Behavioral Neuroscience, Molecular Mechanisms
USD Department of Biology
Behavioral Neuroscience
Summers
Rhythmicity & Behavior
Sensory input for Rhythmicity
Afferent path to the SCN
Figures of Rhythmicity
Retina-RGC-SCN
Yawning Circadian Rhythms
Efferent SCN output
Integration of Rhythms into Behavior
Molecular SCN
end  Acronyms/Abbreviations   Syllabus
Glu
VIP
AVP
GABA
5-HT
Gene Interactions:
1) Drosophila

2) CRY protein

3) In vertebrates PER/CRY inhibit CLOCK/BMAL1
proteins then form complexes (PER/CRY and PER/PER) that enter the cell nucleus and interact with the CLOCK/BMAL1 complex so as to inhibit the transcription process and hence the production of PER and CRY
the Brain from Top to Bottom

Ions in the Biological Clock:
SCN ion changes driving cyclic action potentials

Spontaneous firing in SCN neurons is dependent on the activity of a slowly inactivating Na+ channel (2) which opens at around -60 mV, depolarizing cells and activating fast Na+ channels (3) and high-voltage activated Ca2+ channels (4). Action potentials are then terminated by Ca2+-dependent (6 and 7) and independent K+ channels (5). During the subjective night (left), efflux through a tetraethylammonia (TEA)-sensitive K+ channel (1) hyperpolarizes SCN neurons, decreasing their chance of reaching firing threshold. During an action potential, reduced Ca2+ influx through L-type channels (4) and K+ efflux through fast-delayed rectifier channels, and enhanced activity of Iberiotoxin (IBTX)-sensitive Ca++ activated K+ channels result in broader action potentials and slower repolarization. During the subjective day (right) soluble cytoplasmic factors suppress activity of hyperpolarizing TEA-sensitive K+ channels (1), promoting action potential discharge. Enhanced L-type Ca++ Currents (4) and K+ currents through fast delayed rectifier channels (5) promote rapid action potential upswing and repolarization. Additionally, a relatively greater activity of IBTX-insensitive Ca++ activated K+ channels (7) during the projected day may also promote rapid repolarization, enabling SCN neurons to maintain higher firing rates than during the subjective night. (Brown and Piggens 07 Prog Neurobiol 82: 229-255)

Entrainment in early night

Mechanisms underlying photic-type resetting in SCN neurons during the early subjective night. Glutamate released from the retinohypothalamic tract activates AMPA and NMDA receptors on SCN neurons, triggering Ca2+-influx through NMDA receptors and T type channels. This Increase in intracellular Ca2+ is augmented by Ca2+ release from intracellular stores through ryanodine receptors (RyR). Increased intracellular Ca2+ activates nitric oxide synthase (NOS) and Ca++-calmodulin dependent protein kinase II (CamKII), which promotes extracellular regulated kinase1/2 (ERK) phosphorylation. Dexras 1 also enhances ERK phosphorylation at this phase. pERK in turn activates transcription factors which alter gene expression. Additionally, PACAP co-released with glutamate feeds back presynaptically to enhance glutamate release and acts postsynaptically activating the adenylyl cyclase (AC)-protein kinase A (PKA) signaling pathway. This activates cAMP response element binding protein (p-CREB). In conjunction with ERK-regulated transcription, pCREB alters the expression of genes including upregulation on the Per1 gene. The resetting signal received by retino-recipient cells is then propagated to other cells by various neuromodulators including nitric oxide (NO), VIP and GRP(Brown and Piggens 07 Prog Neurobiol 82: 229-255)

Entrainment late at night or early morning

Mechanisms underlying photic-type resetting in SCN neurons during the late subjective night. Glutamate released from the retinohypothalamic tract activates AMPA and NMDA receptors on SCN neurons, triggering Ca2+-influx through NMDA receptors and L type channels. Increased Ca2+ activates nitric oxide synthase (NOS) which promotes phosphorylation of extracellular regulated kinase1/2 (p-ERK) and cAMP response element binding protein (pCREB) via protein kinase G (PKG). At this phase Dexras 1 reduces the ability of PACAP to enhance cAMP signaling, which through an unknown mechanism, opposes PKG-dependent activation of CREB. In conjunction with ERK-regulated transcription, pCREB alters the expression of genes including upregulation on the Per1 gene. The resetting signal received by retino-recipient cells is then propagated to other cells by various neuromodulators including nitric oxide (NO), VIP and GRP)(Brown and Piggens 07 Prog Neurobiol 82: 229-255)

Entrainment by AVP
1) PER/CRY regulate AVP
PER/CRY binds to CLOCK/BMAL1 on Ebox regulating AVP synthesis

proteins CLOCK and BMAL1 bind to the E-box element not only on the per gene but also on the gene for vasopressin. Like the production of the protein PER, the production of vasopressin will be interrupted when a sufficient number of PER molecules have entered the cell nucleus and bound to the CLOCK/BMAL1 complex, thus deactivating the production of mRNA not only for PER but for vasopressin as wellthe Brain from Top to Bottom
2) AVP signaling stimulates SCN neuronal discharge

Phase dependent effects of exogenously applied receptor agonists and antagonists in the SCN. During the projected day endogenous AVP signaling stimulates SCN neuronal discharge and exogenous application of AVP produces no further increase in firing, whereas blocking AVP signaling with a V1 receptor antagonist reduces firing rate. Conversely, the antagonist produces little effect on firing during the projected night since V1 receptors are not being activated, while stimulation of these receptors with exogenously applied AVP increases action potential firing(Brown and Piggens 07 Prog Neurobiol 82: 229-255)