1. Feynman's Unanswered Question:
Does the brain have a fast clock to synchronise its many related activities
in the same way a computer is strobed by its fundamental clock?
New interest in the role of brain rhythms to 'bind' image segments (W. Singer) or to imprint odour patterns (W. Freeman) has kept Feyman's question currrent, if unanswered.
2. Time vs. Space Choreography:
There is a great need for more kowledge about neural time to complement
the increasing information about neural space. e.g. homeobox genes provide
beautiful examples of the
production of spatially-repetitive structures, but temporal periodicity
in development (just as important if patterns are to be generated) is only
just being studied (e.g. cHairy and lunatic
fringe genes that have 90 min periodicity in the production of somites
in chick embryos).
3. Representation of neural time does not map onto experiential time.
Note the special problems here, where a temporal pattern has to be
represented with neurons.
cf. 1. Penfield's experiments with electrical stimulation of the temporal
lobe of humans undergoing neurosurgery; the impression can be MUCH longer
than teh duration of the
stimulation.
2. 'Filling in' of a long dream sequence that was very short-lived;
again, the perception of duration bears no relation to teh duration of
the related mental activity.
Introspecting Two Clocks:
Experiential Timing: Imagine two clocks, one running faster than the
other. Imagine you are the clock, aware only of intervals between ticks.
Since the slow clock will have a larger
ëslabsí of ëexperienceí that intervene between
each of its ticks, more ëexperienceí will pass it by. Paradoxically
then, the slower ticking clock will experience more rapidly passing time.
This viewpoint helps to explain those moments when time appears to slow
down, or even stop.
e.g. as you are hurtling toward an imminent collision; or when you
suddenly meet a very special person after a long absence.
The slowing of time that one experiences in those situations is a function of the 'speed-up' of the clock rate of key pacemaker brainstem nuclei like the locus coeruleus.
Interval timing: The subjective sensation can be turned around if one
is conscious of the passage of time and goes about marking its passage.
This would be as if the two clocks each had eyes that they could use to
look around and compare their rates with each other. In this situation,
the internal feeling that the faster clock was experiencing a slower passage
of time (experiential time) would be overidden by the 'count' of
intervals of the clock's hands that was observed 'directly from outside'.
In this latter case, the timing mechanism is called "interval counting".
This is the mechanism one uses to wake at a specific time, or to estimate
the passsage of time
accurately. Very accurate interval timing is important in many species.
e.g. small birds foraging in the Arctic at the approach of winter have
to know exactly how to budget time in
different places (Melissa Bateson).
Interval timing takes place in the basal ganglia, e.g. substantia nigra,
according to the results of brain scanning studies. Time distortions are
a common by-product of the effects of
dopaminergic drugs that act on the basal ganglia.
These two different time systems in the brain, experiential timing and
interval timing (there are bound to be more varieties of time, such as
circadian time) help to account for the
paradoxical differences we may experience in time.
Time stood still when they met
cf. Time flies when you are having fun
[The second aphorism stands in contrast to the first example, where
slowing of time occurs during intense excitement, (rapid ticking of the
'clock') such as with an imminent collision
or an intensely-exciting rendezvous. The difference probably can be
accounted for by the 'self-conscious' element that brings in interval counting....just
as a boring wait can seem
interminable once we become conscious of it and start counting the
moments].
Measuring Small Time Intervals:
Although communication around the nervous system utilises action potentials
that last around 1 millisecond, much smaller time intervals are regularly
measured in a variety of
time-as-place structures.
1. Electric fish:
Mormyrids (African) and Gymnotiforms (S. American) are 'weakly electric
fish. Some of their many species hold the record for time discrimination
in vertebrates (microbats and
marine mammals using sonar come a close second). The jamming-avoidance
response of Gymnotus (Mormyriforms) can detect 10 nanoseconds. The aggregations
of neurons
involved (e.g. cerebellum and electroreceptive nucleus) are enormously
enlarged, in keeping with ideas that a larger array of neurons can divide
up the time into a larer number of
smaller intervals.
2. Microbat audition:
Simmons has examples of microbat discriminations that appear to involve
time intervals as small as the electric fish, around 10 ns, although not
everyone agrees with the interpretation.
Combination sensitive neurons in Pteronotus auditory cortex recorded
by Suga and his colleagues, have indisputable optimal time intervals in
the microsecond range.
