The Autonomic Nervous System

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1 自主神經系統及下視丘及睡眠生理 Autonomic Nervous System Hypothalamus Sleep Principle of Neuroscience ( 第五版 Ch 47) 楊靜修老師

Parasympathetic NS: gain and conserve energy for the body 1. Increase secretion & motility (salivary gland, GI) 2. Decrease HR Sympathetic NS: energy-consuming 1. Decrease GI 2. Increase HR, BP 3.

3 Parasympathetic NS: gain and conserve energy for the body 1. Increase secretion & motility (salivary gland, GI) 2. Decrease HR Sympathetic NS: energy-consuming 1. Decrease GI 2. Increase HR, BP 3. Bronchi relax 4. Blood glucose increase 5. NE, Epi release increase ANS ( 屬 PNS 但可反應 CNS) - 大腦的天線 ( 接收訊習 ) - 將大腦訊習傳給全身臟器 (ANS 可以反應大腦許多功能及問題, 所以有機會為 biomaker) Parasympathetic nervous system Sympathetic nervous system

4 Reflex arch of autonomic nervous system Visceral receptors integrated stimulation Visceral effector Afferent autonomic pathway Efferent autonomic pathway CNS CNS: central nervous system

5 IML: intermediolateral horn

6 交感神經 : IML: intermediolateral horn IML--para v.c. 換 cell-- 回 spinal nerve (8%) 分泌 ACh -- 分支出去分泌 NE IML--pre v. 換 cell-- 分泌 NE IML--adrenal medulla-- 分泌 NE C fiber

7 T 1 75% 8% ACh 其他為 NE L 3 ACh 1. 分布較少 2. 反應較不連續且為局部作用 S 2 -S 4 22 對

8 Sympathetic nervous system NE receptor: Adrenergic receptor 短 ANS (Autonomic nervous system) 長長短 a 1 -receptor: contraction BP b 1 -receptor: HR contractility b 2 -receptor: relaxation M 2 receptor Parasympathetic nervous system ACh receptors Nicotinic receptor: N receptor Muscarinic receptor: M receptor

10 Voluntary command: Move! M o t o r n e u r o n Involuntary command: Rest & digest. Involuntary command: Emergency!

11 以作用到的 receptor 種類決定何種反應 CNS

13 Prejunctional autoreceptors

14 Rate limiting step In vesicle DBH PNMT

15 Tissue, blood, urine 可檢測濃度 MAO: monoamine oxidase COMT: Catechol-O-methyl transferase

16 合成之酵素 choline-o-acetyltransferase degradation

17 Mechanisms of signal transduction

18 Neurotransmitter receptors in the peripheral ANS (adrenoceptors)

19 Neurotransmitter receptors in the peripheral ANS (cholinoceptors)

20 T 1 L 3 S 2 -S 4

21 HR 以副交感影響為主 1. 不完全什麼臟器都有兩者控制 2. 興奮及抑制都有副交感系統過度興奮並不好但是維持生存所必需

Figure 49-6 Both acetylcholine (ACh) and a luteinizing hormone-releasing hormone (LHRH)-like peptide are released by presynaptic cells at synapses in the sympathetic chain

23 Figure 49-6 Both acetylcholine (ACh) and a luteinizing hormone-releasing hormone (LHRH)-like peptide are released by presynaptic cells at synapses in the sympathetic chain ganglia in the bullfrog. The two transmitters produce different types of postsynaptic potentials in different postganglionic neurons because of their actions on different receptors..

24 Autonomic neurons use a variety of chemical transmitters Ganglionic transmission involves both fast and slow synaptic potentials Norepinephrine and acetylcholine are the predominant transmitters in the ANS ATP and adenosine have potent extracellular actions Many different neuropeptides are present in autonomic neurons

25 A central autonomic network coordinates autonomic function Central autonomic network Brain stem and spinal circuits Baroreceptor reflex Sympathetic NS ANS Parasympathetic NS

26 Neuronal Regulation of Cardiovascular System Baroreceptor Reflex Response (BRR) 感測端 tonic excitation vasomotor center 反應端交感神經系統副交感神經系統

27 副交感源交感源感測端 Figure 49-9 Pathways that distribute visceral sensory information in the brain.

28 副交感交感 Figure Pathways that control autonomic responses.

