LA VENTANA DE EDICIÓN MÁSCARAS

of the endogenous circadian rhythm to the 24-hour day (Ruberg et al, 1996). This may involve a subset of, as yet undefined, retinal photoreceptors, or a novel photopigment, either or both of which could subserve photo-entrainment (Foster, 1998).

2.2.2: The Central Circadian Pacemaker: The Suprachiasmatic Nuclei of the Hvpothalamus

The suprachiasmatic nuclei (SCN), in both man and mammals (Moore, 1992; Mai, et al 1991; Cassone et al, 1988) are small, paired, ovoid neuronal masses within the ventral area o f the hypothalamic division of the diencephalon. Each nucleus contains approximately 8 - 10,000 neurones, and lies to either side of the base of the III ventricle, immediately superior to the optic chiasm (Diagram 5) (van den Pol, 1991a). The SCN drive overt circadian ihythms, and the 24 hour patterns observed in physiological systems and behaviours are mirrored perfectly by their spontaneous cycle of neuroactivity (Hastings, 1997a). Much of the research into the function of this area of the brain has been carried out using the hamster model, but

comparable cellular topography and phenotypes are seen in human SCN (Moore, 1992; Mai etal, 1991).

The SCN show characteristics that allow them to be designated as the endogenous pacemaker (see below) (Welsh et al 1995; Ding et al 1994; Watanabe, et al 1993), and they are the only circadian pacemakers identified in the mammalian brain, to date (Hastings, 1997). Individual neurones within the SCN can each, individually, act as an oscillator (Welsh et al, 1995), and appear to be coupled within each nucleus to form a network that functions as a circadian pacemaker or the biological ‘clock’ (Hastings, 1997; Hastings, 1997a; Ikonomov et al, 1994; Moore and Bernstein, 1989). The SCN do not require functionally intact optic tracts for normal, circadian rhythms to be maintained in all cases (Watanabe, et al 1993; Ding et al

1994; Welsh et al 1995), and it is thought that the SCN may not be the only central circadian oscillator (Hastings, 1997a).

The SCN have two functional subdivisions: The ventro-lateral area, which receives the major retinal (RHT) input (see below) and the dorso-medial area Wiich receives only a sparse retinal input (Moore, 1992; Mai et al, 1991; (Zassone, et al, 1988). It is not certain exactly which conçonents of the SCN generate the circadian (pacemaker) signal, but activity of the vasoactive intestinal polypeptide (VIP) neurones in the ventro-lateral area, arginine

vasopressin (AVP) cells in the dorso-medial area, and local astrocytes is implicated (see Hastings, 1997 for review). A distinct subpopulation of VIP cells, which are reactive to nitric oxide synthetase (NOS) have been identified in the rostral half of the ventrolateral division of

DIAGRAM 5: THE MAJOR HYPOTHALAMIC NUCLEI

Hcjroventnc

nucleus us

Preopnc atm Post e< tor_nucleus

- vemTromedioi nucleus Anter*ca nucieu — MomiTitUCfy Arcuutc nucleus ' Infund OU'Unt Optic cnjastr. Hypopnysts

Nuclei of the supra-optic region are shaded blue, and include the suprachiasmatic nucleus (SCN) and the paraventricular nucleus (hPVN)

Nuclei of the middle (tuberal) region are shaded yellow Nuclei of the caudal (mammillary ) region are shaded red.

The pre-optic area is shaded gray, and lies rostral to the supra-optic region

the SCN, and appears to be innervated by the retinohypothalamic tract (RHT) (see review: Reuss, 1996). Both the VIP and A VP are co-localised within y-amino butyric acid (GABA)- ergic neurones (Moore and Speh, 1993), so that the net output of the SCN is inhibitory (Moore, 1996). The inhibitory output of the SCN activity is especially marked during the day, or at times of very bright environmental light and low at night or times of darkness. Imposed light will produce an increase in their activity at any time (Inouye, 1984; see also Moore, 1997a, for review).

