Temperatures effect on Chemiluminescence :: essays research papers

Temperature's effect on Chemiluminescence Sitting by a fire on a fall night one would not think of a campfire as cold light. Could there be such a thing? â€Å"Cold light† is what the word luminescence means (Fluorescent Mineral Society, 1 of 2). Cold light can be seen at many different temperatures. Not only does cold light exist, but there are several types of luminescence including bioluminescence or â€Å"living light†, photoluminescence or fluorescence, â€Å"day-glow†, and phosphorescence which is delayed luminescence or â€Å"afterglow† (Fluorescent Mineral Society, 1 of 2). Chemiluminescence is when two or more chemicals mix and react to create light energy. An example of bioluminescence is a firefly. The production of light in bioluminescent animals is caused by converting chemical energy to light energy (Bioluminescence, 1 of 1). In a firefly, oxygen, luciferin, luciferase (an enzyme), and ATP combine in the light organ in a chemical reaction that creates cold light (Johnson, 42). This bright, blinking light helps the male firefly attract female fireflies as a possible mate. Other examples of bioluminescent organisms are fungi, earthworms, jellyfish, fish, and other sea creatures (Berthold Technologies, 1 of 2). Light sticks work in a similar way. When you â€Å"snap† a light stick, the chemical in the glass capsule mixes with a chemical in the plastic tube and creates light energy. Instead of the chemicals used by a firefly, other chemicals are used to create a glow. The light stick that you can buy at a store usually contains hydrogen peroxide, phenyl oxalate ester, and fluorescent dye (New York Times Company, 1 of 3). The light stick will glow the same color as the fluorescent dye placed in it. In luminescence, the chemical reaction â€Å"kicks an electron of an atom out of its ‘ground’ (lowest-energy) state into an ‘excited’ (higher-energy) state, then the electron give back the energy in the form of light so it can fall back to it’s ‘ground’ state (Fluorescent Mineral Society, 1 of 2). Controlling chemiluminescent light was how Omniglow Incorporated became the first company to produce light sticks. In 1986, when the first light stick was invented, scientists thought they could make a lot of money selling light sticks. However, since they had to make light sticks by hand, it was harder for them to produce very many of them. Until machines were invented to make light sticks, it cost too much money to make them by hand.

The Apa Ethical Principles for Psychologists and Code of Conduct

The APA Ethical Principles for Psychologists and Code of Conduct: Cultural Sensitivity and Diversity – is the code culturally encapsulated and biased? Emmanuel Mueke Author Note Emmanuel Mueke. Independent Researcher. Correspondence regarding this article should be addressed to Emmanuel Mueke, P. O. Box 44935 – 00100. Nairobi, Kenya. Contact: [email  protected] com Abstract This paper explores the American Psychological Association (APA) Ethical Principles for Psychologists and Code of Conduct as regards the issue of multicultural and diverse professional practise.Its aim is to establish whether diversity and cultural variety and differences are adequately provided for in the body of the document. Psychologists are mandated to provide services to a multitude of culturally diverse and varied clients in a manner that is both professional and ethical. In such situations cultural sensitivity is fundamental and has been elevated to best practice. The code has been question ed as to the efficacy of its cultural sensitivity; firstly in terms of whether the code itself is culturally encapsulated and secondly whether there exists an explicit or implicit cultural bias.To address this issue we shall undertake a look at the code; its inherent limitations and shortcomings. Secondly the issue of the importance of cultural sensitivity and its translated application in matters of ethical service delivery shall be addressed. Keywords: APA Ethical Principles for Psychologists and Code of Conduct, ethics, multicultural, diversity, bias. The APA Ethical Principles for Psychologists and Code of Conduct: Cultural Sensitivity and Diversity – is the code culturally encapsulated and biased?Cultural sensitivity and professional ethics are central to the provision of psychologists’ services; this has led to the APA issuing guidelines in an effort to ensure that best practice is not only aspired to but more importantly achieved. This paper examines the Code of Conduct and the pursuant Guidelines on Multicultural Education, Training, Research, Practice, and Organizational Change for Psychologists (APA, 2002). Analysis of these documents will establish the existence of mechanisms to ensure protection against cultural bias and effective promotion of cultural sensitivity.Literature Review In the 2002 APA Ethical Principles for Psychologists and Code of Conduct several principles were outlined to ensure that cultural sensitivity was adopted as the guiding policy for practicing psychologists. The first mention of the issue of diversity and its effect on professional practice is in Principle E, which engenders awareness of and respect for cultural differences and admonishes the practitioners to try and eliminate the effect of biases upon their work and not to condone any activities of others based on prejudice. Further under Section 3. 