29 Autonomic pharmacology Ganglionic blockers (transmission and receptor) -block sympatheric and parasympathetic nerve activity (other factor) Drugs that inhibit synthesis of neruotransmitter Drugs that inhibit release of neruotransmitter Drugs that promote release of neruotransmitter Drugs that interfere with storage of neurotransmitter Drugs that affect neuronal uptake Drugs that inhibit metabolism of neurotransmitter Drugs that block autonomic receptors Drugs that stimulate autonomic receptors Adrenoceptor-activating drugs Adrenoceptor-antagonist drugs Chlinoceptor-activating & chlinesterse-inhibiting drugs Cholinoceptor-blocking drugs

Drugs that inhibit synthesis of neruotransmitter Drugs that interfere with storage of neurotransmitter Drugs that affect neuronal uptake Drugs that inhibit release of

30 Drugs that inhibit synthesis of neruotransmitter Drugs that interfere with storage of neurotransmitter Drugs that affect neuronal uptake Drugs that inhibit release of neruotransmitter Drugs that promote release of neruotransmitter Drugs that stimulate autonomic receptors Drugs that block autonomic receptors Drugs that inhibit metabolism of neurotransmitter

Drugs that affect neuronal uptake and inhibit synthesis of neruotransmitter Drugs that promote release of neruotransmitter Drugs that inhibit metabolism of neurotransmitter

31 Drugs that affect neuronal uptake and inhibit synthesis of neruotransmitter Drugs that promote release of neruotransmitter Drugs that inhibit metabolism of neurotransmitter Drugs that interfere with storage of neurotransmitter Drugs that inhibit release of neruotransmitter Drugs that stimulate autonomic receptors Drugs that block autonomic receptors

32 The Hypothalamus Integrates Autonomic and Endocrine Functions With Behavior head ganglion of ANS

33 Hypothalamus: Homeostasis 內分泌系統之控制中樞飽食中樞, 飲水中樞, 體溫調節中樞, sexual behavior & 血壓調控, sleep/wake, circadian rhythms Neuroendocrinology External environment Internal condition Hypothalamus Pituitary gland Nervous system Hypothalamus Posterior pituitary Anterior pituitary

34 The hypothalamus serves this integrative function by regulation of five basic physiological needs: It controls blood pressure and electrolyte composition by a set of regulatory mechanisms that range from control of drinking and salt appetite to the maintenance of blood osmolality and vasomotor tone. It regulates body temperature by means of activities ranging from control of metabolic thermogenesis to behaviors such as seeking a warmer or cooler environment. It controls energy metabolism by regulating feeding, digestion, and metabolic rate. It regulates reproduction through hormonal control of mating, pregnancy, and lactation. It controls emergency responses to stress, including physical and immunological responses to stress by regulating blood flow to muscle and other tissues and the secretion of adrenal stress hormones.

35 The Hypothalamus Contains Specialized Groups of Neurons Clustered in Nuclei 重點 : 下視丘各核區參與之生理功能 4 g/1400 g adult human brain weight

36 重點 : 下視丘各核區參與之生理功能 LHA PVN MPO AH SCN SON DMH PHA VMH AN

37 Figure The structure of the hypothalamus. DMH LHA SON AN VMH

38 The Hypothalamus Controls the Endocrine System 下視丘前葉甲狀腺素 Guillemin and Schally, 1977 Nobel Prize

39 內分泌系統簡介下視丘腦下垂體甲狀腺腎上腺性腺

Figure 49-12 The hypothalamus controls the pituitary gland

40 Figure The hypothalamus controls the pituitary gland both directly and indirectly through hormone-releasing neurons.

41 後葉 PVN (paraventricular nucleus) SON (supraoptic nucleus)

