Nervous System Three basic functions Sensing changes with sensory receptors Interpreting and remembering those changes Reacting to those changes with effectors 1 Major Structures of the Nervous System 2 1
Functions of the Nervous Systems The sensory function of the nervous system is to sense changes in the internal and external environment through sensory receptors. Sensory (afferent) neurons serve this function. The integrative function is to analyze the sensory information, store some aspects, and make decisions regarding appropriate behaviors. Association or interneurons serve this function. The motor function is to respond to stimuli by initiating action. Motor(efferent) neurons serve this function. 3 Nervous System Divisions Neuron & Glia (Neuroglia) Central Nervous System (CNS) -- Brain & Spinal Cord Peripheral Nervous System (PNS) Output: Motor Nerves -- Cranial Nerves & Spinal Nerves (1) Autonomic Nervous System (ANS) (2) Somatic Nervous System (SNS) (3) Enteric Nervous System (ENS) Input: Sensory Nerves 4 2
(CNS) (PNS) Cranial Nerves Spinal Nerves 5 Organization of the Nervous System 6 3
Neuron 7 Structure of Neurons 名稱 細胞體 (soma or cell body ) 樹突 (dendrites) 軸突 (axon) 軸突末 ( 終 ) 端或神經末梢 (axon terminals) 起始段 ( 軸突丘 ) (axonal hillock or initial segment) 特性內有細胞核及胞器 ( 如內質網 粒線體 等 ), 因此細胞內可以合成許多酵素及蛋白質 類固醇 醣類 等主要功能為接受訊號的地方 主要功能為 運送物質的地方 或者傳遞電訊號位於軸突最末端有許多細細長長的肥大結構, 主要功能為分泌神經傳導物質 位於軸突與細胞體的連接處, 主要功能為產生動作電位 ( 電訊號 ) 的地方 8 4
Cellular Communication Intracellular communication 動作電位 ( 電訊號 ) Synapses Chemical synapses Electrical synapses Intercellular communication Chemical messengers 9 Chemical Synapse Presynaptic terminal Synaptic vesicle Postsynaptic cell Synaptic cleft 10 5
Functional Classes of Neurons 11 Functional Classes of Neurons 名稱 感覺神經元 (sensory neurons) 傳入神經元 (afferent neurons) 中間神經元 (interneurons) 聯絡神經元 (association neurons) 運動神經元 (motor neurons) 傳出神經元 (efferent neurons) 特性 a. 接受器接收到訊號後, 會經由刺激把訊號傳到中樞 b. 大部份的傳入神經元位在 CNS 之外, 只有少數在 CNS( 只有少部份的軸突 ; 神經末梢進入到 CNS 大部份的軸突 cell body 在 PNS) c. 傳入神經元通常沒有樹突 a. 訊號整合 b. 所有的中間神經元皆落在 CNS 內 a. 把訊號從中樞傳出, 傳到作用器 cell ( 如腺體, 骨骼肌 or 其他神經 cell) b. 傳出神經元的 cell body 位於 CNS 內, 但神經末梢和大多數的軸突都在 PNS 內 12 6
Structural Classes of Neurons 13 神經相關名稱 神經 (Nerves) 神經纖維 (Nerve fibers) 神經節 (Ganglia) 神經核 (Nucleus) 神經徑 (Nerve tract) 成束的神經纖維 定義 包括 (1) 感覺神經纖維 ;(2) 運動神經纖維總稱為混合神經纖維 (mixed nerves) 中樞神經以外 ( 周邊 ) 細胞本體聚集在一起 中樞神經內的細胞本體聚集在一起 中樞神經相連區域的神經纖維聚集處 14 7
Functional Classes of Glia Cells 支持細胞位置功能 許旺氏細胞 (Schwann cells) 寡樹突細胞 (Oligodendrocytes) 衛星細胞 (Satellite cells) 星形細胞 (Astrocytes) 小神經膠細胞 (Microglial cells) 室管膜細胞 (Ependymall cells) 周圍神經 中樞神經 周圍神經 中樞神經 中樞神經 中樞神經 環繞所有周圍神經軸突, 形成神經鞘膜, 或稱為許旺氏鞘 ; 環繞周圍神經形成髓鞘 形成中樞神經軸突的髓鞘, 為中樞神經的白質 支持感覺及自律神經節中的神經元 環繞血管並覆蓋腦微血管形成血腦障壁 (Blood Brain Barrier, BBB) 中樞神經的阿米巴狀細胞, 有吞噬功能 形成腦腔 ( 室 ) 及脊髓腔的內櫬, 覆蓋微血管叢形成分泌腦脊髓液的脈絡叢 15 Functional Classes of Glia Cells Neuroglia of the CNS Neuroglia of the PNS 16 8