1, unfair discrimination on any basis including culture is prohibited, combined with Section 3. 03 which admon ishes the practitioners from engaging in any behaviour that would be demeaning to a person of different culture. The issue of ethical provision of services is not just about preventing discrimination or harassment to persons of different cultures but it is also about ensuring that they are provided with adequate and competent services as they well deserve; to this effect Section 2. 01 provides what has been termed a boundary of competence.The boundary is intended to ensure that the services provided are effective in the specific circumstances faced; to this effect first it limits a psychologist to only undertake to provide services within the boundary of his expertise, education and experience and secondly it mandates that a psychologist must undertake the training or education necessary to provide the requisite services to the target populace, this training or education taking into account all factors that have a bearing on effective service delivery such as age, gender, ethnicity et cetera.Lastly under Section 9. 06 (APA, 2002) when interpreting assessment results a psychologist is mandated to take into account all the factors relevant, including the cultural differences of the assessment subject, that might nuance the results in any way. To translate these into effective practice the APA published the Guidelines on Multicultural Education, Training, Research, Practice, and Organizational Change for Psychologists (APA, 2002); which was meant to embody diversity aspirations for professionals.This document built on the precedent established by the Guidelines for providers of psychological services to ethnic, linguistic, and culturally diverse populations (APA, 1990). It translated the Principles previously outlined into six different guideline rules with the appropriate commentary on the way to best achieve such targets. The guidelines are; 1. Psychologists are encouraged to recognize that, as cultural beings, they may hold attitudes and beliefs that can detri mentally influence their perceptions of and interactions with individuals who are ethnically and racially different from themselves 2.Psychologists are encouraged to recognize the importance of multicultural sensitivity/responsiveness, knowledge, and understanding about ethnically and racially different individuals 3. As educators, psychologists are encouraged to employ the constructs of multiculturalism and diversity in psychological education 4. Culturally sensitive psychological researchers are encouraged to recognize the importance of conducting culture-centred and ethical psychological research among persons from ethnic, linguistic, and racial minority backgrounds 5.Psychologists strive to apply culturally-appropriate skills in clinical and other applied psychological practices 6. Psychologists are encouraged to use organizational change processes to support culturally informed organizational (policy) development and practices Discussion The Guidelines admit the existence of a Eurocentric bias in the psychological profession and posit themselves as an ever-evolving solution; changing as further empirical research on the issue is undertaken.Moreover the document places a time limit on its validity in order to spur further research on the issue of multicultural practice. In order to ensure its efficacy the APA set up a task force whose sole purpose was to look into the implementation of the guidelines with a view to providing proper feedback by identifying pertinent implementation and infusion recommendations. The task force produced a report on the infusion of the paradigm shift in service delivery outlining how this should be undertaken; Report of the APA Task Force on the Implementation of the Multicultural Guidelines (APA, 2008).The report split the guidelines into two categories the first being those whose implementation fell unto the practitioners and into this category they placed the first and second guidelines. The rest were in the category of thos e whose implementation required facilitation by the APA both in terms of administrative structures and funding; for example the APA was tasked with establishing an Office of Diversity Enhancement and hiring a Chief Diversity Officer to run it. The Office’s purpose is ensuring that there is diversity across the organization which