FIGURE 1.

Output and input pathways of the central circadian timing system in the mammalian brain that may be involved sundowning–related behavioral aggression and circadian dysfunction in Alzheimer’s disease and related dementias. The master circadian pacemaker, is the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN releases the fast neurotransmitter GABA, as well as several peptides including vasoactive intestinal peptide (VIP) and argine vasopressin (AVP) from its major axonal output pathway to the nearby subparaventricular zone (SPZ). The GABAergic SPZ regulates rhythms of locomotor activity, sleep-wake, and feeding via pathway to the dorsomedial hypothalamus (DMH), and regulates rhythms of aggression propensity via a pathway to the ventromedial hypothalamus (VMH). The SCN is entrained to the daily light-dark cycle by input from intrinsically photosensitive retinal ganglion cells, which release pituitary adenylate cyclase activating polypeptide (PACAP) and glutamate (GLU) via the retinohypothalamic tract (RHT). The RHT also densely innervates the SPZ in most nocturnal mammals, but provides little or no innervation of the SPZ in many diurnal mammals, including humans (indicated by dashed line). A cholinergic (ACh) input to the SCN from the basal forebrain has been suggested in rats, but is absent in mice (indicated by dashed line). Cholinergic input to the SCN has also been reported from the laterodorsal tegmentum (LDT), pedunculopontine tegmentum (PPT) complex, which also releases GABA and GLU. Serotonergic (5HT) inputs to both the SCN and SPZ have been reported from the midbrain raphe complex. Finally, the geniculo-hypothalamic tract (GHT), originating from the retinoreceipient (not shown here) ventral lateral geniculate nucleus (LGN) and intergeniculate leaflet (IGL) of the thalamus, provides an input of GABA and neuropeptide Y (NPY) to both the SCN and SPZ. Structures are not drawn to scale.