Weeks 1-2: Trigger Features
1. Hubel DH and Wiesel TN 1959
Receptive fields of single neurones of the cat striate cortex. J. Physiol
(Lond) 148:574-591
This is the first description of orientation selectivity and binocular
integration in striate cortex, work for which H & W received the Nobel
Prize.
There are many text-book accounts and later papers.
This work appeared at the same time as Paper 2, Lettvin et alís
description of ìbug detectorsî in the frog retina.
Note that both these papers were presaged by HBBarlow, who talked about
the ìpsychology of the frogís retinaî in his seminars,
but hid the messsage in the discussion of his 1953 paper (ìSummation
and inhibition in the frogís retinaî) instead of making it
more prominent.
2. Lettvin JY, Maturana HR, McCulloch WS & Pitts WH 1959 What the frogís eye tells the frogís brain. Proc. Inst. Radio Engrs NY 47:1940
3. Gross CG Rocha-Miranda CE and Bender DB 1972
Visual properties of neurons in inferotemporal cortex of monkeys. J.
Neurophysiol. 35:96-111
This is another classic in describing the feature-selecting properties of visual neurons. The famous ìhand detectorî described here took 9 hours of intense study to elucidate. Gross and his co-workers also found ìeyeî and ìfaceî neurons, extreme specificity that was scoffed at by many prominent neuroscientists at the time (JDPís lips are sealed) but have been adundantly confirmed since. The study of complex stimulus requirements in inferotemporal cortex is now a cottage industry in Japan (see RIKEN web-site).
4. Fitzpatrick DC Kanwal JS Butman JA Suga N. 1993
Combination-sensitive neurons in the primary auditory cortex of the mustached bat. J Neuroscience 13:931-940
Sugaís extraodinary work on the auditory cortex means that he is now a mandatory invitee to any meeting on the organisation of corex, even though many visua cortical specialists are loth to admit that there might be a better story emanating from a bat!
This work requires a little knowledge of the batís life style,
Doppler shift sonar, etc , just as finding the optimal stimulus of the
cortical neurons would have been quite IMPOSSIBLE without prior knowledge
of the precise auditory stimuli (calls and echoes) in which the bat is
immersed.
Extraordinary work...well summarised in Suga N Scientific American
?1990, an article a little too general and easy to be presented.
Click here to see a Mustache Bat in action.
Here are some relevant websites on this week's theme, kindly provided by Brendan Peng.
http://hebb.mit.edu/courses/9.03/persistentactivity/sld006.htm
http://Ishome.utsa.edu/courses/IntroNeurolab/Assign08sensory/percepti.htm
http://members.aol.com/nonverbal3/primate.htm
http://dogfeathers.com/java/spirals.html
WEEK 3:
Retinal Plasticity: Asscoc. Prof. Shaun Collin>
Collin, S. P. and Pettigrew, J. D. (1988) Retinal topography in reef
teleosts.
I. Some species with well-developed areae but poorly-developed streaks.
Brain Behaviour and Evolution 31: 269-282.
II. Some species with prominent horizontal streaks with high density
areae. Brain Behavior and Evolution 31: 283-295.
This pair of papers expands the ìTerrain Theoryî of Hughes
to include reef fish, where the topographic distribution of the retinal
ganglion cell layer of a range of species is examined and compared to each
speciesí chosen ecological niche. The visual field, the axes of
specialisation and the behaviour of each species is examined to investigate
retinal plasticity. The topography of this cell population actually changes
with respect to the visual environment of each species, varying from multiple
areae centrales and foveae to a horizontal band-shaped specialisation called
a visual streak.
Easter, S. S. Jr. (1992) Retinal growth in foveated teleosts: Nasotemporal
asymmetry keeps the fovea in temporal retina. The Journal of Neuroscience
12(6) 2381-2392.
This paper presents convincing evidence of how the fovea remains in
temporal retina in a a host of reef fish where the retina continues to
grow throughout life. By exploiting the fact that each new generation of
ganglion cells sends its axons into the optic nerve as a cohort, labelling
studies reveal that some specie possess asymmetric growth (with specialisations)
and some symmetric growth (no specialisations).
Collin, S. P., Hoskins, R. V. and Partridge, J. C. (1998) Seven retnal
specializations in the tubular eye of the deep-sea pearleye, Scopelarchus
michaelsarsi: A case study in visual optimization. Brain Behaviour and
Evolution 51: 291-314.
The strange tubular eyes of deep-sea fishes is investigated with respect
to how the eye is adapted for detecting bioluminescent light sources. A
restricted dorsal visual field and a divided retina, pose quite difficult
visual problems for the pearleye to survive in this dark and inhospitable
environment.
