Human Frontier Science Program “Networks, genetics, clocks and psychosis: a multi-disciplinary and multi-scale approach”
The lack of information on the physiological basis of the neuronal control of mood severely limits the study of mood disorders. Recent evidence suggests that the circadian (~24-hr) timekeeping system in mammals can trigger mania or depression. Circadian mistiming has also been shown in animals or patients showing symptoms of mania or depression. Here, we study how the central circadian pacemaker, located in the suprachiasmatic nucleus (SCN) of the hypothalamus, controls and is regulated by mood. Functionally, the SCN appears homogeneous and most SCN neurons contain the inhibitory neurotransmitter GABA. In reality, however, SCN cells display heterogeneity; many but not all SCN neurons contain the intracellular molecular clock and some SCN neurons can be further distinguished by their neuropeptide content. Further, we recently showed that neurons in the SCN show a wide variety of electrical states, from hyperpolarization during the night to a novel depolarized states during the day. Consequently, neurons and subregions in the SCN vary in their key cellular and molecular properties. Here, we use behavioral, genetic, and pharmacological models of mania and depression and determine alterations in SCN timekeeping at molecular, cellular, and network levels. Experimental results will be incorporated into detailed mathematical models, which will then predict future experiments. This will identify which network states of the SCN (or states of subpopulations of SCN neurons) trigger manic or depressive symptoms. We will also determine how mutations in key components of the intracellular circadian clock are linked with mood and lead to changes in the overall state of the SCN. Finally, we will determine if desynchronized timekeeping among SCN neurons or pathological electrical activity, triggers mood phenotypes.