Behavioral Neuroscience Summers

Rhythmicity & Behavior Sensory input for Rhythmicity Afferent path to the SCN Circadian Rhythms

Efferent SCN output Integration of Rhythms into Behavior Glu

VIP AVP GABA 5-HT

Figures of Rhythmicity Retina-RGC-SCN Molecular SCN end  Acronyms/Abbreviations   Syllabus

BIOLOGICAL RHYTHMS
XII. Integration of Rhythms into Behavior: Activity 			

	A. Spontaneous firing in SCN neurons 
	
		1. VIP ð VPAC2 in shell AVP neurons maintains membrane depolarization
		   ð threshold ð usual Na+ ð Ca++ ð K+
		
			a. slowly inactivating1 then fast2 Na+ channels 
		
			b. slow opens around -60 mV
			
				i. depolarizing activates fast Na+ and highV Ca++ channels

				
		2. Per gene activity requires Na+ depolarization
		
			a. VPAC2 ð CREB ð CRE activates Per
		
		3. PER + CRY + CK1e ðñ Rev/Erba + Rora
		
			a. REV/ERBa + RORa ðñ Clock + BMal
		
			b. strongest Per rhythm in SCN shell
			
			c. Per ðñ PermRNA ðñ PER TF activity directly ðñ VIP + AVP

				i. Fast acting response, promotes a stonger rhythm

				ii. but... PER TF activity indirectly ðò VIP or AVP

					1) by PER TF ðò Bmal and Clock 

						a) slow acting 24h photophase ð scotophase response

					2) BMAL/CLOCK heterodimer TF directly ðñ VIP + AVP
	
		
		4. CLOCK + BMAL ðñ Per + Cry ð PER + CRY + CK1eðòPer + Cry 
		   via build up + interaction with CLOCK/BMAL at E-box

			a. photophase build-up silences Per + Cry at night
		
			b. degradation of PER/CRY during scotophase ð
			   ð absent at the onset of photophase
			
		
		5. Action potentials are terminated by K+ channels 
		
			a. some K+ channels are independent of Ca++ and some dependent 
	
					
	B. During the night decreasing chance of SCN firing ® 2-4 Hz frequency 
		
		1.  K+ efflux hyperpolarizes SCN neurons
		
			a. slow outward flux
			
				i. TEA sensitive K+ channel
				    (tetraethylammonia)
		2. Slower de- & re-polarization also ® 2-4 Hz
		
			a. reduced Ca++ influx
			
				i. [Cl-]i lower  
			
			b.  reduced efflux through fast-delayed rectifier K+ channels
			
				i. enhanced activity of IBTX-K+ channels
				                    (iberiotoxin sensitive)
					(1) Ca++ activated   
		
		3.   Evening Light - entrainment ð retinal ganglion cells ð RHT 

			a. RHT ðñ Glu ð AMPA/NMDA-R on SCN core VIP neurons
			
			b. ðñ Ca++ influx ðñ NOS + CamK2
			
				i. NMDAR, T-channels, intracellular ryanodine-R (RyR).  

			c. ðñ pERK ðñ transcription factors ðñ Per1 gene expression

				i. ðñ soluble cytoplasmic factors
				
					a. CLOCK, BMAL1, PER, CRY, CK1e proteins?

			d. PACAP àñ AC/cAMP/PKA àñ pCREB ð CRE àñ Per1 expression
			         àñ Glu release 

			e. Glu àñ core neuron action potentential àñ VIP/GRP in SCN shell
				
				i. NOS àñ NO àñ activity of surrounding cells
				
				ii. GABA signals synchronize SCN neurons
				
				iii. cascades of "clock" gene expression first in SCN core 
				     ðñ spreading into the shell
			
			f. phase shifts rhythm by maintaining 8-10 Hz rhythm 
			   longer into the day
	
			
		4. Darkness àò RGC àò SCN core àòshell àòGABAA ð PVN àñ MFB through SPVZ ð 
		   ð Spinal Cord latHorn sympathetic motor neurons ð SCG àñ NE àñ b2 àñ Pineal 
		   àñ Melatonin ð blood ð feedback phase-shifts SCN
		
			a. SCN ð timing of Pineal melatonin synthesis and release
			
				i. melatonin ð temporal info to peripheral systems
				
					(1) but also to SCN
			
			b. greatest feedback sensitivity at dusk

			
			c. melatonin ð MT1 receptor ðñ outward K+ current 
			    TEAK+ð hyperpolarizes SCN neurons ðò discharge
				
				i. melatonin desensitizes MT2 ð PKC
				
			d. protects initiation time of 2-4 Hz rhythm from RHT entrainment
			
				i. or initiates earlier 2-4 Hz rhythm
		
				
		5. Retina ð optic nerve ð IGL ð GHT àñ GABA/NPY ð SCN shell ð HGT

			a. GABAA àò SCN firing rate when necessary 
			
			b. NPY àñ Y5 receptor àò cAMP àò NMDA phase shift
			
			c. blocks VIP terminal output on AVP neurons in shell
			
			d. to balance photic & non-photic information
		
				i. stimuli àò cellular discharge ð non-photic phase-resetting
				   exciting cells produces photic-type phase shifting
	
				   
		6. IGL ð mRaphé ð 5-HT ð SCN core 5-HT1B 
		
			a. presynaptic inhibition of Glu & GABA release involve 5-HT1B-R 
		
			b. Stimulation of Glu release involve 5-HT7-R
			
				i. blocks GABAA effect ð delays onset of 2-4 Hz rhythm
	
			   
	C. During the day - fast action potential discharge
	
		1. soluble cytoplasmic factors suppress TEA-K+ channels 
		
			a. [Cl-]i higher
		
		2. Faster de- then re-polariaztion
		
			a. Enhanced L-type Ca++ currents
		 
			b. K+ currents through fast delayed rectifier channels 
		
			c. promote rapid action potential upswing and repolarization
			
	D. Actual behavior is rhythmically modulated in tune with multiple environmental events
	
		1. \ multiple sensory modality inputs
		
		2. Locomotor Activity must be coordinated with:
		
			a. sleep/wake cycles
			
				i. light, proprioception
				
			b. body temperature cycles
			
				i. tactile
				
				ii. Tob & sleep/wake cycles can move out of phase
				
			c. eating/energy cycles
			
				i. tactile
				
			d. cycles of affect
	
	
	E. Multiple sensory zeitgeibers require coordination - SCN Efferents
	
		1. SCN Master Clock coordinates Multiple Oscillators
		
			a. coupled circadian oscillators (core + shell)
			   pacemaking via a neuronal network
		
				i. Maintenance of circadian functioning does not 
				   require an intact neuronal network
				   
				ii. entrainment does
		
								
		2. retina, thalamus, hypothalamus, retrochiasmatic area, pineal, habenula,
		   pituitary, kidney, reproductive organs, endocrine glands,
		   have "clock" gene oscillators with weaker rhythmic signals 
		   in the absence of SCN
		
			a. Hypothalamic generation and integration of rhythms are modulated by
			   AVP, somatostatin (intrinsic to SCN), VIP, enkephalin, substance P(retinal fibers), 
			   NPY, Glu, GABA, 5-HT...
	
	
		3. SCN shell ð SPVZ ð DMH
		   SCN shell ð POA
		   
			a. AVP/Glu ð reset sleep/wake cycle
			
				i. stimulates "clock" gene àñ per
				
				ii. cell produces VIP, cardiotrophin-like cytokine and prokineticin 2
				
					(1) paracrines
			
			b. GABA ð resets cycle in opposite direction