1. How do Dopamine, Serotonin influence the Mood, Sleep, Attention, Learning?
54陳芷安 91蔡逸松

2. What Is the Difference Between Dopamine & Serotonin?
Similarities
Neurotransmitters
mood and emotion, regulate appetite, sex, aggression
mental illnesses, such as depression, bipolar disorder and schizophrenia.
Both neurotransmitters, strongly connected to mood and emotion, regulate appetite, sex, aggression and cognitive function, and are targeted in the treatment of mental illnesses, such as depression, bipolar disorder and schizophrenia.
多巴胺、血清素為神經傳導物質，和情緒、食欲、性欲、認知功能有關，並與精神疾病( bipolar disorder and schizophrenia)的療有關。
Origins of the neurotransmitters
Serotonin is synthesized from the amino acid tryptophan, while dopamine is manufactured from L-dopa, which is produced by tyrosine.
血清素由胺基酸triptophan合成，多巴胺由胺基酸tyrosine

3. Serotonin‘s Role Dopamine‘s Role
emotion, appetite and sensory perceptions
sleep, pain perception, body temperature, blood pressure and hormonal activity.
learning, aggression and cognitive processes(認知過程) .
movement, mood, motivation and pleasure
Decreased →Parkinson's disease
Increased
→schizophrenia
血清素: 情緒、食欲、感知、睡眠、痛覺、體溫、血壓、賀爾蒙活性、學習、攻擊性、認知過程
多巴胺: 動作、心情、動機、愉悅
缺: Parkinson's disease
多: schizophrenia

4. Dopaminergic Pathway in the Brain
1.Mesolimbocortical pathway
VTA→limbic system:
1.amygdala
2.nucleus accumbens 3.hippocampus
2.Mesostratal pathway
1.Mesolimbocortical pathway皮質邊緣路徑
ventral tegmental area(VTA)→limbic system(amygdala, nucleus accumbens, hippocampus) and the cortex
DA participate in the performance of specific congitive functions, such as verbal learning.
Abnormality→Schizophrenia
2.Mesostratal pathway
midbrain(substantia nigra) →striatum(caudate nucleus and putamen)
**A midbrain structure that provides DA to forebrain, especially the basal ganglia.
few cells→thousands of synapses
function in motor control, loss→movement problems of Parkinson’s disease
－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－
ventral tegmental area (VTA)腹側被蓋區→limbic system邊緣系統(amygdala杏仁核, nucleus accumbens伏隔核, hippocampus海馬) and the cortex皮質
DA participate in the performance of specific congnitive functions, such as verbal learning.(多巴胺參與特定認知功能的執行，如語言學習)
Abnormality→Schizophrenia(異常→精神分裂症)
2.Mesostratal pathway皮質底層路徑
midbrain中腦(substantia nigra黑質) →striatum紋狀體(caudate nucleus and putamen) (尾狀核和殼核)
**A midbrain structure that provides DA to forebrain, especially the basal ganglia.(一中腦結構可提供多巴胺給前腦，特別是基底節)
few cells→thousands of synapses(少數細胞→成千上萬細胞突觸)
function in motor control控制行動, loss→movement problems of Parkinson’s disease(壞掉會導致帕金森氏症)
中腦(黑質)
midbrain(substantia nigra)
→striatum(紋狀體)(caudate nucleus and putamen)
皮質邊緣路徑　　　　　　皮質底層路徑 2. 1.
(尾狀核和殼核)
back

5. Serotonergic Pathway in the Brain
Dorsal raphe
1.→視丘、下視丘、基底節basal ganglia、海馬、皮質
2. →小腦、脊髓
Serotonin=5-HT
Raphe nuclei: string of nuclei midline of the midbrain that contain most of the serotonergic neurons
中縫核 ex. Dorsal raphe
Few but widespread neurons
其中Dorsal raphe(midbrain nuclei)提供最多serotonergic projection
→視丘、下視丘、基底節basal ganglia、海馬、皮質
→小腦、脊髓
Serotonin→sleep state(14), mood, sexual behavior, anxiety…
增強5-HT活性的藥物: antidepressant ex. Prozac (16)
至少有15種Receptor, 藥物的不同效果depend on作用在 which subtypes of receptors.
－－－－－－－－－－－－－－－－－－－－－－－－
Serotonin血清素=5-HT
Raphe nuclei中縫核 : string of nuclei midline of the midbrain that contain most of the serotonergic neurons(位於中腦，擁有大部分的血清素神經元)
ex. Dorsal raphe中縫背
Serotonin→sleep state, mood, sexual behavior, anxiety…
增強5-HT活性的藥物: antidepressant抗憂鬱藥 ex. Prozac百憂解
back