Locket, N. A. (1985) The multiple bank rod fovea of Bajacalifornia drakei,
an alepocephalid deep-sea teleost. Proceedings of the Royal Society of
London B. 224: 7-22.
This paper examines a pure rod fovea unlike any other in nature. Normally
comprised of cones, this fovea possesses multiple banks of rods in association
with a deep retinal pit. The function of foveas in other animals is discussed
with respect to how a fovea may be used for detecting point sources of
bioluminescent light in the deep-sea. Developmental and functional considerations
of the multiple bank arrangement are presented.
PL 379 Week 4 readings:
Lecture 2: Plastic Tuning of Feature Filters.
1. Retino-tectal vs. Geniculostriate Pathways:
Retinal feature detectors
Retinal concentric organisation
Heterogeneous, small neurons
Homogeneous classes (M&P)
Genetically-prewired
Plastic at cortical levels
Close connection to motor
Indirect motor connection (but NB Dorsal stream)
Midbrain relay
Midbrain skipped
Panoramic/streak
Frontal/foveal/binocular
2. Visual Cortical Plasticity. Plasticity for all stimulus dimensions
Ocular dominance
Orientation. (initially controversial but now accepted
from optical recording experiments (Sengpiel /Bonhoeffer, Nature Neuroscience
99)
Binocular Disparity
Direction of motion
Size/terminations/edges
Spatial frequency
3. Modulation of Visual Cortical Plasticity:
Ketyís postulate for the monoaminergic system: NE,
DA, 5-HT and ACH.
Minipump experiments in kittens and cats: NE
Electrical stimulation experiments in cats and rats: ACh and
NE
1. Hubel, D.H. and Wiesel, T.N. 1970 The period of susceptibility to the physiological effects of eye closure in kittens. J. Physiol. 206: 419-436
2. Blakemore, C. and Van Sluyters, R. C. (1974) Reversal of the physiological effects of monocular deprovation in kittens: further evidence for a sensitive period. J. Physiol. 237: 195-216
3. Kasamatsu, T., Pettigrew, J.D., and Ary, M. (1979) Restoration of visual cortical plasticity by local microperfusion of norepinephrine. J. Comp. Neurol., 185: 163-182.
4. TI: Cortical map reorganization enabled by nucleus basalis
activity
AU: Kilgard-MP; Merzenich-MM
SO: SCIENCE-. MAR 13 1998; 279 (5357) : 1714-1718
PY: 1998
5. Pettigrew, J.D. and Kasamatsu, T 1978 Local perfusion of noradrenaline maintains visual cortical plasticity Nature 271: 761-763
This paper is a bit old, but it has stood the test of time, despite many controversies about the difficult methodology. I have left out one of the controversies that concerns the role of the cholinergic system in plasticity. I can provide the refs if anyone is interested.
(for more details on methodology, also see
Kasamatsu, Pettigrew and Ary 1979 Restoration of visual cortical perfusion
by local perfusion of norepinephrine Journal of Comparative Neurology 185:163-182)
6. Kasamatsu T and Heggelund P. (1982) Single cell responses in cat visual cortex to visual stimulation during iontophoresis of noradrenaline Experiemental Brain Research 45: 317-327
The importance of this paper is that it shows that noradrenaline has an effect on plasticity, rather than on the established connections responsible for receptive field properties. There are many papers that deal with the effect of iontophoresed NA on responses of single neurones, but this is one of the few that examines the effect of NA on the ability of the cell to change its connections as a result of experience.
WEEK 5: Comparative Physiology of Binocular Vision:
1. Stereopsis in owls:
a. Nieder A, Wagner H. Horizontal-Disparity Tuning of Neurons in the
Visual Forebrain of the Behaving Barn Owl.
J Neurophysiol. 2000 May;83(5):2967-2979.
b. Pettigrew JD, Konishi M. Neurons selective for orientation and binocular
disparity in the visual Wulst of the barn owl (Tyto alba).
Science. 1976 Aug 20;193(4254):675-8.
2. Two visual pathways: Tectofugal vs. Geniculostriate
a. Benowitz LI, Karten HJ.
Organization of the tectofugal visual pathway in the pigeon: a retrograde
transport study.
J Comp Neurol. 1976 Jun 15;167(4):503-20.
3. Similarities and differences in the visual pathways for stereopsis
in owls and mammals
a. Medina L, Reiner A. Do birds possess homologues of mammalian primary
visual, somatosensory and motor cortices?
Trends Neurosci. 2000 Jan;23(1):1-12. Review.
