of phosphorylation in the ttfl mechanism is known, the specific kinetics are yet to be elucidated. as a result, per and cry function as negative repressors and inhibit the transcription of per and cry. over time, the per-cry heterodimers degrade and the cycle begins again with a period of about 24.5 hours. the integral genes involved, termed “clock genes," are highly conserved throughout both scn-bearing vertebrates like mice, rats, and birds as well as in non-scn bearing animals such as drosophila. electrophysiology neurons in the scn fire action potentials in a 24-hour rhythm, even under constant conditions. at mid-day, the firing rate reaches a maximum, and, during the night, it falls again. rhythmic expression of circadian regulatory genes in the scn requires depolarization in the scn neurons via calcium and camp. thus, depolarization of scn neurons via camp and calcium contributes to the magnitude of the rhythmic gene expression in the scn. further, the scn synchronizes nerve impulses which spread to various parasympathetic and sympathetic nuclei. the sympathetic nuclei drive glucocorticoid output from the adrenal gland which activates per1 in the body cells, thus resetting the circadian cycle of cells in the body. without the scn, rhythms in body cells dampen over time, which may be due to lack of synchrony between cells. many scn neurons are sensitive to light stimulation via the retina. the photic response is likely linked to effects of light on circadian rhythms. in addition, application of melatonin in live rats and isolated scn cells can decrease the firing rate of these neurons. variances in light input due to jet lag, seasonal changes, and constant light conditions all change the firing rhythm in scn neurons demonstrating the relationship between light and scn neuronal functioning. clinical significance irregular sleep-wake rhythm (iswr) disorder irregular sleep-wake rhythm (iswr) disorder is thought to be caused by structural damage to the scn, decreased responsiveness of the circadian clock to light and other stimuli, and decreased exposure to light. people who tend to stay indoors and limit their exposure to light experience decreased nocturnal melatonin production. the decrease in melatonin production at night corresponds with greater expression of scn-generated wakefulness during night, causing irregular sleep patterns. major depressive disorder major depressive disorder (mdd) has been associated with altered circadian rhythms. patients with mdd have weaker rhythms that express clock genes in the brain. when scn rhythms were disturbed, anxiety-like behavior, weight gain, helplessness, and despair were reported in a study conducted with mice. abnormal glucocorticoid levels occurred in mice with no bmal1 expression in the scn. alzheimer's disease the functional disruption of the scn can be observed in early stages of alzheimer's disease (ad). changes in the scn and melatonin secretion are major factors that cause circadian rhythm disturbances. these disturbances cause the normal physiology of sleep to change, such as the biological clock and body temperature during rest. patients with ad experience insomnia, hypersomnia, and other sleep disorders as a result of the degeneration of the scn and changes in critical neurotransmitter concentrations.