Membrane Potential (-50 ~ -70 mv) 17 膜電位相關名稱 Potential (Potential difference) Membrane potential (Transmembrane potential) Equilibrium potential Resting membrane potential (Resting potential) Graded potential Action potential Synaptic potential 定義 The voltage difference between two points The voltage difference between the inside and outside of a cell The voltage difference across a membrane that produces a flux of a given ion species that is equal but opposite the flux due to the concentration gradient affecting that same ion species The steady transmembrane potential of a cell that is not producing an electric signal A potential change of variable amplitude and duration that is conducted decrementally; it has no threshold or refractory period A brief all-or-none depolarization of the membrane, reversing polarity in neurons; it has a threshold and refractory period and is conducted without decrement A graded potential change produced in the postsynaptic neuron in response to release of a neurotransmitter by a presynaptic teminal; it may be depolarizing (an excitatory postsynaptic potential or EPSP )or hyperpolarizing (an inhibitory postsynaptic potential or IPSP) 18 9
Change in MP 19 Two Types of Ion Channels Leakage (nongated) channels are always open -nerve cells have more K+ than Na+ leakage channels -as a result, membrane permeability to K+ is higher -explains resting membrane potential of -70mV in nerve tissue Gated channels open and close in response to a stimulus -results in neuron excitability 20 10
Ion Channels Gated ion channels respond to voltage changes, ligands (chemicals), and mechanical pressure. Voltage-gated channels respond to a direct change in the membrane potential. Ligand-gated channels respond to a specific chemical stimulus. Mechanically gated ion channels respond to mechanical vibration or pressure. 21 Ionic Basis of RMP 22 11
Ionic Basis of AP 23 24 12
Ionic Basis of AP Refractory period 25 All-or-None Law (AP) 26 13
Propagation of AP 27 Propagation of AP Saltatory Conduction 28 14
Speed of Impulse Propagation The propagation speed of a nerve impulse is not related to stimulus strength. larger, myelinated fibers conduct impulses faster due to size & saltatory conduction Fiber types A fibers largest (5-20 microns & 130 m/sec) myelinated somatic sensory & motor to skeletal muscle B fibers medium (2-3 microns & 15 m/sec) myelinated visceral sensory & autonomic preganglionic C fibers smallest (0.5-1.5 microns & 2 m/sec) unmyelinated sensory & autonomic motor 29 Graded Potential 30 15
Axon = Cable 31 Release of NTs/Chemical Synapse Ca 2+ AP Axon AP Ca2+ Ca 2+ Ca 2+ Inactive protein kinase Calmodulin Active protein kinase Synaptic vesicles Synapsin-P exocytosis Releases of NTs 32 16
Action potential reaches end bulb and voltage-gated Ca +2 channels open Ca +2 flows inward triggering release of NTs NTs crosses synaptic cleft & binding to ligand-gated receptors Synaptic delay is 0.5 msec One-way information transfer 33 Removal of Neurotransmitter Diffusion move down concentration gradient Enzymatic degradation acetylcholinesterase Uptake by neurons or glia cells neurotransmitter transporters Prozac = serotonin reuptake inhibitor 34 17