4. Modelling stereopsis: The most successful machine algorithms for
stereopsis use a comparison between raw images of each eye.
a. Harris JM, Parker AJ. Objective evaluation of human and computational
stereoscopic visual systems.
Vision Res. 1994 Oct;34(20):2773-85.
WEEK 6: Cerebellum:
1. Llinas , Rodolfo R. Scientific American
Sci Am 1975 Jan;232(1):56-71
The cortex of the cerebellum.
This article has very nice diagrams that can be used by the first presenter to refresh class memory about the components of the cerebellar circuit. JDP disagrees with Llinasí views on the function of the cerebellum, particularly the complete quarantining of the two major input pathways to the Purkinje cell (the exact opposite of the Marr thesis), but the diagrams are nice.
2. Marr, D. 1969 A theory of cerebellar cortex J Physiol (London) 202:437-470
When it appeared, this was the only theoretical paper ever published
in the Journal of Physiology during its long history, a testimony to the
impact and relevance of the ideas of the late David Marr. It is a difficult
paper to master completely.....best suited to someone with a theoretical/mathematical
bent....but it is very rewarding and is still fresh 30 years later.
Some of the details of Marrís theory have been shown to be false
(e.g. the sign of the synaptic change at the parallel fibre-Purkinje cell
synapse is probably LTD, rather than the LTP that Marr predicts), but many
of his ideas are still currrent, such as his suggestion for using synaptic
plasticity to linki the most divergent neural pathway in the brain (the
mossy fibre circuit to Purkinje cells) to the most convergent neural pathway
in the brain (the olivo-cerebellar climbing fibre path).
3.Their P, Dicke PW Haas and Barash S 2000 Nature 405:72-75 Encoding of movement time by populations of cerebellar Purkinje cells.
Hot off the press, this is a slightly technical and difficult paper
(although less of a brain stretcher than Marr's paper). I have included
it because it provides excellent evidence, using modern techniques, of
a key role for the cerebellum in time analysis, as postulated originally
by Braitenberg and as suggested by cerebellar structure. I would like the
student who picks this paper to try to take up the authors' lead and to
imagine how the kind of time analysis shown for saccadic eye mevements
could be used in other, more general, situations.
4. Thach WT 1978 J Neurophysiol 41(3):654-76
Correlation of neural discharge with pattern and force of muscular activity,
joint
position, and direction of intended next movement in motor cortex and
cerebellum.
This paper shows the real world difficulties of doing actual experiments on the cerebellum during behaviour.
Contrast the relative ease of running through a few thousand stimulus
possibilities while studying a visual neuron, with the great difficulty
of arrnaging for the animal to run through a similar range of motor possibilities!
5. Bell CC, Han VZ, Sugawara Y, Grant K J Exp Biol 1999 May;202 ( Pt 10):1339-47
Synaptic plasticity in the mormyrid electrosensory lobe.
The mormyrid electrosensory lateral line lobe (ELL) is one of several different sensory structures in fish that behave as adaptive sensory processors. These structures generate negative images of predictable features in the sensory inflow which are added to the actual inflow to minimize the effects of predictable sensory features. The negative images are generated through a process of association between centrally originating predictive signals and sensory inputs from the periphery. In vitro studies in the mormyrid ELL show that pairing of parallel fiber input with Na+ spikes in postsynaptic cells results in synaptic depression at the parallel fiber synapses. The synaptic plasticity observed at the cellular level and the associative process of generating negative images of predicted sensory input at the systems level share a number of properties. Both are rapidly established, anti-Hebbian, reversible, input-specific and tightly restricted in time. These common properties argue strongly that associative depression at the parallel fiber synapse contributes to the adaptive generation of negative images in the mormyrid
While this paper is not specifically on the cerebellum, it does concern the torus, which has a very similar structure and developmental origin in fish. The paper is listed because of the striking nature of the results obtained in the beautiful electric fish preparation where in vitro approaches allow the cellular basis to be clarified and the wealth of information about the special requirements of electroreception allows a clear view of the behavioural relevance.
The ìanti-Hebbianî plasticity shown by the electric fish torus stongly hints at one functional role of the cerebellum (to null out self-induced stimulation so that uncontaminated stimuli from the real world are more prominent). The basic ideas are similar to those that have been proposed repeatedly for the cerebellum, but for which the support has been less convincing because of technical difficulties related to poor control of the behavioural variables that can be manipulated so precisely in electric fish.
Other source papers from the Bell lab.