The importance of this work lies in the mechanism of ìinitialisingî
the time measurement. By looking at the varieties of 'combination sensitive'
neurons that measure delay between the
outgoing sonar signal and teh returning echo, one can see that some
are common and some are unknown, even though physically possible. In particular,
one never sees combination-
sensitive neurons that are sensitive to a returning first harmonic
(FM1). In other words, while one sees FM1-FM2, FM1-FM3, FM2-FM2, FM3-FM3......one
does not see
FM1-FM1, FM2-FM1 or FM3-FM1. Since the first harmonic is often suppressed
by microbats, the most parsimonious explanation of these findings is that
the bat "self-stimulates"
with its own call to initiate the delay measuring process and that
the first harmonic is the most important "self-stimulus". By adjusting
the intensity of its first harmonic so it is weak
compared to the other very intense components of the call, the bat
can ensure that the returning echo of the first harmonic is inaudible.
In this way confusion can be reduced.
From the point of view of the present question,
How is the delay measurement initialised?....it is hard to think of any
other explanation for the distribution of types of combination
sensitive neurons, except that they reflect a system that initialises
by self-stimulation. Suga's group have verified this conclusion with a
series of experiments that modify
self-stimulation.
For example, Sugaís work on the delay-sensitive neurons in auditory
cortex of the moustache bat has made it clear how the bat ìinitialisesî
the time counter that measures the delay
from the emission of the sonar pulse to the return of the echo from
the prey object. The ìinitialisationî is triggered by self-stimulation
caused by FM1 in the outgoing pulse (rather
than by a signal from the motor system, for example). By adjusting
he intensity of FM1, the bat can use this for self-stimulation and then
use the echo from the louder FM2 or FM3
to measure the delay.
Microbat Auditory Cortex: Suga
Ref: Scientific Amer.June 1990 Vol 262 #2 pp 60-66 ìBiosonar
and neural computation in batsî
CF-FM bats with Doppler shift compensation:
Allows detection of moths with beating wings in acoustic clutter.
25 years work on he auditory cortex has revealed some details of the
ìcontrol panel in the batís cockpitî (the multiple
auditory cortical areas specialised for different functions).
1. Doppler-shift area (central representation of the acoustic fovea).
2. FM-FM combination sensitive, Delay-tuned area: Target Distance
3. CF-CF combination sensitive, Target Velocity area
4. Target Azimuth Area etc etc
The oganisation of the FM-FM Delay Sensitive Area revelas the strategy
used by the bat to measure delay of the echo. Only 3 combinations are represented,
FM1-FM2, FM1-FM3
and FM1-FM4, revealing that the bat is using FM1 as the initialising
signal. Since FM1 is weak and can be adjusted in intensity, the bat can
use this tone to self-stimulate its auditory
system on sonar pulse emission and then ìlistenî (via
the FM-FM neurons) to the returning echo of FM2 or FM3 or FM4. The FM-FM
neurons in the Delay Tuned area can then
read out the delay of the echo (target distance) . This arrangement
avoids the need for the motor system to communicate the time of sonar emission
to the auditory system, and
minimises confusion that could arise from the sonar of other bats,
since the quiet FM1 is just loud enough to be heard by the bat itslef,
but not loud enough to carry far or produce an
echo from a distant target.
3. Motor Cortex: Throwing Spears and Spearing Semantics (Words)
Bill Calvin has argued, in a number of readable books on the
brain, that an increase in temporal precision is one of the driving forces
behind the expansion of hominid cortex. Extreme
temporal precision is required for accurate throwing and this may have
helped the evolution of asymmetry and enlargement of the forebrain.
Considerable temporal precision is involved in word production, formants
at the appropriate intervals by the Left hemisphere which has good temporal
precision, in contrast to the
prosodic variations in tone produced by the Right hemisphere. This
is one good reason for the R/L asymmetry observed in hominid temporal cortex........more
neurons being required,
a la electric fish, to come up with the required temporal precision.
Oscillators and Clocks:
Molecular details of neural clocks are gradually becoming available.