42 Table 49-3 Hypothalamic Substances That Release or Inhibit the Release of Anterior Pituitary Hormones Hypothalamic substance Anterior pituitary hormone Releasing Thyrotropin-releasing hormone (TRH) Corticotropin-releasing hormone (CRH) Thyrotropin, prolactin Adrenocorticotropin, β -lipotropin Gonadotropin-releasing hormone (GnRH) Luteinizing hormone (LH), follicle-stimulating hormone (FSH) Growth hormone-releasing hormone Growth hormone (GH) (GHRH or GRH) Prolactin-releasing factor (PRF) Prolactin Melanocyte-stimulating hormone-releasing factor (MRF) Inhibiting Prolactin release-inhibiting hormone (PIH), dopamine Growth hormone release-inhibiting hormone (GIH or GHRIH; somatostatin) Melanocyte-stimulating hormone release-inhibiting factor (MIF) Melanocyte-stimulating hormone (MSH), β -endorphin Growth hormone, thyrotropin Melanocyte-stimulating hormone (MSH)

43 TRH, CRH, GnRH, GRH GIH, PRF PIH, MRF 下視丘前葉

44 前葉

45 下視丘前葉甲狀腺

46 下視丘前葉性腺

47 下視丘前葉腎上腺皮質素

48 壓力 Short-term & long-term nervous system & endocrine system 神經系統內分泌系統內分泌系統內分泌系統

49 全自動控溫系統 Homeostasis set point, receptor, effector

50 全自動控溫系統 Homeostasis set point, receptor, effector

51 Temperature Regulation Receptor (hypothalamus) AH/POA heat sens. cell 2/3 cold sens. cell 1/3 PH AH Heat conservation (shivering) Heat dissipation (sweat)

52 Glucostatic Hypothesis of Appetite Regulation Satiety Center ( 飽食中樞 )-VMH Feeding Center ( 餵食中樞 )-LHA glucostats: 位於 VMH 內, 其 glucose 利用可控制 VMH 細胞活性 VMH - LHA eat

53 Relation to Cyclic Phenomena Infradian (longer than one day) menstral cycle Circadian (approx. one day) sleeping, body temperature, various hormones, drinking, locomotor activity Ultradian (shorter than one day) feeding, respiration, heart rate, nerve impulse discharge Circadian rhythm: light signal from retina SCN

55 Circadian Rhythms Witte et al. 1998, Physiology & Behavior

57 Sleep Physiology Introduction-sleep 幾乎佔我們生命的 1/3 時間 Sleep 的原因 ( 日夜變化代謝 [ 被動 ] 學習記憶 [ 主動 ] 仍不知??) 人的最佳睡眠時間每人不同, 睡 7 h, 睡不好會產生疾病幾天 (2-3 w) 不睡會死亡 Sleep 睡眠各期腦波變化 frequency amplitude 德國 Hans Berger, 1929 第一位記到人的腦波圖 (1935 年始睡醒腦波 1953 年才發現 REM) 如何檢測睡眠品質? Sleep 主觀檢查 ( 問卷 ) PSQI 表 Sleep 客觀檢查 ( 生理參數變化 ) 人不動 ( 手上拿東西東西掉表示睡著 ; 床動記錄儀 ; active watch) EEG EMG EOG- 因為同時發生所以拿來作為睡眠代表 ( 不見得是對只有溫血動物記的到腦波 ) 睡眠偵測及分期標準 (R&K, 1968 訂 ) 大鼠以 K&Y lab 為例目前仍在等待新自動判讀方法客觀與主觀睡眠評估對應仍不佳原因不知?? Sleep 理論 ( 每種理論都不是唯一 ) 睡眠中心 ( 動物實驗 [ 解剖及行為方法 ] 及其它人的研究集合而成可解釋 ) Homeostatic Regulation of Sleep 睡眠疾病種類很多 ; 睡眠品質不好與許多疾病有關用 sleep/wake 當作是工具來分類以 K&Y lab 為例

58 睡眠主觀評量 PSQI > 5 或 7 表示有睡眠問題 ν ν 0, 1, 2, 3 分 0, 1, 2, 3 分

59 SSS 嗜睡量表 Stanford Sleepiness Scale 其它 VAS 量表

60 Epworth Sleepiness Scale ESS 嗜睡問卷調查總分 8 分以下為正常 8-10 分灰色地帶分是輕為嗜睡 12 分以上是嗜睡

61 Cycling of Human Sleep 睡眠客觀評量 >13 Hz 8-13 Hz <4 Hz

62 Polysomnography in Human

63 Stages of Sleep 人 - 仍需技術員判讀 Stage W (wakefulness) Stage 1 (NREM1) Stage 2 (NREM2) Stage 3 (NREM3) NEW! ---- slow wave sleep and replaces the R&K nomenclature of stage 3 and stage 4 sleep---- Stage R (rapid eye movement, REM) 睡眠偵測及分期標準 (R&K, 1968 訂 )