Three Possible Responses Small EPSP occurs potential reaches -56 mv only An impulse is generated threshold was reached membrane potential of at least -55 mv IPSP occurs membrane hyperpolarized potential drops below -70 mv 35 Neurotransmitters 分類 Amines Catacholamines 化學分子 乙醯膽鹼 (acetylcholine) 組織胺 (histamine) 血清張力素 (serotonin, 5-hydroxytryptamine; 5-HT) 多巴胺 (dopamine) 腎上腺素 (epinephrine) 正腎上腺素 (norepinephrine) Amino acids 天門冬胺酸 (aspartic acid) γ- 胺基丁酸 (GABA) 麩胺酸 (glutamic acid) 甘胺酸 (glycine) Polypeptide 昇糖激素 (glucagon) 胰島素 (insulin) 生長激素釋放抑制因子 (somatostatin) P 物質 (substance P) 促腎上腺皮質分泌激素 (ACTH) 血管收縮素 II (angiotensin II) 腦內啡 (endorphins) 促甲狀腺激素釋放激素 (TRH) 血管加壓素 ( 抗利尿激素, ADH) 膽囊收縮素 (CCK) 36 18
Endorphins 平常有在運動的人, 對疼痛的指數比較高, 也就是對疼痛的耐受性較高 運動時, 腦內嗎啡 ( 內源性嗎啡 ;endorphins) 分泌會增加 Endorphins 被分泌出來, 其具有止痛的效果 會使人有快樂的感覺, 所以當你適度運動流完汗後, 會感到很舒服, 這就是和 endorphins 增加有關 像運動員和劇烈運動的人, 都曾說會感到一種與 endorphins 劑量提高有關的特殊陶醉感或快感 37 Synaptic Potential EPSP IPSP 38 19
Spatial & Temporal Summation 39 Synaptic Potential EPSP ACh/Nicotincic R/NMJ IPSP ACh/Muscarinic R/heart 40 20
AP & EPSP 特性 開啟離子閘門的刺激刺激所產生的初期效果再極化的產生傳導距離去極化及 Na channels 最大去極化加成 (summation) 作用不反應期藥物的作用 去極化 Na channels 開啟 K channels 開啟 沿著軸突產生 有 +40mV 無加成, 遵循全或無定律 有 動作電位 (AP) 可被河豚毒素 (tetrodotoxin) 抑制, 但不被南美箭毒 (curare) 抑制 興奮性突觸後電位 (EPSP) 乙醯膽鹼 Na 及 K channels 開啟胞內正電荷隨時間及距離消失 1-2 mm, 為局部的電位無接近零 EPSPs 的加成, 產生有等級的去極化無可被南美箭毒抑制, 但不被河豚毒素抑制 41 Nicotinic ACh Receptor/NMJ ECF ACh Ion channel Na + Binding site Cell membrane K + ICF 42 21
Muscarinic ACh Receptor/Heart ACh ECF ACh binds to receptor K + Cell membrane ICF M-R G-Protein K + K + channel 43 AChE/Postsynaptic Cell Membrane Presynaptic axon ACh Presynaptic axon Acetylcholinesterase (AChE) Receptor Postsynaptic cell Postsynaptic cell 44 22
Release & Inactivation of NE Prozac Coacine Amphetamine MAO(Monoamine oxidase) 45 COMT(Catechol-O-methyltransferase) Catecholamine Biosynthetic Pathway 46 23
Effect of NE Adrenergic receptor NE Adenylate cyclase Ion channel Cell membrane G-Protein (camp) Opens ion channels Other cellular effects 47 Condition Alzheimer s disease Clinical depression Epilepsy Huntington disease Hypersomnia Insomnia Mania Myasthenia gravis Parkinson s disease Schizophrenia Sudden infant death syndrome ( crib death ) Tardive dyskinesia Excessive sleeping Inability to sleep Symptoms Memory loss, depression, disorientation, dementia, hallucinations, death Debilitating, inexplicable sadness Seizures, loss of consciousness Personality changes, loss of coordination, uncontrollable dancelike movements, death Elation, irritability, overtalkativeness, increased movements Progressive muscular weakness Tremors of hands, slowed movements, muscle rigidity Inappropriate emotional responses, hallucinations Baby stops breathing, dies if unassisted Uncontrollable movements of facial muscles Imbalance of Neurotransmitter in brain Deficient ACh Deficient NE and/or 5-HT Excess GABA leads to excess NE and DA Deficient GABA Excess 5-HT Deficient 5-HT Excess NE Deficient ACh receptors at neuromuscular junctions Deficient DA Deficient GABA leads to excess DA Excess DA Deficient DA 48 24