There is still no compelling picture of how the rhythms are generated by
any of these oscillators (I personally find
it unsatisfying, for instance, that there is no idea where one obtains
a time constant of around 24 hours from a bunch of proteins like TIM and
PER. Teresa Chay has some models that
are much more attractive and plausible to me than all the molecular
biology of per and tim. Teresa focusses on calcium ion fluxes into the
major intracellular compartments, such as the
endoplasmic reticulum. It is easy to imagine the ER like an hour glass,
gradually filling up with calcium ions, then emptying again when it fills
up and reverses the polarity of ion
channels)
A. Nanoseconds:
The record on the planet for short time interval detection is 10 nanosec...by
Gymnotus, a mormyrid electric fish from Africa. It is not clear if there
is an oscillator that mimicks this
short period, but the mechanism is generally believed to be the considerable
enlargement of the neural apparatus for electroreception, especially
the torus and cerebellum that are
enormously enlarged in these electric fish.
A delay line with more neurons strung along it can obviously divide
time into smaller and smaller intervals.
B. Microseconds:
Mammals have a voltage-sensitive, Ca2+ independent, contractile protein,
in the cell wall of the motile outer hair cells of the cochlea.
This protein changes the length of the outer hair cell in synchrony
with microphonic potentials in the cochlea (note the uniqely-large generating
potential of +150mV).
This protein can therefore follow oscillations at least to 100kHz
(10 microsecs), the frequencies used by some marine mammals and some microbats.
The invention of this new
protein has enabled mammals to invade some niches that are barred to
other vertebrates (like birds, whose hearing is limited to frequencies
below 10 kHz--100 microsecs).
C. Seconds:
i. Hyperpolarisation-sensitive cationic channels (Ih....also
called If ...for "funny") are now described and cloned from oscillating
tissues (e.g. sperm head, cardiac muscle, brain).
Triggered by hyperpolarisation, they allow a ramp of depolarisation
to drift the cell's membrane potential back toward resting before shutting
off. The steepness of the ramp of
depolarisation determines the frequency of the oscillation, which is
around the 1 sec range for Ih in the tissues described.
ii. Bacterial Chemotaxis:
There is a 1-2 sec switch between the two phases of bacterial taxis:-
'go' (when the bacterial 'outboard motor' is spinning and propelling the
bacterium in a straight line).....and 'stop'
(when the flagellar power is turned off and the bacterium tumbles randomly
at the mercy of Brownian motion).
The molecular details of this switch have been investigated by Dennis
Bray and involve a network of proteins such as tyrosine kinases. The switch
is beautifully regulated. The 'go'
phase is lengthened if an attractant is detected, whereas the 'stop'
phase is lenthened if a relllent substance is detected. Despite these sensory
modifications of the switch period, it
always returns to the baseline period, a form of adaptation.
I think that the basic machinery for the 'stop' and 'go' switch in bacteria
may have been retained during evolution. It is such a fundamental aspect
of behaviour and is linked so strongly
to sensory processing. Whether it shares a molecular link with bacteria
or not, the Right hemisphere=stop and Left hemisphere=go connection is
a useful mnemonic.
D. Hours to Days:
Circadian rhythms have evolved independently a number of times, judging
by the duplication of biochemical effort in different organisms.
i. Drosophila, Mammals and Birds: transcription of per and tim genes
lead to translation of PER and TIM proteins which dimerise. The heterodimer
turns off transcription.
ii. Neuropora. frq gene transcription and translation leads to protein
FRQ turning off transcription when it gets into the nucleus, just like
the per tim system of animals, but note that
the genes are independent..
iii Cyanobacteria (Synechococcus). A 3 gene, negative feedback sytem
kaiA, kaiBC.
The point of comparing these diverse systems is to show that all involve
a transcriptional clock with negative feedback from the gene products back
to the genes. A positive-feedback
limb has also been found in each of these systems that re-activates
the cycle.
When it comes to very slow oscillators, transcriptional clocks seem
to be the way to go. ?Perhaps there were RNA clocks in the pre-DNA world.
Where does the slow speed of the circadian clock come from?
This question is still unanswered. My early favourite, the transcriptional
process itself, seems to be ruled out by the fact that transcription, as
slow as it is, and as large as some of these
genes are (per is hundreds of kB long), is still completed for teh
circadian clock genes in a fraction of the circadian period.
Current focus seems to be on the availability of the TIM and PER proteins,
which are unstable and kept in low concentrations by degradative processes
and membrane
recycling/ubiquitination unless there is no light.
But note that pure transciptional clocks may exist without any need
for protein intermediation. e.g. the 90 min period of lunatic fringe and
cHairy, involved in somite formation in
chick development, seems not to involve a protein translation intermediate
and may be purely transcriptional.
