The Neural Basis Of Orcadian Rhythms

It is most probable that sleep and waking stem from an inherent cycle of neuronal activity that can be influenced dramatically by changes in sensory stimulation. This is demonstrable not only in humans and laboratory animals, but also in invertebrates. Thus, while we cannot be sure that other animals sleep in the same way that we do, they do show a circadian cycle of motor activity. In some (nocturnal) species, such as the rat, this activity is actually highest during darkness. Even aplysia, the sea hare, has such a rhythm but this is more like that of humans in being maximally active during daylight (diurnal).

These rhythms seem to be innately programmed although they can be adjusted. For instance, in a normal environment, the sleep-waking cycle of humans is obviously synchronised ('entrained') with the (24-h) dark-light cycle whereas it assumes a period of around 25-27 h in a (time-free) environment where there are no diurnal cues. Interestingly, when humans are in a time-free environment, the change in the rhythm of

Neurotransmitters, Drugs and Brain Function. Edited by R. A. Webster ©2001 John Wiley & Sons Ltd body temperature does not follow the change in the sleep-waking cycle. Generally, it becomes shorter (to as little as 20 h), rather than longer, which suggests that these cycles are regulated in different ways. Entrainment has also been shown in aplysia which, after exposure to a normal dark-light cycle, retains a cyclic pattern of activity for a number of days even if subjected to continuous light.

At its most fundamental level, the circadian cycle rests on the influence of so-called 'clock genes'. These genes have been studied most extensively in insects but they have also been found in humans. Their protein products enter the cell nucleus and regulate their own transcription. This feedback process is linked to exposure to light and so it is not surprising that visual inputs are important for maintenance of circadian rhythms. However, it is not the reception of specific visual information, transmitted in the optic nerve to the lateral geniculate nucleus (LGN) and visual cortex (i.e. visual discrimination), that is responsible for the rhythm but the more simple, almost subconscious, reception of light.

The fibres conveying this sensation arise in the retina but diverge from the optic nerve and travel in the retinohypothalamic tract (RHT) to innervate the suprachiasmatic nucleus (SCN), a small nucleus which is found in the anterior hypothalamus above the optic chiasma (Fig. 22.3). Destruction of the RHT leads to 'free-running' rhythmic behaviour and so this pathway seems vital for coupling the circadian rhythm to the light cycle. A deficit in information carried in this pathway could help to explain why the blind often suffer from disrupted sleep patterns. Another prominent input to the SCN comes from the intergeniculate leaflet (in the lateral geniculate nucleus (LGN) complex) via the geniculohypothalamic tract (GHT) and, whereas the retinohypothalamic pathway seems to be essential for light-entrainment of the circadian rhythm, the LGN seems to be influenced by rhythmic variations in non-photic inputs such as changes in motor activity. Of course, the LGN is obviously influenced too by visual inputs and, together with the GHT projection to the SCN, can be regarded as an indirect retino-hypothalamic pathway which appears to be inhibitory on SCN neurons. A neuronal input to the SCN from 5-HT neurons in the median Raphe nucleus is another possible route for setting the circadian clock (entrainment) by non-photic stimuli (Fig. 22.1).

Destruction of the SCN, the target of all these pathways, abolishes the synchronised circadian rhythms in locomotor and autonomic function which clearly points to this nucleus as a crucial centre for the control of cyclic function. However, there seems to be some topographical organisation of the neurons in the SCN in respect of their function and the transmitters they release. Whereas those in the dorsomedial zone of this nucleus (or nuclei, since it is paired) contain arginine vasopressin (AVP) or angiotensin II and GABA, neurons in the ventrolateral zone contain vasoactive intestinal peptide (VIP), gastrin-releasing peptide (GRP) and GABA. It is these latter neurons which form the core of the nucleus and show rhythmic pacemaker function. In fact, when maintained in culture, they even display a metabolic rhythm which has the same phase as that of SCN neurons in vivo. Unfortunately the presence of GABA in these neurons means that they must be inhibitory and so could not directly stimulate any brain function when activated, e.g. by light inputs, although they could dampen melatonin secretion (see below).

Neurons within the SCN innervate those hypothalamic areas which have a crucial role in the regulation of the reproductive cycle, mood and sleep/arousal, as well as regions such as the basal forebrain and the thalamus which help to determine the state of arousal. They also project to the pineal gland to govern the synthesis and release of

Figure 22.1 Pathways projecting to and from the suprachiasmatic nucleus (SCN). Inputs from photoreceptors in the retina help to 'reset' the circadian clock in response to changes in the light cycle. Other inputs derive from the lateral geniculate complex and the serotonergic, Raphe nuclei and help to reset the SCN in response to non-photic stimuli. Neurons in the SCN project to the hypothalamus, which has a key role in the regulation of the reproductive cycle, mood and the sleep-waking cycle. These neurons also project to the pineal gland which shows rhythmic changes in the rate of synthesis and release of the hormone, melatonin

Figure 22.1 Pathways projecting to and from the suprachiasmatic nucleus (SCN). Inputs from photoreceptors in the retina help to 'reset' the circadian clock in response to changes in the light cycle. Other inputs derive from the lateral geniculate complex and the serotonergic, Raphe nuclei and help to reset the SCN in response to non-photic stimuli. Neurons in the SCN project to the hypothalamus, which has a key role in the regulation of the reproductive cycle, mood and the sleep-waking cycle. These neurons also project to the pineal gland which shows rhythmic changes in the rate of synthesis and release of the hormone, melatonin the hormone, melatonin, which is another factor involved in the control of the 24-h cycle.

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