helps with the ethical provision of services across multicultural diversity.Conclusion Having gone through the Code of Conduct, the pursuant Guidelines and the Implementation Report there is no evidence of cultural bias and encapsulation; rather there is incontrovertible evidence of contrived and concerted efforts to address the bias existent in the profession and its philosophy. References American Psychological Association. (1990). Guidelines for providers of psychological services to ethnic, linguistic, and culturally diverse populations. Washington, DC: Author. Retrieved from www. apa. org/pi/oema/guide. html American Psychological Association. (2 002).Ethical principles of psychologists and code of conduct. American Psychologist, 57, 1060-1073. Retrieved from www. apa. org/ethics. code. html American Psychological Association. (2003). Guidelines on multicultural education, training, research, practice, and organizational change for psychologists. American Psychologist, 58, 377-402. (See www. apa. org/pi/multiculturalguidelines/homepage. html) American Psychological Association. (2008). Report of the Task Force on the Implementation of the Multicultural Guidelines. Washington, DC: Author. Retrieved from http://www. apa. org/pi/

Do you believe that Macbeth is a complete villain Essay

Macbeth is a play, which was written by William Shakespeare, and first published in 1623 (during the reign of King James I of England). Macbeth was a hero and also a loyal subject and friend of the King, Duncan. He gave no quarter on the battlefield, due to his brutal courage, e.g. Macbeth â€Å"unseamed† a Norwegian â€Å"from the nave to the chaps† and â€Å"fixed his head† onto the Scottish battlements, during the battle at the beginning of the play. This proved his patriotism for his country, and his respect for the King. By fighting for his country, Scotland, he achieved in return the respect that he deserved from the King. Macbeth was plagued with conflicting qualities; for example, one was the humane and courteous way he treated his wife, i.e. Macbeth referred to his wife (in his letter to her – in Act 1, Scene 5) as â€Å"my dearest partner of greatness†. Also in this scene, he addressed her as â€Å"My dearest love†. On the other hand, this did not prevent him from acting in the opposite way in battle as a cruel warrior. Once the witches had prophesised that Macbeth would be king â€Å"hereafter† (Act 1, Scene 3), Macbeth seemed to have been drawn in by this advance information i.e. he started, and seemed â€Å"to fear†. This reaction indicates that he was a very gullible being, who tended to believe what was said. Then again, if one were informed that one was to be king, then one might believe it, as it is a desirable privilege. This represents honest ambition, at this stage, without seeming to involve any nefarious actions on Macbeth’s part. Also, the mental images that would come into one’s mind could heighten one’s level of gullibility and boost one’s self-esteem. This scene also tells us, as readers, that Banquo, on the other hand, is not so easily convinced, and to us, this demonstrates a stronger character. Banquo obviously doubted the witches’ predictions, as he questioned Macbeth’s response by asking, â€Å"why do you start, and seem t o fear†. Another important part of the story, which points out a particular frailty of Macbeth’s, occurs later on in Act 1, Scene 3, when Macbeth lied to Banquo. He pretended to Banquo that his â€Å"dull brain was wrought† to divert Banquo’s thoughts about him, by being devious – as one might expect from a villain – so that Banquo would no longer believe that Macbeth trusted the witches’ predictions. Even after finding that the first prediction of the witches was true, Banquo warned him, basically, that even if the witches told him some little truth, later they would deceive him. Another example of Macbeth’s deceit against Banquo comes in Act 2, Scene 1, when Macbeth denied that any thoughts of the witches were in his mind: â€Å"I think not of them†¦Ã¢â‚¬  In the next scene (Act 1, Scene 4), irony and duplicity emerge. This happens because Shakespeare emphasised Duncan’s respect for Macbeth, with Duncan saying such things as â€Å"worthiest† whilst addressing Macbeth. However, as Macbeth later on in the story kills Duncan, this belies his true political intention of power seeking, and perhaps not solely of his own volition, but driven by his wife’s ambitious self-interest. Macbeth does not seem to be a villain, but rather a considerate man who actually has redeeming qualities. When he arrived home a few days after the battle, he advised his wife, Lady Macbeth, of the King’s arrangements to sleep at their castle that night. Shakespeare revealed her to be a ruthless schemer, who cared about nobody when it came to power. This is proved when she decided that they had to kill Duncan, to fulfil the witches’ prophecies. Later on (in Act 1, Scene 