The Pacemaker

Much is known about the anatomy and morphology of the SCN. The SCN is located in the anteroventral hypothalamus and consists of a pair of nuclei bordering the third ventricle at midline. Experimental lesions of the SCN result in the abolishment or severe disruption of most circadian rhythms, including locomotor activity, feeding, drinking, body temperature, sleep-wake, cortisol, melatonin, and growth hormone secretion. The unique functionality of the SCN is underscored by the fact that neonatal ablations of the SCN in rats permanently abolish circadian rhythms; thus, no other brain region can take over the function of the SCN. Although SCN lesions do not interfere with thermoregulation, eating, drinking, hormonal secretion, and so on, the temporal organization of homeostatic regulation is lost.

The SCN can be divided into two primary anatomical subdivisions, each with several neuronal subfields. The first subdivision, the shell, receives input from the basal forebrain, thalamus, and brain stem, whereas the second subdivision, the core, receives visual input, both direct, the retinohypothalamic tract (RHT), and indirect, intergeniculate leaflet (IGL), as well as afferents from the midbrain raphe, hypothalamus, and thalamus. The core subdivision, analogous to the ventrolateral SCN (vlSCN), projects densely to the shell, but reciprocal projections from the shell, analogous to the dorsomedial SCN (dmSCN), are sparse. Both the core and shell have commissural connections with homologous areas in the contralateral SCN.

In both the core and shell SCN, distinct subfields of SCN neurons exist. The retinorecipient zone of the vlSCN contains most of the neurons containing vasoactive intestinal peptide (VIP), gastrin-releasing peptide (GRP), and peptide histidine isoleucine (PHI). In contrast, the dmSCN contains most of the neurons containing arginine vasopressin (AVP) and somatostatin (SS). Notably, the VIP neurons form extensive connections both within the SCN and with extra-SCN targets. Photoinduction of c-Fos occurs in VIP neurons; thus, they are implicated in photic entrain-ment. The AVP- and SS-containing neurons are predominantly found in the dmSCN. These neurons exhibit robust circadian rhythms in peptide synthesis both in constant conditions and in hypothalamic slice preparations. More recently, it has been shown that GABA is colocalized in all neurons throughout the SCN and, thus, appears to be the principal small neurotransmitter in the mammalian SCN. A number of studies have also provided evidence for nitric oxide (NO) as an SCN neurotransmitter. Because the nitric oxide synthase-containing cells are found within VIP neurons, the putative role for NO is in mediating the effects of light.

The SCN also possesses a mechanism for generating autonomous circadian rhythms in individual pacemaker cells and the ability to synchronize these autonomous pacemaker cells. Electrophysiological evidence has strongly suggested that the generation of circadian rhythms within the SCN is by autonomous cell pacemakers and is not an emergent property of a population of cell oscillators as once thought. However, the intracellular mechanisms responsible for circadian rhythms and the mechanisms of cell-cell electrical coupling remain poorly understood.

The Insomnia Battle

The Insomnia Battle

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