinal cord to higher order
receptors
...
taste and
olfaction) integrate information across multiple primary
afferents, and some types of primary afferents are
multi-modal (more than one sensation can be evoked
by activation)
...
i
...
the pattern of
activation forms the basis of perception
...
)

Slide 17

The capsaicin (chilli) receptor:
TRPV1

capsaicin, the active ingredient of
capiscum or chili peppers
Strength measured in ‘Scoville Units’
(Wilbur Scoville, 1912)
Jalapeño, 5000 Scoville units

The TRPV1 channel is the paradigmatic TRP channel
in terms of our understanding of how they function to
transduce stimuli
...
, (1997) Nature 389: 816-24
In vivo function of the receptor (KO mice):
Caterina et al
...

Scoville= strength of chilli hotness
Capaicin is a vannilloid, therefore mutants eat chilli
based food, as hot as possible but others which still
have the sense of capsaicin pain/heat wont
...


Similarly, pharamaceutical companies are working to
generate synthetic anandamide mimics for use as
analgesics
...

Hence the synthetic structures
...

So: plants have probably evolved synthesis of
chemicals such as capsaicin and pipericin to subvert
the function of nociceptors
...

It binds to receptor in place where anademide would
bind, therefore activates at 37 degrees (body temp)
rather than 40 so feels hot/thermosensation by
stimulating TRP channel
...

Bottom three are synthetic vanniloids

Slide 19

TRPV1 can be activated by multiple
methods:
- acidification (lemon) near the outer
pore region
- double knot toxin from Earth Tiger
tarantula: locks the pore into an
open configuration, feels v painful!

If a TRPV1 channel is activated by any of these
ligands, the sensory effect is still the same
...


- Capsaicin, lowers the temperature
activation from 43oC to 37oC
And can be sensitised by:
- signal transduction mechanisms
(on cytoplasmic loops), Ca2+, PKA,
PLC, PIP2 (product of PLC)

Why is this important? For the longer
term perception of pain
...


After injury you have inflammatory soup- ATP
...

Theres a synapse in dorsal root, body in middle
outside in ganglian
...

Signal transduction a longer term response in cell
Different neurones contribute to pain
If TRPA1 is a mechanosensor, then the inflammation
caused by the injury will produce pressure, potentially
contributing to TRPA1 activation
...

Labelled line- sensed in one way (pain)!
Sensitivity after injury is term: hyperalgesia

Slide 21

The circuitry in the spinal cord, the first site of integration:
Stratification within the dorsal horn: major input to the CNS: represents second
order processing, (direction, strength of signal) immediate response and
modulation of signal
...

Descending system alters responses of reflex
circuits
...

Neurons=plastic, can learn over time
...
Pain is a strong stimulus

Send neuron back to make pre synaptic
Therefore where opium/pain reducing mechanisms
Interneuron always crosses the spinal cord heads up
sends crosses to central medulla (see slide)
...

No single structure deals with pain
...


Slide 25

But is the model: 1 TRP channel to one temperature range?
The coding of temperature in the Drosophila brain
Gallio et al
...

Expression patterns showed similar
distribution patterns in the antennae
sending projections to neighbour glomeruli
...

Are the glomeruli acting as a thermostat?

labeled line logic

Slide 26

Summary:
Sensory systems have evolved to inform the CNS of environmental stimuli: Think of
senses in terms of modalities
TRP receptors can transduce many different physical stimuli:
A TRP channel can be activated by different
mechanisms BUT

Some sensory neurons will transduce only one modality
due to labeled line logic
Other sensory neurons can transduce multiple modalities
due to pattern logic (cross-talk between neurons)
Pain is multimodal, and as a strong stimulus has evolved many layers of control
The practical: 1500 word report on the Practical
...

Hand-in: 4
...

2 sensory neurons one to cold one to hot but both
make connections



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