Grant K, Bell C, Han V J Physiol Paris 1996;90(3-4):233-7
Sensory expectations and anti-Hebbian synaptic plasticity in cerebellum-like
structures.
Bell CC, Han VZ, Sugawara Y, Grant K Nature 1997 May 15;387(6630):278-81
Synaptic plasticity in a cerebellum-like structure depends on temporal
order.
WEEKS 7 & 8
PL379 Discussion Topics : Cochlea. J.O. Pickles. 1999.
Choose one paper to discuss, and if you are in the discussion group, read the others for background.
1. Assad, J.A. et al. (1991). Tip-link integrity and mechanical transduction in vertebrate hair cells, Neuron 7, 985-994.
2. Zhao, Y.D. et al. (1996) Regeneration of broken tip links and restoration of mechanical transduction in hair cells. Proc. Natl. Acad. Sci USA. 93 (26), 15469-15474.
3. Assad, J.A. et al. (1989) Voltage dependence of adaptation and active bundle movement in bullfrog saccular hair cells. Proc National Acad Sci 86 2918-2922.
4. Hasson, T. et al. (1997) Unconventional myosins in inner-ear sensory epithelia. J. Cell Biol. 137, 1287-1307.
5. Denk, W. et al. (1995) Calcium imaging of single stereocilia in hair cells: localization of transduction channels at both ends of tip links. Neuron 15 1311-1321.
6. Geleoc, G.S.G. et al. (1999) A sugar transporter as a candidate for the outer hair cell motor. Nature Neuroscience 2, 713-719.
7. Probst, F.J. et al. (1998) Correction of deafness in shaker-2 mice by an unconventional myosin in a BAC transgene SCIENCE-. MAY 29 1998; 280 (5368) : 1444-1447
8. Xiang, M. et al. (1998) Requirement for Brn-3c in maturation and survival, but not in fate determination of inner ear hair cells. Development 125, 3935-3946.
The first paper provides the most direct test yet of the tip link theory of transduction - removing Ca2+ from around the bundle breaks the tip links and abolishes transduction permanently. The second paper makes the amazing observation that after being broken, tip links regenerate over a period of about 12 hours. The third paper analyses the observation that hair cells gradually adapt to a sustained mechanical stimulus. It forms one of the few ways that we have hope of getting further information on how mechanotransduction, or the transformation of a mechanical stimulus to an electrical change in the cells, occurs. In the fourth paper, the myosin composition of hair cells is analysed, and, among other things, shows the presence of myosin associated with the tip link. 5 gives evidence that the transducer channels are at both ends of the tip links. 6 deals not with mechanotransduction, but with the outer hair cell motor, and suggests that a sugar transporter molecule in the outer hair cell membrane acts as the motor. 7 describes a particularly ingenious method at discovering a genetic basis of hearing loss. 8 shows that the POU domain gene Brn-3c is important for "programming" hair cell development.
Background reading: "An Introduction to the Physiology of Hearing" (2nd edition, 1988) J.O. Pickles (kept at desk, Biol. Sci.). Chapters 3 and 5 on the cochlea.
Pickles J.O., Corey D.P. (1992) Mechanoelectrical transduction by hair cells. Trends Neurosci 1992 Jul;15(7):254-259.
If you have problems getting any of these papers, come and see me (Ritchie
C, level 2, room C206).
WEEKS 9 and 10: Circadian clocks and Biological Timekeepers:
Students please note that I have combined all the references for these two weeks. Please organise amongst yourselves which papers to present.
1 Morton-Firth CJ, Bray D
J Theor Biol 1998 May 7;192(1):117-28
Predicting temporal fluctuations in an intracellular signalling pathway.
We used a newly developed stochastic-based program to predict the fluctuations
in numbers of molecules in a chemotactic signalling pathway of coliform
bacteria. Specifically, we examined temporal changes in molecules of CheYp,
a cytoplasmic protein known to influence the direction of rotation of the
flagellar motor. Signalling molecules in the vicinity of a flagellar motor
were represented as individual software objects interacting according to
probabilities derived from experimentally-observed concentrations rate
constants. The simulated CheYp molecules were found to undergo random fluctuations
in number about an average corresponding to the deterministically calculated
concentration. Both the relative amplitude of the fluctuations, as a proportion
of the total number of molecules, and their average duration, increased
as the simulated volume was reduced. In a simulation corresponding to 10%
of the volume of a bacterium, the average duration of fluctuations was
found to be 80.7 ms, which is much shorter than the observed alternations
between clockwise and counter clockwise rotations of tethered bacteria
(typically 2.6 s). Our results are therefore not in agreement with a simple
threshold-crossing model for motor switching.However, it is possible
to filter the CheYp fluctuations to produce temporal distributions closer
to the observed swimming behaviour and we discuss the possible implications
for the control of motor rotation.