Human Clock Variants:
Dysrhythmias in humans are becoming increaingly recognised as a source
of important behavioural differences.
I have already drawn your attention to the different interhemispheric
rhythms of bipolar subjects. While the genetics of altered bipolar rhythms
are not at all clear, there are very clear examples of human rhythm polymorphism:-
Larks vs Owls: Kratzenberg and co-workers studied the clock
gene and found variants that correlated with the circadian habits of the
probands. One clock variant had a short free-running period (found in the
"larks" who rose and retired early) and a longer period variant in the
"owls" who slet in and retired late). Since all circadian rhythms synchronise
to the daily light-dark schedule, one could ask why different free-running
periods would have any effect on behaviour once the rhythm was synchronised?
The explanation lies with the slightly different ways in which the activity
cycle of short and long rhythms becomes integrated into the synchronised
24-hr rhythm (see diagram).
The Locus Coeruleus:
Literally, the "blue spot", visible in unstained human brain sections
in the floor of the IVth ventricle because of the concentration of copper-containing
phenol oxidase for synthesis of noradrenalin.
Projects everwhere in the brainy.....a huge burden upon the small number
of neurons involved that has not increased their number in evolution of
hominids, despite the enormous expansion of the the cerebral cortex. Therefore
vulnerable and the first system that degenerates in Alzheimer's disease.
Pacemaker neurons.
Active during "orienting" and arousal. Note sophistication of "orienting
response". Big Ben anecdote.
Silent during sleep.
NA modulates the level of plasticity by activating NMDA synapses. "Now
print" signal. Contrast running from lion with lying safely on the cave
floor.
Specifity comes about because of timing. LC fires when current input
is not predicted by brain model of the world that has been set up in cortex.
Subiculum output of hippocampus represents summation of all cortical aeas
that has been "inverted" to give a complementary representation. When the
subiculum input to LC matches the current sensory input, there is no activation
of LC (boredom). When the sensory input in unpredicted by the cortical
model, LC is activated and leads to arousal, whose effect is plasticity
of cortex produced by NA. This leads to updating of the model and a return
of LC stability. Another consequence of LC activation is alteration of
experiential time, so that intensely emotional experiences, as well as
being memorable are accompanied by a slowing of the experience of time.
Melatonin and Sleep:
Melatonin is one of the most powerful and efficient anti-oxidants known.
Diffuses across all boundaries.
Secreted by the pineal, the eye and probably other parts of thebody
(?skin) during sleep. Highest concentration in youth.
Powerful up-regulatory effect on cellular immunity.
If it is such good stuff, why not flood body with it all day instead
of just at night?
Not clear, but why sleep instead of doing "runnung repairs" on the
brain while one is awake?
Perhaps the post-mitotic brain, unlike the liver that can make new
cells if one is damaged irrreparably by oxidation, must shut down some
operations for repair of oxidation damage. This might include those operations
(such as the use of mono-amines which are highly unstable in oxidation)
that would be disrupted by a powerful anti-oxidant like melatonin. Those
who have suffered jetlag, where one is forced to be up and about despite
high levels of melatonin produced by your still-asleep brain, will have
some sympathy with this view.
References and Notes:
Outer Hair Cell Motor:
Gale JE, et al.
The outer hair cell motor in membrane patches.
Pflugers Arch. 1997 Jul;434(3):267-71.
Ashmore J, et al.
Hearing in the fast lane.
Curr Biol. 1999 Aug 29 July/12;9(15):R572-R574.
2 : Geleoc GS, et al.
A sugar transporter as a candidate for the outer hair cell motor.
Nat Neurosci. 1999 Aug;2(8):713-9.
Bacterial Chemotaxis:
1 : Abouhamad WN, et al.
Computer-aided resolution of an experimental paradox in bacterial chemotaxis.
J Bacteriol. 1998 Aug;180(15):3757-64.
2 : Bray D.
Signaling complexes: biophysical constraints on intracellular communication.
Annu Rev Biophys Biomol Struct. 1998;27:59-75. Review.
3 : Bray D, et al.
Receptor clustering as a cellular mechanism to control sensitivity.
Nature. 1998 May 7;393(6680):85-8.
Hyperpolarisation-activated cation channels:
Biel M, et al.