6. At least four interacting neural systems underlie sleep…
前腦 腦幹 橋腦 下丘腦
Forebrain System:
display SWS
Brainstem System :
wake up the forebrain
Pontine System :
trigger REM sleep
Hypothalamic System :
affects the other 3 brain regions and determine whether the brain will be awake or asleep
Sleep mechanism

7. Sleep: EEG 沉睡期 1.Behavioral arousal 2.EEG arousal
(Electroencephalography)
沉睡期
出現Delta wave,
差異在於其數目。
腦電圖: 通過醫學儀器腦電圖描記儀將人體腦部自身產生的微弱生物電放大記錄而得到的曲線圖。記錄電位改變或腦波。藉由黏在頭皮上的電極來測量大腦皮質中數千個神經細胞的快速變動電位。
Vertex spike: stage1的特色, 尖銳的波峰
Sleep spindle: stage2, 短的一段段睡眠紡錘
Delta waves: 振幅大、慢的delta波, in stage3, stage4
Note: waking, stage1, REM are similar.
Waking: 振幅小、高頻率的波的混合
SWS: slow-wave sleep: slow-wave出現時就是SWS, 分為stage1~4.
行為覺醒: 有行為表現的覺醒(ex.對刺激的探究反應等)
腦電覺醒: EEG由高振幅慢波變成低震幅快波
1.Behavioral arousal
2.EEG arousal

9. Reticular formation The reticular formation wakes up the forebrain
(Upstream activation)
Reticular formation
An extensive region of the brainstem (extending from the medulla through the thalamus) that is involved in arousal.
Forebrain System:
display SWS
Brainstem System :
wake up the forebrain
Pontine System :
trigger REM sleep
Hypothalamic System :
affects the other 3 brain regions and determine whether the brain will be awake or asleep
Reticular formation(網狀結構): 從脊髓延伸出來，經過丘腦的一部分廣泛的腦幹區域，和覺醒有關。(Forebrain前腦、Midbrain、Upper pons、Lower pons、Upper medulla、Lower medulla)
Moruzzi and Magoun, 1949: 利用電極刺激動物的reticular formation, show rapid awakening; 該區域病變的動物造成永久的睡眠。
前腦: 加強大腦的SWS, reticular formation叫醒前腦
->前腦系統和腦幹網狀結構似乎將大腦從SWS到awake之間推來推去。
1970 Jones動物實驗: 破壞中腦黑質的DA系統後，動物表現“行為不覺醒”、“腦電覺醒”。
證明行為覺醒的維持與中腦黑質-紋狀體系統功能有關。(Mesostratal pathway)
*帕金森氏患者有睡眠問題，整天處於困倦狀態。可能是因為dopamine的不足造成無法正常維持行為覺醒狀態。
早期的睡眠理論較強調血清素的影響，下張投影片。
1970 Jones’s exp: DA system

10. Reticular formation Raphe System and Serotonin
Thalamus丘腦
Basal forebrain基底前腦
Basal ganglia基底節
Raphe System and Serotonin
1967 Michel Jouvet ‘s Thm
1999 Boutrel’s exp
Midbrain
Upper pons
Lower pons
Raphe Nuclus中縫核
Locus Coeruleus藍斑
Upper mudulla
Raphe Nuclus中縫核: in 腦幹中線 use Serotonin
Locus Coerleus藍斑: in Dorsal pons 背側橋腦 use NE
>>The Raphe System, Michel Jouvet, and Sleep Theories
Michel Jouvet (1967) emphasized a system of neurons coursing in the midline of the brainstem called the raphe (pronouned “ra-FAY”) nucleus (see the figure). These neurons use the neurotransmitter serotonin, and Jouvet proposed that serotonin release throughout the brain promotes sleep, especially SWS.
MJ假設中縫核(raphe nucleus)利用血清素的釋放到整個大腦，促進SWS睡眠。(因為activity降低了)
For example, the drug parachlorophenylalanine (PCPA) blocks the synthesis of serotonin, producing a decrease in transmitter levels and a reduction in sleep. Likewise, mice with the serotonin 1B receptor knocked out display less SWS than control mice do (Boutrel et al., 1999). However, the broad controlling role once attributed to serotonin in neurochemical models of sleep must now be tempered by the recognition that other transmitters also seem to be part of the sleep story (see the table).
例如: PCPA這種藥物能block血清素的合成，造成傳導物質的水平降低、睡眠減少。
血清素1B receptor 被剔除的基因剔除鼠的SWS表現也比控制組的老鼠少。
但是現在知道控制睡眠的不僅有血清素，還有正腎上腺素和乙醯膽鹼.
Figure 1  The Raphe Nucleus, Locus Coeruleus, and Their Projections
Table 1  Neural Activity of Neurotransmitter Systems during Sleep and Arousal