Drug Actions at Synapses 49 Drug Tryptophan Reserpine Curare Botulinus toxin Tertodotoxin Neurotransmitter Serotonin Norepinephrine Acetylcholine Acetylcholine Acetylcholine. Affected Mechanism of Action stimulates neurotransmitter synthesis Decrease packaging neurotransmitter into vesicles Decreases neurotransmitter in synaptic cleft decrease neurotransmitter release Block Na channels Effect Sleepiness Decreases blood pressure Muscle paralysis Muscular weakness Muscle paralysis Nerve gas Neostigmine Nicotine Acetylcholine Acetylcholine Acetylcholine Blocks enzymatic degradation of neurotransmitter in postsynaptic cell (AChE) Blocks enzymatic degradation of neurotransmitter in postsynaptic cell (AChE) Stimulates synthesis of enzyme that degrades neurotransmitter Spastic paralysis Muscle contraction Increases alertness 50 25
Drug Neurotransmitter Affected Mechanism of Action Effect Valium GABA Enhances receptor binding Decrease anxiety Cocaine Norepinephrine Blocks reuptake Euphoria Tricyclic antidepressants Norepinephrine Blocks reuptake Mood elevation Monoamine oxidase inhibitors Norepinephrine Blocks enzymatic degradation of neurotransmitter in presynaptic cell Mood Elevation Prozac and related drugs Serotonin Blocks reuptake Mood Elevation 51 古柯鹼 (Cocaine) 是一種和安非它命 (amphetamines) 作用相似的中樞興奮劑, 在美國有濫用此藥物的趨勢 服用此藥早期會有快樂並且較世故的感覺, 但長期持續服用則造成退縮 憂慮, 對高劑量藥物的依賴 並會引起嚴重心血管及腎臟疾病而導致心臟及腎衰竭 古柯鹼對中樞神經的作用導致抑制突觸前軸突末梢對單胺類的再吸收作用而造成對使用多巴胺及其它單胺類神經傳導物質之神經路徑的過度刺激 52 26
Benzodiazepines 是一種鎮靜安眠類藥物, 可加強 GABA 在腦及脊髓的作用 GABA 是一種神經傳導物質, 可抑制脊髓支配骨骼肌神經元的活性 所以靜脈注射該類藥可抑制癲癇持續狀態 (status epilepticus) 時的肌肉收縮及藥物過量和中毒時所產生的徵狀 由於 GABA 對大腦有廣泛的抑制作用, 所以似乎也參與情緒的表現 因此二氯平 (Valium) 等 benzodiazepines 類藥劑也用來作為安眠劑 53 肉毒桿菌 (Clostridium botulinum) 是非常毒的菌, 可分為七種亞型 : A~G, 一般臨床用 A 型肉毒桿菌毒素, 1897 年開始有許多眼科醫生用 A 型來治療斜視 不自主的抽動 顏面神經痙攣, 而且還具有除皺的功能 A 型肉毒桿菌毒素的除皺作用機轉 : 一種位於神經末梢可分解突觸蛋白的酵素, 使突觸小泡無法與突觸前細胞膜融合, 則神經傳導物質 (ACh) 就無法被釋放出去, 便造成肌肉無力 ( 使過度收縮的肌肉可以放鬆, 減緩皺紋產生 ) 54 27
神經毒氣 (nerve gas ) 可抑制骨骼肌中 AChE 的活性使 ACh 不被分解, 也就是在突觸間隙的 ACh 濃度相對增高, 相對的作用於突觸後接受器也會增加, 骨骼肌就一直會產生收縮 而持續刺激突觸後細胞導致痙攣性癱瘓 ( spastic paralysis ) 而神經肌肉傳達就會減弱, 用 AChE 抑制劑如 : neostigmine 與神經毒氣很相似, 主要抑制 AChE 作用, 還可以治療重症肌無力 55 Alzheimer s disease 是最常見的老年痴呆症 ; 其病程常於中年開始, 造成進行性的智力退化 阿茲海默氏疾病的原因並不清楚, 但證據顯示和膽鹼激導性神經元 (cholinergic neuron) ( 用 ACh 為神經傳導物質 ) 的減少有關 這些神經元終止於海馬迴 (hippocampus) 及腦皮質 ( 和記憶儲存有關的區域 ) 因為乙醯膽鹼是由 acetyl coenzyme A 和 choline 構成, 所以有人利用攝食大量卵磷脂 (lecithin) 含有膽素來增加腦部的 ACh 到目前為止, 這種營養治療及利用藥物抑制 AChE 以增加乙醯膽鹼的方法只有一點點成效 56 28
重症肌無力 (myasthenia gravis) ACh 接受器被免疫系統的抗體摧毀, so 即使有 ACh 也是無法作用, so 骨骼肌無法有利的收縮, 肌肉就會無力 可利用 neostigmine 來作治療, 雖然骨骼肌上的 ACh 接受器被破壞, 但還有少許接受器存在, 如果分泌出來的 ACh 很容易被破壞, 也是沒辦法作用到接受器, 所以為了增加 ACh 的濃度, 因此利用 neostigmine 抑制 AChE, 使 ACh 沒辦法代謝, 則 ACh 濃度就會變高, 容易作用到稀少的 ACh 接受器上, 讓骨骼肌稍微收縮 57 快樂才是終點 58 29