Gauss, R., Seifert, R., and Kaupp, U.B. 1998. Molecular identification
of a hyperpolarization-activated channel in sea urchin sperm.
Nature 393, 583-587.
[You can choose either of these "molecular" studies of biological clocks for presentation.]
2. McGrew MJ, Dale JK, Fraboulet S, Pourquie 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.
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.
Palmeirim I, Henrique D, Ish-Horowicz D, Pourquie Cell 1997 Nov 28;91(5):639-48
Avian hairy gene expression identifies a molecular clock linked to vertebrate
segmentation and somitogenesis.
We have identified and characterized c-hairy1, an avian homolog of the
Drosophila segmentation gene, hairy. c-hairy1 is strongly expressed in
the presomitic mesoderm, where its mRNA exhibits cyclic waves of expression
whose temporal periodicity corresponds to the formation time of one somite
(90 min). The apparent movement of these waves is due to coordinated pulses
of c-hairy1 expression, not to cell displacement along the anteroposterior
axis, nor to propagation of an activating signal. Rather, the rhythmic
c-hairy mRNA expression is an autonomous property of the paraxial mesoderm.
These results provide molecular evidence for a developmental clock linked
to segmentation and somitogenesis of the paraxial mesoderm, and support
the possibility that segmentation mechanisms used by invertebrates and
vertebrates have been conserved.
3. Papers by Teresa Chay on slow rhythms.
Chay's work is notable because it provides, unlike virtually all the
other work on slow rhythms, a plausible physical basis for the molecular
escapement of a clock with a slow rhythm. .......a cellular compartment
that gradually fills up with Ca2+ ions, like an hour glass or egg timer.
JDP finds this model much more satisfactory than the other vague models
that are available. In Chay's formulation, the clock period can be altered
by changing the Ca2+ permeability into the compartment (like making a bigger
hole in the waist of the hour glass) or by changing the size of the compartment
(e.g. bigger cell or bigger ER) just as one has different sized timers
from egg- to hour- size.
Chay TR Biol Cybern 1996 Nov;75(5):419-31
Electrical bursting and luminal calcium oscillation in excitable cell models.
It is shown in this paper that electrical bursting and the oscillations
in the intracellular calcium concentration, [Ca2+]i, observed in excitable
cells such as pancreatic beta-cells and R-15 cells of the mollusk Aplysia
may be driven by a slow oscillation of the calcium concentration in the
lumen of the endoplasmic reticulum, [Ca2+]lum. This hypothesis follows
from the inclusion of the dynamic changes of [Ca2+]lum in the Chay bursting
model. This extended model provides answers to some puzzling phenomena,
such as why isolated single pancreatic beta-cells burst with a low frequency
while intact beta-cells in an islet burst with a much higher frequency.
Verification of the model prediction that [Ca2+]lum is a primary oscillator
which drives electrical bursting and [Ca2+]i oscillations in these cells
awaits experimental testing.
Experiments using fluorescent dyes such as mag-fura-2-AM or aequorin
could provide relevant information.
Chay TR Neural Comput 1996 Jul 1;8(5):951-78
Modeling slowly bursting neurons via calcium store and voltage-independent
calcium
current.
Recent experiments indicate that the calcium store (e.g., endoplasmic
reticulum) is involved in electrical bursting and [Ca2+]i oscillation in
bursting neuronal cells. In this paper, we formulate a mathematical model
for bursting neurons, which includes Ca2+ in the intracellular Ca2+ stores
and a voltage-independent calcium channel (VICC). This VICC is activated
by a depletion of Ca2+ concentration in the store, [Ca2+]cs. In this model,
[Ca2+]cs oscillates slowly, and this slow dynamic in turn gives rise to
electrical bursting. The newly formulated
model thus is radically different from existing models of bursting
excitable cells, whose mechanism owes its origin to the ion channels in
the plasma membrane and the [Ca2+]i dynamics. In addition, this model is
capable of providing answers to some puzzling phenomena, which the previous
models could not (e.g., why cAMP, glucagon, and caffeine have ability to
change the burst periodicity). Using mag-fura-2 fluorescent dyes, it would
be interesting to verify the prediction of the model that (1) [Ca2+]cs
oscillates in bursting neurons such as Aplysia neuron and (2) the neurotransmitters
and hormones that affect the adenylate cyclase pathway can influence
this oscillation.