11. Sleep Serotonin Dopamine Normal secretion ↓ Increase dreaming
melatonin↑: REM
serotonin ↑: awake and active
Light→serotonin (power)
→pineal gland (synthesis)
→melatonin
dark →melatonin
Normal secretion ↓
Increase dreaming
Sleep well
While light increases the production of serotonin, darkness spurs on the synthesis of melatonin. Paired together, these two neurotransmitters are key in maintaining the sleep cycle.
Disrupting the Rhythm
Jet lag, serotonin production cycle follows that of your home time zone and has trouble getting on track.
Winter, when sunlight inadequately triggers the production of serotonin, sleep cycles can also be interrupted.
夢是一種妄想與幻覺的狀態，經由大腦基本機制激發。而神經傳導物質多巴胺(dopamine)，會使這種作用更加強化。「多巴胺假說就是我們為何作夢的核心。」
the brain chemical dopamine plays a critical role in regulating sleep and brain activity associated with dreaming.  
When dopamine levels were dramatically reduced, the mice could no longer sleep. When dopamine levels were increased, the mice exhibited brain activity associated with dreaming during wakefulness.  
The same processes likely occur in humans, according to the researchers. They said the findings give insight into the sleep problems common among patients suffering from, a neurodegenerative disorder in which brain cells containing dopamine die or become impaired.  

12. Mood Serotonin Dopamine Symptoms of Low Level • Difficulty focusing
• The smallest task can seem like a chore.
• Chronic fatigue
• Appetite/sleep disturbance
• Low libido
• Low to no self-esteem
• Social withdrawal
Effect
affection
feeling
excited, happy
Dopamic nurons in VTA is the basic unit of nuron which promote the emotional brain
Serotonin Syndrome
Serotonin syndrome is a condition found when a high level of serotonin is in the brain. Most people may think this is a good thing because serotonin keeps the body in a "happy place," but this is not the case. When someone is treated for depression using medication, most antidepressants increase serotonin levels in the brain. However, there are also other medications that affect the serotonin levels. For example, if a person takes medication to help with his migraines while at the same time taking antidepressants, the two drugs will interact and cause serotonin syndrome. Because this condition can cause death, the symptoms can occur within minutes, and they are as follows:
• Rapid heartbeat
• Hallucinations
• Diarrhea and vomiting
• Change in blood pressure
• Coordination loss
中腦腹側蓋區(VTA)的多巴胺(dopamine)神經元是啟動情緒腦的基本的單元，主管人的慾望、快感以及情緒等，同時也扮演導致毒癮現象的重要角色。愛情其實就是腦里產生大量多巴胺作用的結果。所以，吸煙和吸毒都可以增加多巴胺的分泌，使上癮者感到開心及興奮。根據研究所得，多巴胺能夠治療抑鬱症；而多巴胺不足則會令人失去控制肌肉的能力，嚴重會令病人的手腳不自主地震動或導致帕金森氏症。

13. Medial Regions of the Brain Involved in Emotions
杏仁核 –恐懼(emotion)—恐懼制約—learning
海馬—記憶—learning
杏仁核 海馬 海馬旁迴

14. The study of brain mechanisms at work during economic decision making.
Neuroeconomics

15. Brain Reward Systems
Early studies: establishing the generality of their function and their neurochemical bases.
Animal experiments: animals can withstand electric shock, exert significant physical effort, and even reduce food intake to obtain electrical stimulation in appropriate brain areas.
早期Brain Reward Systems(腦獎勵系統)研究: 建立一個具一般性的功能，以及其神經化學基礎。
動物實驗指出: 動物能忍受電擊、消耗大量體力、甚至減少食物攝取，都是為了獲得腦特定區域的電位刺激。(ex: 老鼠不斷按按鍵使多巴胺注入，而廢寢忘食餓死)
多巴胺是一種腦獎勵系統中的共同貨幣，而此特定區域和腦的多巴胺系統有關。(除了DA還有NE、serotonin等)

