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From the work presented in the earlier part of this review of the literature, it is clear that the circadian timing system and the sensory nervous system share certain neuro-anatomical areas, to form sites where the sensory system may act upon the circadian timing system, and vice versa.

The components of the circadian timing system are all structures within the nervous system (Moore, 1995). These are the visual pathways (mediating light, and particularly crepuscular light, entrainment), the central circadian pacemaker structures, and the pathways that couple the central pacemakers to effector systems within the CNS e3q)ressing circadian function. This final section of the literature review will concentrate principally on the last of these

components - the paths that connect the circadian activities of the ‘clock’, or master pacemaker, to other elements o f the neurological system, and vice versa. The first two of these are considered in the earlier sections of the Literature Review. But it is also necessary to consider the visual entrainment pathways. These have significant input to the thalamus and hypothalamic areas - that is, to the areas of the brain that process afferent information from the skin, and also have reciprocal connections with the central pacemaking structures.

4.1: VISUAL ENTRAINMENT PATHWAYS:

The process of entrainment ensures that elements of the neural system which show a circadian pattern of activity, and the structures / systems that they influence, are in phase with the external light / dark cycle. This is primarily achieved by the influence of environmental light on the retina, and direct and indirect retinal links with the suprachiasmatic nuclei (that is the retinohypothalamic tract [RHT], the intergeniculate leaflet [IGL] and, indirectly, the

geniculohypothalamic tract [GHT]). In addition to the light-influenced, neurophysiological connections, feedback from non-photic physiological and behavioural variables also affects input to the central pacemaker (Please refer to Section 2, above) (Moore, 1995). In general, each area that receives projections from the SCN, or has reciprocal connections with the SCN, also receives a direct input fi'om the retinal ganglion cells, and light-induced activity of the SCN cells inhibits activity in many areas that are innervated by SCN efferent connections (Moore, 1996).

4.1.1: The Retinohypothalamic Tract;

The central circadian timing system is programmed to the external light / dark cycle by input from a population of ganglion cells, which project from non-visual photoreceptors of the retina (Foster et al, 1991; Card et al, 1991), as the retinohypothalamic tract (RHT). The largest subdivision of this tract of fibres terminates within the ventrolateral area of the suprachiasmatic nucleus (SCN), within the (central) master pacemaker, to ‘drive’ the circadian timing system. A small tract within the RHT also projects to the intergeniculate leaflet (IGL) of the thalamus (Pickard, 1985), so that neural impulses generated in a diurnal pattern by light-induced activity of the retina are transmitted directly to both the

hypothalamus and thalamus.

4.1.2: Intergeniculate Leaflet (IGL) and Geniculohypothalamic Tract (GHT):

The lateral geniculate complex of the thalamus, of which the intergeniculate leaflet (IGL) is part, receives a direct retinal input via the optic nerve, and is a major factor in the processing of visual information. But the IGL is also in communication with the SCN via the

geniculohypothalamic tract (GHT) (Moore and Card, 1994), so that the IGL-GHT system integrates photic and non-photic information, to modulate SCN pacemaker function (Moore, 1995; Moore and Card, 1994; Moore, 1992a). The IGL also receives projections from the noradren-, serotonin- and acetylcholine-ergic nuclei of the brainstem, so that the SCN is also (indirectly) influenced by projections from the brainstem to the IGL. The midbrain

serotoninergic system also has a major in ta c t on visual regulation of the circadian system (Miller et al, 1996). There appears to be a large degree of pre-synaptic interaction in the SCN between the glutamergic projection from the retina, the neuropeptide Y- (NPY) containing projection from the IGL, and the serotoninergic projection from the raphe, due to their anatomical juxtaposition within the SCN (Miller et al, 1996). For example, it is thought that serotonin may modulate photic input to the ‘clock’ by gating glutamate release from the RHT. However, there does not appear to be a physiological interaction between the raphe /

serotonin and IGL / NPY afferents in the SCN, although it is thought that the median raphe appears to modulate rhythmicity, via its direct projection to the SCN (Miller et al, 1996). The IGL also has a projection to the posterior limitans nucleus (PLi), which is another area within the thalamus, which receives a direct retinal innervation. This suggests that either the PLi also has a significant role in rtiythm regulation, or the IGL is the only nucleus that communicates with the circadian and pretectal visual systems, as well as the visual tectum (Taylor et al,