4. Martha Gillette's group study the mammalian circadian oscillator in vitro....a technical tour de force that permits cellular and molecular analysis of this hypothalamic nucleus as it ticks away the days (at least for 3 days in the dish anyway).
One of the big puzzles is how the 24 hr hr rhythm generated by these
hypothalamic neurones is connected to outputs.
The other big puzzzle I have already alluded to.viz:- what mechanism
is responsible for the long period? The time taken to transcribe the Timeless,
Per and Clock genes is too short to account for the 24 hr period and models
based on life times of proteins are pretty ad hoc. Could Teresa
Chay's model be relevant here too?
J Neurosci 1999 Jun 15;19(12):RC15
Oscillation and light induction of timeless mRNA in the mammalian circadian clock.
Tischkau SA, Barnes JA, Lin F, Myers EM, Soucy JW, Meyer-Bernstein EL,
Hurst WJ, Burgoon PW, Chen D, Sehgal A, Gillette
MU
Nature 1998 Jul 23;394(6691):381-4
A neuronal ryanodine receptor mediates light-induced phase delays of
the circadian
clock.
Ding JM, Buchanan GF, Tischkau SA, Chen D, Kuriashkina L, Faiman LE,
Alster JM, McPherson PS, Campbell KP, Gillette
MU
Department of Cell and Structural Biology, Neuroscience Program, University of Illinois, Urbana 61801, USA.
Circadian clocks are complex biochemical systems that cycle with a period
of approximately 24 hours. They integrate temporal information regarding
phasing of the solar cycle, and adjust their phase so as to synchronize
an organism's internal state to the local environmental day
and night. Nocturnal light is the dominant regulator of this entrainment.
In mammals, information about nocturnal light is transmitted by glutamate
released from retinal projections to the circadian clock in the suprachiasmatic
nucleus of the hypothalamus. Clock resetting requires the activation of
ionotropic glutamate receptors, which mediate Ca2+ influx. The response
induced by such activation depends on the clock's temporal state: during
early night it delays the clock phase, whereas in late night the clock
phase is advanced. To investigate this differential response, we sought
signalling elements that contribute solely to phase delay. We analysed
intracellular calcium-channel ryanodine receptors, which mediate coupled
Ca2+ signalling. Depletion of intracellular Ca2+ stores during early night
blocked the effects of glutamate. Activators of ryanodine receptors induced
phase resetting only in early night; inhibitors selectively blocked delays
induced by light and glutamate. These findings implicate the release of
intracellular Ca2+ through ryanodine receptors in the light-induced phase
delay of the circadian clock restricted to the early night.
Ciba Found Symp 1995;183:134-44; discussion 144-53
Intrinsic neuronal rhythms in the suprachiasmatic nuclei and their adjustment.
Gillette MU, Medanic M, McArthur AJ, Liu C, Ding JM, Faiman LE, Weber ET, Tcheng TK, Gallman EA
Department of Cell & Structural Biology, University of Illinois, Urbana 61801, USA.
The central role of the suprachiasmatic nuclei in regulating mammalian
circadian rhythms is well established. We study the temporal organization
of neuronal properties in the suprachiasmatic nucleus (SCN) using a rat
hypothalamic brain slice preparation. Electrical
properties of single neurons are monitored by extra-cellular and whole-cell
patch recording techniques. The ensemble of neurons in the SCN undergoes
circadian changes in spontaneous activity, membrane properties and sensitivity
to phase adjustment. At any point in this cycle, diversity is observed
in individual neurons' electrical properties, including firing rate, firing
pattern and response to injected current. Nevertheless, the SCN generate
stable, near 24 h oscillations in ensemble neuronal firing rate for at
least three days in vitro. The rhythm is
sinusoidal, with peak activity, a marker of phase, appearing near midday.
In addition to these electrophysiological changes, the SCN undergoes sequential
changes in vitro in sensitivities to adjustment. During subjective day,
the SCN progresses through periods of sensitivityto cyclic AMP, serotonin,
neuropeptide Y, and then to melatonin at dusk. During the subjective night,
sensitivities to glutamate, cyclic GMP and then neuropeptide Y are followed
by a second period of sensitivity to melatonin at dawn. Because the SCN,
when maintained in vitro, is under constant conditions and isolated from
afferents, these changes must be generated within the clock in the SCN.
The changing sensitivities reflect underlying temporal domains that are
characterized by specific sets of biochemical and molecular relationships
which occur in an ordered sequence over the circadian cycle.
Science 1994 Dec 9;266(5191):1713-7
Resetting the biological clock: mediation of nocturnal circadian shifts
by glutamate
and NO.