16. Value Assessment In DA system To augment reward-producing behaviors:
Generating learning signals
學習的機制: Montague, P.R. et al. (1996) A framework for mesencephalic dopamine systems based on predictive Hebbian learning. J. Neurosci. 16, 1936–1947
Adaptively updating goal states and attentional focus in working memory
注意力的機制: Braver, T.S. and Cohen, J.D. (2000) On the control of control: the role of dopamine in regulating prefrontal function and working memory. In Attention and Performance (Monsell, S. and Driver, J., eds), pp.713–737, Academic Press
越來越多證據顯示多巴胺系統在價值評估上的重要作用。動物為了擴大 reward-producing behaviors 而生成學習信號、並自適應地更新目標，以及更新工作記憶中的注意力集中點。(工作記憶7+-2秒，容量十分有限所以必須集中注意力於某物)
雖然DA和NE的計算模型都被找到，他們之間的作用關係還沒被找到。
學習的機制: Montague, P.R. et al. (1996) A framework for mesencephalic dopamine
systems based on predictive Hebbian learning. J. Neurosci. 16,
1936–1947
注意力的機制: Braver, T.S. and Cohen, J.D. (2000) On the control of control: the role
of dopamine in regulating prefrontal function and working memory. In
Attention and Performance (Monsell, S. and Driver, J., eds), pp.
713–737, Academic Press

17. increases motivation or desire towards the reward
Learning
Serotonin
Dopamine
Hippocampus accepted serotonin.
1.increase: hippocampus activated, learn and memorize better
2.reduce: forgettable, Degenerative brain or atrophy.
rewarding experiences
Dopamine
increases motivation or desire towards the reward
induce learning
release
愉悅: 演化為基本心理作用，功能為塑造行為。(Cabanac, 1992)
界定各種行動的"價值"的共通貨幣=多巴胺。
行動的酬賞或情感結果反映出該行動是否值得去做(價值)。
"想要(wanting)"與"喜歡(liking)"
想要: 愉悅的預期 - 誘因動機(incentive motivation)
喜歡: 體驗的愉悅 - 情感酬賞
想要=共通貨幣=多巴胺，意即所有事件的酬賞都能活化"腦的多巴胺系統"。
Dopamine is released (particularly in areas such as the nucleus accumbens  and prefontal cortex) by rewarding experiences
中腦多巴胺神經元(Dopaminergic neurons of the midbrain)是多巴胺主要來源。當酬賞(reward)>預期，多巴胺神經放電增加，就會產生該行為的動機(toward 酬賞)。
酬賞會誘發: 學習、行為方式、正向情緒。
Liking可以推動wanting，但其實wanting和多巴胺系統較有關聯。即使rewarding experience是不快的(賭博輸錢、毒品戒斷反應)，多巴胺系統induce人重複導致”多巴胺注入事件”。
The nucleus accumbens is a part of the striatum that integrates information from cortical and limbic brain structures to mediate behaviors the reinforce reward.

18. Limbic System (恐懼制約) Amygdala杏仁核 Nucleus accumbens伏隔核 Hippocampus海馬
*Long-term potentiation:
synaptic plasticity
學習分為四大類: 1.習慣化2.古典制約3.工具制約4.複雜學習
這張slide討論學習理論中古典制約的恐懼制約(學習)
杏仁核接受來自[視丘、大腦皮質、海馬迴]的感覺輸入，將這些刺激建立連結，並轉換為[下視丘、中腦、延髓]所負責的恐懼反應。
恐懼學習會使杏仁核產生長期增益作用(long-term potentiation), 就是CS(conditioned stumulus制約刺激, ex.燈光)到杏仁核的神經通路的突觸傳遞持續增加。
學習影響神經傳導物質:
突觸可塑性(synaptic plasticity): 塗觸後神經細胞受器增加、突觸大小改變、新塗觸的形成。學習可能伴隨新神經細胞的生長。
神經傳導物質的增減，可能因為突觸末梢數量有所增減。
學習->改變突觸->改變神經傳導物質增減 (觀察到的結果)
The amygdalae are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.
杏仁核是杏仁狀的核，位於脊椎動物大腦的顳葉內側，其功能主要為情緒反應的記憶與處理。
The nucleus accumbens (NAcc), also known as the accumbens nucleus or as the nucleus accumbens septi , is a collection of neurons within the striatum. It is thought to play an important role in reward, pleasure, laughter, addiction, aggression, fear, and the placebo effect( 安慰劑效應).
伏隔核是紋狀體內神經的集合，主要與獎勵、快樂、歡笑、上癮、攻擊性、恐懼、安慰劑效應有關。
The hippocampus is a major component of the brains of humans and other mammals. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Like the cerebral cortex, with which it is closely associated, it is a paired structure, with mirror-image halves in the left and right sides of the brain. In humans and other primates, the hippocampus is located inside the medial temporal lobe, beneath the cortical surface.
海馬是人類或其他哺乳類大腦的主要組成，主要與短期記憶到長期記憶的訊息鞏固和空間導航有關，海馬與其緊密相關連的大腦皮質一樣，是一種成對的結構，一半在左腦中而另一半則在右腦中，左右對稱。在人類及其它靈長類動物中，海馬位於皮質表面下方的顳葉內側。
*Learning→ synaptic changing→transmitter changing