7), Macbeth is seen in the soliloquy, expressing his doubts to the reader. As readers, we see his good side when he’s explaining that he’s not a vagabond, by expressing his hesitancy to kill Duncan. One of his comments is, â€Å"First, I am his kinsman and his subject†¦then, as his host†¦Ã¢â‚¬  What Macbeth is actually saying here is that he is a trusted member of Duncan’s kin and army, and also that Duncan is a guest protected by the law of hospitality. This would make t he murder even more unholy, as it’s a form of criminal intent against the unsuspecting king prior to the deed. So here Macbeth is seen actively contemplating murder, on the one hand, while on the other, his conscience tries to inhibit the act. Herein afterwards in this scene, Lady Macbeth uses her persuasive and guileful tactics on Macbeth to change his mind, and agree to go ahead with the murder. Her methods are simple and psychological, since they criticise Macbeth’s manhood. She manages to ridicule his conscience under her scornful attack by using phrases such as â€Å"Was the hope drunk?† and â€Å"Art thou afeard†¦Ã¢â‚¬  Thus, by so doing, she labels him a coward, and coerces him into changing his mind under her pursuing peer pressure and her curses. She then makes things even worse, by threatening to commit the act herself! Now this, to Macbeth – a man – really taunts him into an agreement against his better judgement. In such a fashion, women succeed. After Macbeth murdered Duncan, he went downstairs and started talking to Lady Macbeth. He told her how he regretted his evil deed. He was a man of action, but was confused when he lost his sense of right and wrong. He carried on with the murder, but displayed guilt, remorse and fearful superstition afterwards. An example of his guilt came after he killed Duncan (in Act 2, Scene 2), whilst he was informing Lady Macbeth of his doings and what he heard from Malcolm and Donalbain’s room, next door. He told her what they said during their sleep. His guilt was then admitted: â€Å"But wherefore could not I pronounce ‘Amen’? I had most need of blessing, and ‘Amen’ stuck in my throat.† Evidence that he was full of remorse, came right at the end of Act 2, Scene 2, â€Å"Wake Duncan with thy knocking: I would thou couldst!† This sentence clearly indicated his regretful state of mind, and the quote supports the fact that Macbeth did have some redeeming qualities of conscience. He even has a trace of fearful superstition in his head, as he † heard a voice cry, ‘Sleep no more! Macbeth does murder sleep,’ – the innocent sleep.† These mental images inside his own mind blatantly reflect that he is aware and stricken by them. Therefore, he is still able to discern between good and evil even after the foul deed has been accomplished. When Macbeth kills the two servant guards â€Å"in anger†, he is seen to extend his evil deed and perhaps this can be considered as the point where he has become the â€Å"complete villain†. In spite of a nagging conscience in killing Duncan, he had to continue his evil ways to silence the two innocent guards: â€Å"O, yet I do repent me of my fury, that I did kill them.† Here is a further example of his commitment to evil in spite of conscience and so, his tendency towards malfeasance does not abate. In addition to this unfolding character change, he also deceives all others, including Duncan’s two sons. He deceitfully assumes the role of the angry Thane, driven to lash out at the two guards, who, on the face of it, had killed the king. Once more, he shows duplicity in ‘confessing’ another lie, â€Å"Who can be wise, amazed, temperate and furious, loyal and neutral, in a moment? No man: the expedition of my violent love outran the pauser reason.† So, his conscience is now being overtaken by his evil actions and reflects his weakness in becoming a pawn by acting out the will of his accomplice, Lady Macbeth, and exposes a diminishing personal integrity to the reader. This change in Macbeth develops and is reflected in his fore-planning soliloquy in Act 3, Scene 1, while awaiting the two murderers to enter. He exposes his own discontent, even after becoming King. Fearing Banquo and his son’s succession, any refraining influence of conscience is now deliberately put aside, â€Å"To be thus is nothing†¦our fears in Banquo stick deep†¦to make them kings, the seed of Banquo kings! Rather than so, come, fate, into the list, and champion me to the utterance!† By the end of this scene, Macbeth’s complete change of character is painfully evident, showing his complete absence of concern. At this stage, gone are any troubled thoughts so evident when either considering or enacting Duncan’s demise. Instead, an evil commitment is observed in his cruel remark as Act 3, Scene 1 closes: â€Å"It is concluded: Banquo, thy soul’s flight, if it find heaven, must find it out tonight.