Ding JM, Chen D, Weber ET, Faiman LE, Rea MA, Gillette MU
Department of Cell and Structural Biology, University of Illinois, Urbana 61801.
Circadian rhythms of mammals are timed by an endogenous clock with a
period of about 24 hours located in the suprachiasmatic nucleus (SCN) of
the hypothalamus. Light synchronizes this clock to the external environment
by daily adjustments in the phase of the circadian
oscillation. The mechanism has been thought to involve the release
of excitatory amino acids from retinal afferents to the SCN. Brief treatment
of rat SCN in vitro with glutamate (Glu), N-methyl-D-aspartate (NMDA),
or nitric oxide (NO) generators produced lightlike phase shifts of circadian
rhythms. The SCN exhibited calcium-dependent nitric oxide synthase (NOS)
activity. Antagonists of NMDA or NOS pathways blocked Glu effects in vitro,
and intracerebroventricular injection of a NOS inhibitor in vivo blocked
the light-induced resetting of behavioral rhythms. Together, these data
indicate that Glu release, NMDA receptor activation, NOS stimulation, and
NO production link light activation of the retina to cellular changes within
the SCN mediating the phase resetting of the biological clock.
Science 1998 Jan 16;279(5349):396-9
Extraocular circadian phototransduction in humans.
Campbell SS, Murphy PJ
Laboratory of Human Chronobiology, Department of Psychiatry, Cornell
University Medical College, 21 Bloomingdale Road, White
Plains, NY 10605, USA.
Physiological and behavioral rhythms are governed by an endogenous circadian
clock. The response of the human circadian clock to extraocular light exposure
was monitored by measurement of body temperature and melatonin concentrations
throughout the circadian
cycle before and after light pulses presented to the popliteal region
(behind the knee). A systematic relation was found between the timing of
the light pulse and the magnitude and direction of phase shifts, resulting
in the generation of a phase response curve. These findings
challenge the belief that mammals are incapable of extraretinal circadian
phototransduction and have implications for the development of more effective
treatments for sleep and circadian rhythm disorders.
Delauney,F, Thisse C, Oriane M, Laudet V, and Thisse B. 2000 Science 289:297-300 An inherited functional circadian clock in zebrafish embryos.
This work was widely reported in the media. It emphasises the earlier
work in Drosophila showing that clocks are in all cells and that their
expression in some tissues (e.g. testis and kidney) are even more prominent
than in brain. Note the heterogeneity of the per gene in vertebrates, compared
with Drosophila.
6. Zeitnehmer vs. master Clock: Are transcriptional circadian clocks (such as the PER/TIM and CLOCK/BMAL loops) the master circadian clocks? This question, which might seem out-of-place given the enormous amount of research activity on PER etc, arises for a number of reasons that include the following:-
WEEK 11: FMRI
1. fMRI and Vision.
Brian WANDELL Annu. Rev. Neurosci. 22:145-173 Computational neuroimaging
of human visual cortex.
2. fMRI and Vision
Sereni M. Dale, AM, Reppas JB, Kwong KK belliveau JW etc 1995 Borders
of multiple human visual areas in humans revealed by functional MRI. Science
268:889-893
3. fMRI and Psychiatry:
Manoach DS, Press DZ, Thangaraj V, Searl MM, Goff DC, Halpern E, Saper
CB, Warach S
Biol Psychiatry 1999 May 1;45(9):1128-37
Schizophrenic subjects activate dorsolateral prefrontal cortex during
a working
memory task, as measured by fMRI.
BACKGROUND: Neuroimaging studies of schizophrenic subjects performing working memory (WM) tasks have demonstrated a relative hypoactivity of prefrontal cortex compared with normal subjects. METHODS: Using functional magnetic resonance imaging (fMRI), we compared dorsolateral prefrontal cortex (DLPFC) activation in 12 schizophrenic and 10 normal subjects during rewarded performance of a WM task. Subjects performed a modified version of the Sternberg Item Recognition Paradigm (SIRP), a continuous performance, choice reaction time (RT) task that requires WM. We compared a high WM load condition with a nonWM choice RT condition and with a low WM load condition. RESULTS: Schizophrenic subjects performed the tasks better than chance but worse than normal subjects. They showed greater activation than normal subjects in the left DLPFC but did not differ in the right DLPFC or in the control region. In the schizophrenic group, left DLPFC activation was inversely correlated with task performance, as measured by errors. CONCLUSIONS: These findings contrast with previous studies that demonstrated task-related hypofrontality in schizophrenia. Task parameters that may contribute to this difference are discussed. We hypothesize that the performance and activation differences we observed are also manifestations of prefrontal dysfunction in schizophrenia. They reflect inefficient functioning of the neural circuitry involved in WM.