19. Attention
Selective awareness of perceptual receptivity, involving the activation of certain brain regions.
Attention: 有選擇性地接受知覺，和腦特定區域活化有關。

20. Attention (ADHD for example)
Attention deficit hyperactivity disorder (ADHD)
A common, childhood-onset neurodevelopmental disorder.
Inattention, hyperactivity and impulsivity.
More frequent in males than females
Several genes on the X chromosome have been studied as candidate risk factors for ADHD including the 5-HT2C receptor (HTR2C) gene.
Pathogenesis of ADHD: dopaminergic, serotonergic and noradrenergic neurotransmitter systems
Attention deficit hyperactivity disorder (ADHD) is a common, childhood-onset neurodevelopmental disorder characterized by inattention, hyperactivity and impulsivity.
ADHD is more frequent in males than females.( Several genes on the X chromosome have been studied as candidate risk factors for ADHD including the 5-HT2C receptor (HTR2C) gene. Association between polymorphisms in HTR2C and ADHD were reported in a recent study.)
Molecular genetic and pharmacological studies suggest the involvement of the dopaminergic, serotonergic and noradrenergic neurotransmitter systems in the pathogenesis of ADHD.
ADHD是常見的幼年 神經發展疾病，特徵是注意力缺乏，過動，衝動。好發男性，因為X染色體上的某些基因是ADHD的risk factor，如5-HT2C receptor (HTR2C) gene。
近年來研究的是polymorphisms in HTR2C 。
分子生物學和藥理學研究顯示: ADHD發病機制involve 多巴胺(dopaminergic), 血清素 (serotonergic), 去甲腎上腺素 (noradrenergic)的神經傳導系統。

21. The 5-HT2C receptor (HTR2C) gene is located on human chromosome Xq24.
A subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5-HT)
A G protein-coupled receptor (GPCR) that is coupled to Gq/G11 and mediates excitatory neurotransmission.
The 5-HT2C receptor (HTR2C) gene is located on human chromosome Xq24.
The 5-HT2C receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). It is a G protein-coupled receptor (GPCR) that is coupled to Gq/G11 and mediates excitatory neurotransmission. The 5-HT2C receptor (HTR2C) gene is located on human chromosome Xq24.)
5-HT2C receptor是5-HT receptor的一種亞型(subtype)，binding的factor是叫做5-HT的內源性神經遞質血清素(endogenous neurotransmitter serotonin, 5羥色胺)。
是一種GPCR，coupled to Gq/G11，介中傳導興奮性神經傳導。位於human chromosome Xq24。

22. Polymorphism may be involved in the development of ADHD.
Findings
Polymorphism may be involved in the development of ADHD.
Promoter activity: Single nucleotide substitution polymorphisms (SNP) in the upstream region of the 5-HT2C
The findings provide evidence that the G-allele of the G-697C HTR2C polymorphism may be involved in the development of ADHD. 
Yuan et al. have suggested that the single nucleotide substitution (SNP)polymorphisms in the upstream region of the 5-HT2C receptor could be involved in the promoter activity, as the -759C and -697G allele had less promoter activity than the -759T and -697C allele.
研究顯示，HTR2C的polymorphism(G-697C的G等位基因)和ADHD發展有關。
5-HT2C receptor上游的single nucleotide substitution (SNP)polymorphisms和promoter活性有關，
promoter activity: -759C and -697G 等位基因<-759T and -697C allele。

23. Findings: SNP in the 5-HT2C

24. Reference 1. eHow.com How Does Serotonin Affect Mood?
How Does Serotonin Affect Sleep?
What Is the Difference Between Dopamine?
2. BMC Research Notes
Investigation of the serotonin 2C receptor gene in attention deficit hyperactivity disorder in UK samples
3. Wikipedia
4. S. Marc Breedlove, Mark R. Rosenzweig, Neil V. Watson, “Biological Psychology”, page.90-93, , , ,

25. 5. Alan G. Sanfey, George Loewenstein, Samuel M. McClure and Jonathan D. Cohen, "Neuroeconomics: cross-currents in research on decision-making", TRENDS in Cognitive Sciences Vol.10 No.3 March 2006, Page 危芷芬, Atkinson & Hilgard’s Introduction to Psychology, page , , 尹艳茹, "睡眠生理-覺醒和睡眠的基本機轉", 南方醫科大學基礎醫學院生理學教研室