64 Sleep stage histogram

65 TST: total sleep time (- all W) TST/TRT=SE% WASO: wake after sleep onset Arousal no Arousal index: arousal no/ TST TRT: total recording time

66 Sleep latency SWS (S3+S4) SWS/TST=SWS% REM, REM% S1, S2, S3 S1%, S2%, S3%

67 The First of Sleep Center Research VLPO Science 1996, 271:216~218

68 C-fos protein expression in VLPO In VLPO neuron : cfos-immunostined A. Dark period (15%) B. Light period (63%) C. Sleep deprivation (83%) Fos protein: Normal sleep neuron activated SD

69 J. Neuroscience 2002, 22(11): VLPO VLPO Lesion VLPO VLPO evlpo

70 Summary

71 The ascending arousal system promotes wakefulness First pathway-thalamus-thalamocortical (yellow pathway) pedunculopontine (PPT) laterodorsal tegmental nuclei (LDT)-ACh Second pathway -hypothalamus-cortex (red) tuberomammillary nucleus (TMN)-His ventral periaqueductal gray matter (VPAG)-DA dorsal and median raphe nuclei-5-ht locus coeruleus (LC)-NA Basal forebrain (BF)-ACh, GABA lateral hypothalamus (LHA)-ORX, MCH Neurotransmitters : histamine (His), dopamine (DA), serotonin (5-HT), noradrenaline (NA), orexin (ORX) melanin-concentrating hormone (MCH), aminobutyric acid (GABA) Nature (2005)

72 The VLPO Promotes Sleep Show the key projections of the VLPO to the main components of the ascending arousal system. tuberomammillary nucleus (TMN) A10 cell group raphe cell groups the locus coeruleus (LC) lateral hypothalamus (LHA; green), pedunculopontine (PPT) laterodorsal tegmental nuclei (LDT) Nature (2005)

73 Flip-Flop Switch Model ( 正反器 all-or-none) GABA (fast), Gal (slow) 1. Self-reinforcing loop 2. Wake-Sleep transition quickly 3. Homeostatic forces 起動力量必需夠大腦中有類似的運作模式 Saper et al. Nature (2005)

74 Homeostatic Regulation of sleep Set point During prolonged wakefulness Accumulate: need to sleep Sleep deprivation Accumulate neurotransmitter: Adenosine

75 Adenosinergic modulation ATP degradation adenosine in basal forebrain-increase sleep propensity Adenosine antagonist effects of caffeine Behavioural Brain Research 2000,115 :

76 Extracellular conc in basal forebrain Addition of adenosine in basal forebrain Behavioural Brain Research 2000,115 :

77 Behavioural Brain Research 2000,115 :

78 T 1 75% 8% ACh L 3 ACh 1. 分布較少 2. 反應較不連續且為局部作用 S 2 -S 4

..), sleep (VLPO)/wake (TMN, LH), circadian rhythms (SCN) Neuroendocrinology External environment

80 Hypothalamus: Homeostasis 內分泌系統之控制中樞 (PVN, SON, AN, ME...) 飽食中樞 (VMH, LHA), 飲水中樞 (CVO, SFO, MPO), 體溫調節中樞 (PH, AH, POA), sexual behavior, 血壓調控 (PVN...), sleep (VLPO)/wake (TMN, LH), circadian rhythms (SCN) Neuroendocrinology External environment Hypothalamus pituitary gland (Hormones) Internal condition nervous system (head ganglion of ANS) Hypothalamus Posterior pituitary Anterior pituitary

81 Sleep-Awake Circuit Awake Pathway Sleep Pathway Sleep center: GABA LDT: laterodorsal tegmental nuclei, PPT: pedunculopontine TMN: tuberomammillary nucleus, Raphe: raphé nuclei, LC: locus coeruleus VLPO: ventrolateral preoptic nucleus

Chapter 8

Chapter 8 Consciousness, The Brain and Behavior 識行 I. States of Consciousness 識狀 (I) Electroencephalogram The electroencephalogram provides one means of defining the states of consciousness. 了識狀 Electric