4.2: PROJECTIONS TO AND FROM THE SCN;

4.2.1: Afferent SCN Projections:

As well as the RHT and IGL / GHT afferent paths outlined above, the SCN receive afferent input from other CNS areas. These include input from the raphe nuclei and the limbic system: • There is a major input to the SCN originating from the inhibitory serotoninergic neurones

of the midbrain raphe nuclei (indicated above; see also below) (Morin, 1992). Their terminal plexus within the SCN largely overlaps those of the RHT and GHT, so that the raphe:SCN projection appears to modulate pacemaker function, in a similar manner to the IGL-GHT projection, with serotonin acting as an inhibitor of SCN sensitivity to

environmental light. The median raphe nucleus projects to the SCN but not to the IGL, and the dorsal raphe nucleus projects to the IGL but does not project to the SCN (Meyer- Bemstein and Morin, 1996). The effects of social and behavioural cues on the circadian timing system (Klein et al, 1991) appear to be mediated by the raphe:SCN projection (Jacobs and Azimitia, 1992).

• Additional excitatory input to the SCN (in rat) arises from projections from central structures that are part of, or are highly influenced by the limbic system. These include the infra limbic cortex, the lateral septal nucleus, the paraventricular thalamic nucleus (tPVN), the medial pre-optic area, certain hypothalamic nuclei (including the

ventromedial - dorsomedial-, and posterior-hypothalamic nuclei), the zona incerta, and the ventral subiculum (Moga and Moore, 1996)

There are a number of other afferent inputs to the SCN, and other projections from the RHT to the medial and lateral hypothalamus, outwith the SCN, but their possible circadian functions have not yet been identified (Miller et al, 1996).

4.2.2 Efferent SCN Projections (Moore, 1996):

Projections from the SCN connect directly and indirectly with a number o f CNS areas that are involved in sensory processing (Diagram 7). The major SCN efferent projections that are noted in the hamster and rat are thought to be characteristic of all mammals (Miller et al,

1996, Kalsbeek et al, 1993). It is thought that the efferent fibres from the SCN to the

subparaventricular zone of the hypothalamus (the inhibitory projection between the SubPVZ - see below), the paraventricular nuclei of the hypothalamus and the thalamus (hPVN and tPVN) and the medial hypothalamus in particular, all have a special role in the transmission of the ou^ut signal from the SCN circadian clock. These structures, and therefore other structures that receive their projections, will all be influenced by SCN circadian activity. The efferent connections of the SCN include major projections to other areas of the hypothalamus,

and lesser projections to the basal forebrain, and the midline thalamus (Watts, 1991; see also Moore, 1996). The information (from primary projections to the forebrain and midline hypothalamus) is relayed to the secondary forebrain areas involved in higher functions (Moore, 1997a). These direct and indirect SCN efferent projections include:

• A projection to the anterior thalamus, ventrolateral septum, and bed nucleus of the stria terminalis (parts of the limbic system, which receive projections from the raphe nuclei) • A reciprocal lateral thalamic projection to the IGL (see above), and to the retrochiasmatic

area of the thalamus (see above)

• A projection to the paraventricular nucleus of the thalamus (tPVN)

• A projection the pre-commissural nucleus and olivary pretectal nucleus (an area which receives DCN projections [Bull and Berkley, 1984] )

• There is a substantial projection to a region ventral to the paraventricular nucleus of the hypothalamus (hPVN), called the sub-paraventricular zone (SubPVZ). This area in turn sends projections to most of the same sites as the direct efferents of the SCN. In particular, the projections of the SubPVZ reach the dorsomedial hypothalamic nucleus, the ventral tuberal area and the ventromedial nucleus. From the ventromedial nucleus, some projections continue on into the posterior hypothalamic area, the anterior paraventricular (tPVN) thalamic nucleus, and also to the periaqueductal grey (Watts,

1991).