4. fMRI and Motor Systems:
J Neurophysiol 1999 Jun;81(6):3065-77
Mesial motor areas in self-initiated versus externally triggered movements
examined
with fMRI: effect of movement type and rate.
Deiber MP, Honda M, Ibanez V, Sadato N, Hallett M
Human Motor Control Section, Medical Neurology Branch, National Institute
of Neurological Disorders and Stroke, National Institutes of
Health, Bethesda, Maryland 20892-1428, USA.
Mesial motor areas in self-initiated versus externally triggered movements
examined with fMRI: effect of movement type and rate. The human frontomesial
cortex reportedly contains at least four cortical areas that are involved
in motor control: the anterior supplementary motor area (pre-SMA), the
posterior SMA (SMA proper, or SMA), and, in the anterior cingulate cortex,
the rostral cingulate zone (RCZ) and the caudal cingulate zone (CCZ). We
used functional magnetic resonance imaging (fMRI) to examine the role of
each of these mesial motor areas in self-initiated and visually triggered
movements. Healthy subjects performed self-initiated movements of the right
fingers (self-initiated task, SI). Each movement elicited a visual signal
that was recorded. The recorded sequence of visual signals was played back,
and the subjects moved the right fingers in response to each signal (visually
triggered task, VT). There were two types of movements: repetitive (FIXED)
or sequential (SEQUENCE), performed at two different rates: SLOW or FAST.
The four regions of interest (pre-SMA, SMA, RCZ, CCZ) were traced on a
high-resolution MRI of each subject's brain. Descriptive analysis, consisting
of individual assessment of significant activation, revealed a bilateral
activation in the four mesial structures for all movement conditions, but
SI movements were more efficient than VT movements. The more complex and
more rapid the movements, the smaller the difference in activation efficiency
between the SI and the VT tasks, which indicated an additional processing
role of the mesial motor areas involving both the type and rate of movements.
Quantitative analysis was performed on the spatial extent of the area activated
and the percentage of change in signal amplitude. In the pre-SMA, activation
was more extensive for SI than for VT movements, and for fast than for
slow movements; the extent of activation was larger in the ipsilateral
pre-SMA. In the SMA, the difference was not significant in the extent and
magnitude of activation between SI and VT movements, but activation was
more extensive for sequential than for fixed movements. In the RCZ and
CCZ, both the extent and magnitude of activation were larger for SI than
for VT movements. In the CCZ, both indices of activation were also larger
for sequential than for fixed movements, and for fast than for slow movements.
These data suggest functional specificities of the frontomesial motor areas
with respect not only to the mode of movement initiation (self-initiated
or externally triggered) but also to the movement type and rate.
WEEKS 12 & 13:
There is a large and growing literature on mood and hemispheric brain asymmetry. See JDP's Bipolar Disorder web page for more background.
1. Ramachandran, V. S. 1994 Phantom limbs, neglect syndromes and Freudian psychology. Int. Rev. Neurobio. 37, 291-333.
Introduces the idea of complementary cognitive styles for each hemisphere (LEFT= Go!, General ignoring discrepancies; RIGHT=Stop! Devilís Advocate enhancing discrepancies).
Also see Ramaís book, which has a vivid account of the anosognosic patient ìMrs Doddsî, whose denial of disease was reversed by Right hemisphere stimulation.
Phantoms in the Brain
VS Ramachandran and s. Blakeslee 1998 Morrow Press
2. Logothetis, N. K., Leopold, D. A. & Sheinberg, D. L. 1996 What is rivalling during binocular rivalry? Nature 380, 621-624.
3.Henriques JB and Davidson RJ 1991 Left frontal hypoactivation in depression. J. Abn. Psychol. 100:535-545
4. Pascual-Leone, A., Rubio, B., Pallardo, F. & Catala, M. D. 1996 Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression. The Lancet 348, 233-237.
5. Pettigrew JD and Miller SM 1998 A sticky interhemispheric switch in bipolar disorder? Proc. Roy. Soc. B 265:2141-2148
6. Shannahoff-Khalsa, D. 1993 The ultradian rhythm of alternating cerebral hemispheric activity. Int. J. Neurosci. 70, 285-298.
7. Bejjani B-P, Damier P, Arnulf I, Thivard L, Bonnet A-M, Dormont
D, Cornu P, Pidoux B, Samson Y, Agid Y 1999 New England J Medicine 340:1476-1480
Transient acute depression induced by high-frequency deep-brain stimulation