The SCN are considered to act as the principal mammalian pacemaker because:

• the circadian periodicity of the ihythm of rest / activity and other physiological variables in the animal is lost if the SCN are removed or destroyed (Klein et al, 1991)

• transplantation of foetal or perinatal SCN to a SCN-lesioned animal restores circadian rhythmicity in the host, but with the period characteristic of the donor animal (Ralph et al, 1990; Lehman et al, 1987)

• electrical stimulation (Rusak and Groos, 1982), or infusion of a number of

neuromodulators or agonists in to the SCN (see review: Morin 1991) changes the phase of behavioural rhythms

• SCN neurones maintain their 24hr pattern of rhythmicity even when isolated from the rest of the brain, in vivo (Meijer and Rietveld, 1989). And circadian rhythmicity is maintained

in vitro in the SCN slice, or even in SCN cells in culture, due to their inherent oscillatory mechanisms (see Miller et al, 1996, for review).

But there is a body of research which suggests that circadian out from the SCN may not be solely a neuronal / synaptic phenomenon. A surgically isolated island of SCN (that is, a viable section of SCN which has no synaptic contacts with other tissue) introduced to the III

ventricle of a SCN-lesioned animal, induces its own circadian rhythm in the host. This indicates that the rhythm may originate from an endocrine discharge from the transplant into the cerebrospinal fluid (CSF) within the III ventricle, as there is no direct synaptic contact between the island transplant and the host (Miller et al, 1996). Also, as SCN pacemaker function is estabhshed prior to synaptogenesis in the foetus, early ‘clock’ communication between cellular components of the foetal SCN must be mediated by non-synaptic transmission (Reppert, 1992). Thus there appears to be at least 2 oscillatory ou^ut

mechanisms for the circadian clock: a primary intra-hypothalamic projection system using classical synaptic transmission, and a potentially global system allowing secretion of diffusible ouQ)ut transmitters into the CSF or the cerebral vasculature. (Miller et al, 1996).

Afferent connections to the SCN (Diagram 6):

There are three major inputs to the SCN: the RHT, the GHT and the raphe projection

1 : The SCN form the major site of termination of the retinohypothalamic tract (RHT), The RHT is made up of retinal ganglion cell axons, which bifurcate, to project to the ventrolateral area of the SCN

2: The other bifurcation from the retinal ganglion cells projects to the intergeniculate leaflet (IGL), which is a subdivision of the lateral geniculate nucleus of the thalamus. The IGL projects back to the ventrolateral division of the SCN via the GABA-ergic neurones of the geniculohypothalamic tract (GHT). The IGL acts the ‘relay station’ of visual processing between the retina and the cortex. It is located between the dorsal and ventral parts of the lateral geniculate nucleus, and shows reactivity both to NPY and to G ABA (Moore and Card,

1994). The GHT provides a secondary visual input to the SCN via NPY neurones synapsing on the VIP neurones of the ventrolateral area of the SCN. The GHT is assumed to play an important role in the generation and maintenance of circadian rfiythmicity, especially the adjustment to phase changes in the light / dark cycle (Reuss, 1996). It also appears to integrate photic and non-photic information, thereby providing entraining information to the pacemaker, to maintain its oscillation to the 24 hour day (Moore, 1996).

3: There is a third visual input to the SCN (in addition to the RHT and GHT), from the dorsal and median r^ h e nuclei, through a serotonin-ergic projection to the VIP neurones of the ventral area of the caudal SCN area, i.e.: the area where the GHT fibres terminate.

In addition to these neuronal projections, neuropeptides also appear to influence the SCN: noradrenaline, originating from neuronal projections from the brainstem, shows a clear circadian pattern within the SCN, with a peak in the subjective day. And retinal activity and acetylcholine both cause similar excitatory effects at the SCN (see review: Reuss, 1996)

Efferent connections from the SCN:

Efferent connections from the SCN transmit information about pacemaker / rhythmic changes to a number of central brain structures. These include diencephalic regions, such as the preoptic area, the sub-paraventricular zone (subPVZ) and the retrochiasmatic area of the

Diagram 6: Direct and Indirect Afferent Connections to the Suprachiasmatic Nuclei (SCN) (after Moore, 1997a)

^ Direct afferent coonectioos Indirect afferent connections

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