Behavioral Neuroscience Summers

text:The Basis of Neuropharmacology 8th Edition - Cooper, Bloom, Roth:read Rhythmicity & Behavior Sensory input for Rhythmicity Afferent path to the SCN Circadian Rhythms Efferent SCN output Integration of Rhythms into Behavior end     Acronyms/Abbreviations     Syllabus

Glu VIP AVP GABA 5-HT Figures of Rhythmicity Retina-RGC-SCN Molecular SCN

BIOLOGICAL RHYTHMS
X. Circadian Rhythms 			

	A. Basic rest-activity cycles about (circa) a day (dian) in 
	   length are closely linked to day-night cycles

		1. circadian rhythms exist for virtually
		   every homeostatic system in the body


	B. Intrinsic Free-Running Circadian Activity - Molecular mechanisms
		
		1. Interacting Negative & Positive Feedback loops

		2. Negative Feedback: essential clock components - transcriptional

			a. clock gene = circadian  locomotor output  cycles  kaput

				i. changes peroid length

				ii. mammalian clock (on chromosome 5 Mus) similar to clock genes
				    in fruit flies & bread mold

			b. BMal gene - partner to clock
			(brain and muscle ARNT-like protein 1)
			
			c. Clock/BMal protein heterodimer is a
			   transcription factor complex
			
				i. contain PAS-bHLH (basic Helix-loop-Helix) allows 
				   protein to bind to another protein and then to DNA

				ii. one of those other proteins is the coactivator Nono 
				    that binds to RNA polymerase II  
				
				iii. binds E-box promoter of Per and Cry genes
				             Per = period   Cry = cryptochrome
				
			d. Per1&2 proteins (PAS) form heterodimers with
			   CRY1&2 proteins (flavoproteins)

				i.  for heterotrimer with Casein Kinase 1e
				
					(1) Per/CRY/CK1e necessary for 
					    nuclear translocation

				ii. negatively regulate BMal/Clock
				
					(1) CRY blocks BMal/Clock histone-3-acetylase
					    coactivator (p300)

				iii. Per/CRY build up over 24h ® ¯ clock/BMal ® start over

		3. Positive Feedback - adds precision (not necessary for the rhythm)
		
			a. Clock/BMal heterodimer also bind and stimulate REV-ERBa
			   and RORa  gene transcription
			   
			b. REV-ERBa/RORa bind to response elements (AGGTCA)
			   in the promotor of clock & BMal genes
		
				i. transcription factors in the T3 (thyroid hormone) receptor family
		
			c. extra copies of clock in genome accelerates cycle
			
			d. positive feedback nudges but does not drive the rhythm
						
		
	C. Intrinsic Free-Running Circadian Activity: autogenic SCN


		1. SCN has cyclic firing activity: Vmr:Vmt ~ 1

			a. high (8-10 Hz) during the day, low (2-4 Hz) at night

				i. intracellular [Cl-] ñ during the day, ¯ at night


		2. GABA acts as an inhibitory transmitter at night via GABAA

			a. ¯ firing frequency

			b. when [Cl-]i is ¯ GABA induces hyperpolarization

			c. GABA  acts to decrease firing further


		3. GABA acts as an excitatory transmitter during the day

			a. ñ firing frequency

			b. when [Cl-]i is ñ GABA induces depolarization

			c. positive feedback

		
	D. Entrainment

		1. cycle can be phase shifted by light, 5-HT, melatonin, VIP/PHI/GRP, 
		   NPY, GABA, substance P, AVP or partial loss of AVP neurons, enkephalin,
		   somatostatin (intrinsic to SCN), cAMP, PKA, pCREB, cGMP, stress or B/F,

			a. light shifts cycles of an organism to coincide with day/night cycles
			
			b. glucose uptake by SCN is significantly greater during daylight       

		2. Photic entrainment 	    

			a. RHT innervates SCN core: releases Glu & PACAP

			b. Glu binds to NMDA receptors® Ca++ ® CAM Kinase

				i. PACAP ® PKA ®pCREB

					(1) pCREB stimulates mPer1 & mPer2
					
					(2) clock is also a photosensitive protein

			c. Ca++ also activates NOS ® NO ® GC ® cGMP


		3. light/Glu/NMDA/NO/CAMK//PACAP/PKA/pCREB in early evening
		   phase delay the rhythm

			a. in the late night or early morning: advance the rhythm

			b. none have any effect in the day


		4. Glu stimulates core neurons which secrete VIP/PHI/GRP (colocalized)
		   (VIP/peptide histidine isoleucine/gastrin-releasing peptide)

			a. VIP/PHI/GRP phase advance/delay 
			   as does light/Glu/NMDA/NO/CAMK//PACAP/PKA/pCREB

				i. VIP & PHI come from the same pre-promolecule

			b. VIP/PHI/GRP neurons project to SCN GABA interneurons

				i. GABA ® GABAB ¯ Glu release ® ¯ phase delay or advance

				ii. VIP/GRP/GABA signals from core spreads 
				    rhythm information (clock genes) to the shell


		5. NPY/GABA impinge on AVP producing neurons
		   in dorsomedial SCN shell

			a. GHT GABA/NPY neurons inhibit VIP/GRP neurons via GABAA
			
				i. indirectly?

			b. rhythmic function is abolished in AVP-lesioned SCN

				i. restored with AVP-cell transplants

		6. Raphé 5-HT neurons project to core

			c. 5-HT phase delays circadian rhythms

				i. 5-HT7 receptor activity inhibits GABAA effect

					(1) GABAB ñ 5-HT release in SCN