† Macbeth’s mind, irrespective of conscience, is now refocused on action – to rid himself of his last nagging fear of Banquo’s lineage superseding his own. It can be argued that from this point, Macbeth has indeed ‘crossed the Rubicon’. He was totally committed to whatever evil deeds the future might hold. He demonstrates this change of mind when replying to his wife’s exhortation in Act 3, Scene 2, â€Å"what’s done is done.† Also, his attitude and mental state is highlighted as he says: â€Å"But let the frame of things disjoint, both the worlds suffer, ere we will eat our meal in fear, and sleep in the affliction of these terrible dreams that shake us nightly.† Again, at the end of this scene, when Macbeth has planned Banquo’s murder, he keeps his wife in the dark about this: â€Å"So, pr’ythee, go with me.† During the banquet, in Act 3, Scene 4, Macbeth is advised of Banquo’s death and Fleance’s escape. This unsettles Macbeth. He feels trapped, â€Å"but now I am cabined, cribbed, confined, bound in to saucy doubts and fears.† Yet he successfully puts on a face for his guests, until Banquo’s ghost appears. Consternation rules and suspicion reigns. Macbeth’s superstitious fear and guilt return, yet his courage does not fail him when the apparition appears: â€Å"Thou canst not say I did it. Never shake thy gory locks at me.† Also When Lady Macbeth asked him, â€Å"Are you a man?†, Macbeth replies, â€Å"Ay, and a bold one, that dare look on that which might appal the devil.† The appearance of Banquo’s ghost sitting in Macbeth’s place signifies that Banquo’s descendants would replace Macbeth’s. Macbeth decides his delusions are a beginner’s fear and lack of experience: â€Å"My strange and self-abu se is the initiate fear, that wants hard use: we are yet but young in deed.† In doing so, he ignores the horrific effect of his outrageous crimes in his country, and reveals the depth of his treason and treachery. It comes as no surprise to discover that Macbeth has a covert intelligence network, â€Å"There’s not a one of them, but in his house I keep a servant fee’d.† So Macbeth’s deviousness and villainous activity persists to support his grip on power over Scotland. Therefore, Macduff, in joining Duncan’s son Malcolm in England, realises only force of arms will recover the situation, since: â€Å"Each new morn, new widows howl, new orphans cry, new sorrows strike heaven on the face, that it resounds as if it felt with Scotland, and yelled out like syllable of dolour.† When Macbeth went to consult the Witches after the Coronation feast, it was because he again followed his own evil self-interest: â€Å"More shall they speak; for now I am bent to know, by the worst means, the worst. For mine own good all causes shall give way†¦Ã¢â‚¬  This pursuit of self is matched by their own evil intention, to ‘Set him up’; â€Å"As, by the strength of their illusion, shall draw him on to his confusion. He shall spurn fate†¦and you all know, security is mortals’ chiefest enemy.† Upon meeting the witches again, Macbeth’s chagrined reaction to the apparitions of the eight Kings – with Banquo’s ghost following – is to curse the event and experience a resurrected fear; † Let this pernicious hour stand aye accursed in the calendar!†, and â€Å"†¦damned all those that trust them!† After this, Macbeth decides to act independently by matching thought to action, and eliminating Macduff’s lands and family. â€Å"This deed I’ll do before this purpose cool†. By doing so, Macbeth has now sunk to his lowest ebb in cowardly treachery against innocent victims. His motive is to punish Macduff for defying him, and lure him back to Scotland as a result of Macduff’s anger. There, Macduff would clearly be in his grasp. Macbeth would then be able to kill him. However, if one compares Macbeth’s despicable characteristics as a king only one quality emerges where it can be safely said he is comparable. This is his courage. In spite of his villainy, his physical courage in facing unpalatable situations of all kinds is never in question. Alas, who would connect him with the qualities that Malcolm (in Act 4, Scene 3) enumerates? – â€Å"†¦justice, verity, temperance, stableness, Bounty, Perseverance, mercy, lowliness, devotion, patience, courage, fortitude†¦Ã¢â‚¬  Macbeth came to realise his own corrupt ways when he faces Macduff on the battlefield, â€Å"Of all men else have I avoided thee: But get thee back, my soul is too much charged with blood of thine already.† Macbeth reacts with Lady Macbeth’s death Stoically but without any true compassion. â€Å"She should have died hereafter†¦Ã¢â‚¬  Towards the end of the play, Macbeth has come to accept his defeat, yet on a personal level he still superstitiously clings to the three hags words, that no man born of woman can harm him, â€Å"I bear a charmed life.† Even after Macduff quotes the details of his caesarean birth, Macbeth is still courageously defiant: † I will not yield†¦and damned be him that first cries ‘Hold, enough’.† Macduff calls to Macbeth, â€Å"yield ye, coward,† and â€Å"We’ll have thee, as our rarer monsters are, painted upon a pole, and underwrit, ‘Here may you see the tyrant’.† Here even Macduff labels Macbeth as a complete and utter ‘tyrant’! In the end, Macbeth’s only virtuous quality proved to be his courage and it was this undaunted approach to all danger in life, which somehow endeared him in death, in spite of his evil ways, as a black hero. However, his gradual change, after showing this virtue at the start of the play, does point to the truth of the adage, â€Å"power tends to corrupt and absolute power tends to corrupt absolutely†. How many of us can discern the shadow of Macbeth in our own lives? Thomas Way 10:C – Macbeth – English GCSE Coursework