Hyperpolarization-activated cation channels: a multi-gene family.
Rev Physiol Biochem Pharmacol. 1999;136:165-81. Review. No abstract
available.
'Lunatic Fringe': 90 min oscillator coupled to somite formation:
1. Dev Biol 1999 Mar 1;207(1):49-61
Dynamic expression of lunatic fringe suggests a link between notch signaling
and an autonomous cellular oscillator driving somite segmentation.
Aulehla A, Johnson RL
Department of Biochemistry and Molecular Biology, University of Texas,
M.D. Anderson Cancer
Center, Houston, Texas, 77030, USA.
The metameric organization of the vertebrate trunk is a characteristic
feature of all members of this
phylum. The origin of this metamerism can be traced to the division
of paraxial mesoderm into
individual units, termed somites, during embryonic development. Despite
the identification of
somites as the first overt sign of segmentation in vertebrates well
over 100 years ago, the
mechanism(s) underlying somite formation remain poorly understood.
Recently, however, several
genes have been identified which play prominent roles in orchestrating
segmentation, including the
novel secreted factor lunatic fringe. To gain further insight into
the mechanism by which lunatic
fringe controls somite development, we have conducted a thorough analysis
of lunatic fringe
expression in the unsegmented paraxial mesoderm of chick embryos. Here
we report that lunatic
fringe is expressed predominantly in somite -II, where somite I corresponds
to the most recently
formed somite and somite -I corresponds to the group of cells which
will form the next somite. In
addition, we show that lunatic fringe is expressed in a highly dynamic
manner in the chick
segmental plate prior to somite formation and that lunatic fringe expression
cycles autonomously
with a periodicity of somite formation. Moreover, the murine ortholog
of lunatic fringe undergoes a
similar cycling expression pattern in the presomitic mesoderm of somite
stage mouse embryos.
The demonstration of a dynamic periodic expression pattern suggests
that lunatic fringe may
function to integrate notch signaling to a cellular oscillator controlling
somite segmentation.
2. Curr Biol 1998 Aug 27;8(17):979-82
The lunatic fringe gene is a target of the molecular clock linked
to somite
segmentation in avian embryos.
McGrew MJ, Dale JK, Fraboulet S, Pourquie O
Laboratoire de genetique et de physiologie du developpement (LGPD),
Developmental Biology
Institute of Marseille (IBDM), CNRS-INSERM-Universite de la mediterranee-AP
de Marseille,
France.
The most obvious segments of the vertebrate embryo are the trunk
mesodermal somites which give
rise to the segmented vertebral column and the skeletal muscles of
the body. Mechanistic insights
into vertebrate somitogenesis have recently been gained from
observations of rhythmic expression
of the avian hairy-related gene (c-hairy1) in chick presomitic mesoderm
(PSM), suggesting the
existence of a molecular clock linked to somite segmentation ([1];
reviewed in [2]). Here, we show
that lunatic Fringe (IFng), a vertebrate homolog of the Drosophila
Fringe gene, is also expressed
rhythmically in PSM. The PSM expression of IFng was observed as coordinated
pulses of mRNA
resembling the expression of c-hairy1. We show that c-hairy1 and IFng
expression in the PSM are
coincident, indicating that both genes are responding to the same segmentation
clock. The genes
were found to differ in their regulation, however; in contrast to c-hairy1,
IFng mRNA oscillations
required continued protein synthesis, suggesting that IFng could be
acting downstream of c-hairy1
in the clock mechanism. In Drosophila, Fringe has been shown
to play a role in modulating
Notch-Delta signalling [3,4], a pathway which in vertebrates has been
implicated in defining somite
boundaries [5-9]. These observations place the segmentation clock upstream
of the Notch-Delta
pathway during vertebrate somitogenesis.
PER and TIMELESS: Circadian Clock Genes.
: Naidoo N, et al.
A role for the proteasome in the light response of the timeless clock
protein.
Science. 1999 Sep 10;285(5434):1737-41.
2 : Sangoram AM, et al.
Mammalian circadian autoregulatory loop: a timeless ortholog and mPer1
interact and negatively
regulate CLOCK-BMAL1-induced transcription.
Neuron. 1998 Nov;21(5):1101-13.
3. Liu K Heintzen C. Loros J and Dunlap JC 1999 Cellular and Molecular
Life Sciences 55: 1195-1205
Regulation of clock genes.