Intrinsic and extrinsic hypothalamic projections result in pacemaker information being relayed to the anterior pituitary, and to the hypothalamic and brainstem (reticular) formations that are involved in the regulation of the autonomic nervous system, the control of

metabolism and body temperature, and the tenporal organisation of the sleep / wake cycles. The control of pineal function is mediated through a direct SCN projection to the

hypothalamic paraventricular nucleus (hPVN), and from there to the upper thoracic

intermedio-lateral cell column, and thence to the superior cervical synqjathetic neurones that project to the pineal gland (Moore, 1996a). Melatonin, secreted from the pineal gland under the direct control of SCN activity, itself feeds back to moderate SCN activity (Moore, 1996; Gillette and McArthur, 1996; Morgan et al, 1994; Lewy et al, 1992; Cassone, 1990; also see Moore, 1997a, for review)

4.3: THE CIRCADIAN TIMING SYSTEM: (Diagram 19)

It is not fully understood how the rather limited projections from the SCN regulate the body- wide and diverse functions that are under the control of the circadian timing system. But the IGL, the retrochiasmatic area of the thalamus, and the sub-paraventricular zone (SubPVZ) must all be considered as components of the circadian timing system, in addition to the SCN pacemaker (Moore, 1995). And the direct connection between the SCN and the thalamic paraventricular nucleus (tPVN) (which is noted in humans, as well as in the animal model) appears also to be of significance in this system (Dai et al, 1997). Therefore, it is reasonable to assume that the efferent connections from all of these areas form part of a system which disseminates circadian rfiythms to other structures and systems (Moore, 1995). For example: • the raphe nuclei have a reciprocal projection with the SCN, and are under the circadian

control of SCN efferents, through, via the release of serotonin. (Miller et al, 1996) • the paraventricular thalamic nucleus (tPVN) projects to the forebrain, to the septum,

amygdala, hippocampus and the cingulate cortex, that is to the limbic areas which are involved in memory, the control of autonomic function, and affective tone (Moore, 1995) • the paraventricular thalamic nucleus (tPVN) also has other projections to the nucleus

accumbens of the striatum (an area which receives projections from the intralaminal nuclei of the thalamus, and from the amygdala) (Moore, 1995)

• the paraventricular nucleus of the hypothalamus (hPVN) has a reciprocal projection back to the SCN (Moga et al, 1993), and its input is reinforced by the rostral projections from the subPVZ

• efferents from the SCN, vdiich overlap the subPVZ projections to the basal forebrain, project into the retrochiasmatic area, to synapse on to second order thalamic neurones which project extensively to the forebrain and brain stem (Morin, 1994)

• areas of the basal forebrain that receive direct / indirect SCN projections themselves project widely to the neocortex, as well as to the brainstem areas that are involved in autonomic regulation, and to the inhibitory neurones of the spinal cord gray

• as well as its reciprocal projection to the SCN, the IGL also projects to

the midline thalamic nuclei, including the thalamic paraventricular nuclei (tPVN) (and regulates the behavioural state)

the sub-thalamic area (the zona incerta, that participates in motor integration and regulation)

the olivary pretectal and tectal zones, and the superior colliculus (which mediate visual function)

Diagram 19:

STRUCTURES AND PATHWAYS OF THE MAMMALIAN CIRCADIAN TIMING SYSTEM

(from Reuss, 1996)

GHT: Geniculohypothalamic Tract IGL: Intergeniculate Leaflet RHT: Retinohypothalamic Tract XL S r

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