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Sleep and dreams
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The Sleep/ Dream/ Wake Cycle

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Help Researchers identify key pathway in the pupil’s response to light Melanopsin-expressing ganglion cells in primate retina signal colour and irradiance and project to the LGN Researchers Identify “Light Meter” that Controls Pupil Constriction
Researchers Identify “Light Meter” that Controls Pupil Constriction Environmental stimulus perception and control of circadian clocks
Researcher
Ignacio Provencio, Ph.D.

Though the frequency of the nerve impulses of the neurons of the suprachiasmatic nuclei is the phenomenon that expresses their rhythmicity, these impulses are not necessary to generate this rhythm. Like a watch whose hands have been temporarily removed, the mechanism that generates the endogenous rhythm of these neurons continues to function even when they are isolated from one another in culture media.

Also, when tetrodoxin (TTX) is applied to these neurons so as to block their sodium channels, it prevents them from producing action potentials but in no way affects the rhythm of their activity. Moreover, when the TTX is removed, the action potentials resume with the same phase and the same frequency as before.

Like the hands of a clock, the action potentials generated by the neurons of the human biological clock enable it to tell what time it is, but not to keep track of how much time has elapsed. It is rather at the molecular level, within the genes, that the most fundamental mechanism of this biological clock resides.

LIGHT-SENSITIVE GANGLION CELLS

A pair of small areas in the hypothalamus, the suprachiasmatic nuclei, are recognized as constituting a central clock that co-ordinates the cyclical variations in several functions of the human body, such as the sleep cycle and the cyclical secretion of hormones. 

The discharge frequency of the cells of the suprachiasmatic nuclei varies according to a regular 24-hour cycle. This rhythmic activity is not the result of communication among the neurons of these nuclei, but rather of feedback loops inside each of these cells.

Scientists reached this conclusion after removing neurons from the suprachiasmatic nuclei of rats and isolating these cells in a culture medium in vitro, where they had no connection with one another. The researchers observed that the activity of each individual neuron continued to vary in a cycle lasting about 24 hours (see sidebar to the left).

But unlike suprachiasmatic nucleus cells in the brain, which synchronize their activity with the day/night cycle, suprachiasmatic nucleus cells in vitro do not. Like any other clock, the human body’s biological clock needs to be reset periodically. For that to happen, every cell in this clock must resynchronize itself daily with external cues that tell it when the day begins and ends. These external cues, also known as Zeitgebers (German for “time givers”), include the ambient temperature, the consumption of meals, ambient noise, and the body’s activity level. But the strongest of these cues is undoubtedly the overall intensity of the ambient light.

There must therefore be a neural pathway that leaves the eye from the retina and transmits the variations in light intensity to the cells of the biological clock in the suprachiasmatic nuclei. Because unlike suprachiasmatic nucleus cells in vitro, which are cut off from any neural connections from the retina, suprachiasmatic nucleus cells that are still in place in the brain can receive this information through the optic nerve.

The cells in the retina that detect light intensity and pass this information on to the suprachiasmatic nuclei are neither rods nor cones, but rather certain ganglion cells that have distinctive properties and that are dispersed among all the other ganglion cells.

Numerous experiments have confirmed this hypothesis. For example, we know that people who are blind maintain a normal biological rhythm. But when people suffer head injuries that completely destroy both optic nerves, then they lose not only their sense of vision but also their ability to regulate their circadian rhythm. Mice whose layer of rods and cones has degenerated completely also preserve their circadian rhythm. Thus all the evidence suggests that it is indeed ganglion cells that constitute the first link in this non-visual light-sensitive system.

In subsequent experiments, various tagging methods have revealed that this particular sub-population of ganglion cells does in fact send axons directly to the dendrites of the neurons of the suprachiasmatic nuclei (see box below).


Source: Ralph Nelson, http://webvision.med.utah.edu

This non-visual system for detecting light intensity also seems to be involved in controlling the pupillary reflex (the process by which the pupil of each eye dilates when the light is too dim and contracts when it is too bright). Certain axons in the retinohypothalamic tract must therefore continue their path beyond the hypothalamus to other cerebral nuclei that are involved in this reflex, such as the lateral geniculate nucleus, the olivary pretectal nucleus, and the Edinger Westphal nucleus (respectively LGN, OPN, and EW in the diagram above).

To identify the targets of the axons of the ganglion cells involved in detecting light intensity, researchers have used “knock-in” mice, in which the tau-lac Z gene has been “knocked in” to (inserted into) the melanopsin-containing ganglion cells. This gene produces a protein that can be stained selectively. And because this protein travels along the axon, its path and its various destinations are thereby revealed.

These experiments showed that the suprachiasmatic nucleus was very densely innervated by the axons of the ganglion cells that produce melanopsin. But several other parts of the brain also receive connections from these cells, in particular, the nuclei involved in the pupillary reflex (as the above illustration shows).

Link : Gene knockout Link : Refining Transgenic Mice Link : L'invalidation d'un gène : le "Knock-Out"
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