Facilitation of Conditioned Fear Extinction

Neuroscience 134 (2005) 247–260 FACILITATION OF CONDITIONED FEAR EXTINCTION BY D-CYCLOSERINE IS MEDIATED BY MITOGEN-ACTIVATED PROTEIN KINASE AND PHOSPHATIDYLINOSITOL 3-KINASE CASCADES AND REQUIRES DE NOVO PROTEIN SYNTHESIS IN BASOLATERAL NUCLEUS OF AMYGDALA Y. L. YANGa AND K. T. LUb* Institute of Biotechnology, Department of Molecular Biology and Biochemistry, National Chia-Yi University, 300 University Road, Chia-Yi, Taiwan b Department of Life Science, National Taiwan Normal University, 88 Ming-Chow Road, Sec 4, Taipei, Taiwan aKey words: extinction, D-cycloserine, MAPK, PI-3 kinase, amygdala. Abstract—Recent results showed that either systemic or intra-amygdala administration of D-cycloserine, a partial agonist at the glycine modulatory site on the glutamate N-methylD-aspartate receptor facilitates the extinction of conditioned fear. Here we evaluated the role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase in the basolateral nucleus of amygdala on the effect of D-cycloserine.The facilitation effect of D-cycloserine on fear extinction and mitogen-activated protein kinase activation was completely blocked by intra-amygdala administration of mitogen-activated protein kinase inhibitor PD98059 (500 ng/side, bilaterally) or U0-126 (20 M/side, bilaterally). Furthermore, phosphatidylinositol 3-kinase inhibitor (wortmannin, 5. 0 g/side, bilaterally) infused into the basolateral nucleus of amygdala signi? cantly reduced both facilitation effect of D-cycloserine and phosphatidylinositol 3-kinase activation.Intra-amygdala administration of a transcription inhibitor (actinomycin D, 10 g dissolved in 1. 6 l vehicle; 0. 8 l per side) and a translation inhibitor (anisomycin, 125 g dissolved in 1. 6 l vehicle; 0. 8 l per side) completely blocked the facilitation effect of D-cycloserine. Control experiments indicated the blockage by actinomycin D or anisomycin were not due to lasting damage to the basolateral nucleus of amygdala or state d ependency. In addition, none of the active drugs used here altered the expression of conditioned fear.These results suggested that phosphatidylinositol 3-kinase and mitogenactivated protein kinase-dependent signaling cascades and new protein synthesis within the basolateral nucleus of amygdala played important roles in the D-cycloserine facilitation of the extinction of conditioned fear.  © 2005 Published by Elsevier Ltd on behalf of IBRO. *Corresponding author. Tel: 886-2-29333149Ãâ€"234; fax: 886-229312904. E-mail address: [email  protected] ntnu. edu. tw (K. -T. Lu).Abbreviations: ACT DCS, actinomycin D D-cycloserine; ACT SAL, actinomycin D saline; ANI DCS, anisomycin D-cycloserine; ANI SAL, anisomycin saline; BLA, basolateral nucleus of the amygdala; CS, conditioned stimulus; DCS, D-cycloserine; EDTA, ethylenediaminetetraacetic acid; ISI, interstimulus interval; MAPK, mitogen-activated protein kinase; NMDA, N-methyl-D-aspartate; PD DCS, PD98059 D-cycloserine; PD SAL, PD9805 9 saline; PI-3K, phosphatidylinositol 3-kinase; US, unconditioned stimulus; U0 DCS, U0-126 D-cycloserine; U0 SAL, U0126 saline; VEH DCS, vehicle D-cycloserine; VEH SAL, vehicle saline; WH DCS, wortmannin D-cycloserine; WH SAL, wortmannin saline. 0306-4522/05$30. 00 0. 00  © 2005 Published by Elsevier Ltd on behalf of IBRO. doi:10. 1016/j. neuroscience. 2005. 04. 003 Fear conditioning occurs when a previously neutral stimulus (conditioned stimulus) is paired with an aversive stimulus (McAllister and McAllister, 1971).Following such pairing the conditioned stimulus is thought to elicit a state of conditioned fear. This is de? ned in animals by their behavior: freezing, autonomic reactivity, and fear-potentiated startle. A large literature indicates that the basolateral nucleus of the amygdala (BLA) is critically involved in both the acquisition and the expression of conditioned fear (Davis, 2000). Neurotoxic lesions or intra-amygdala infusion of glutamate antagonists into the BLA bl ocks the expression of conditioned fear. In addition, local infusion of N-methyl-D-aspartate (NMDA) speci? c antagonists blocks the acquisition of conditioned fear (Miserendino et al. , 1990; Kim et al. , 1991; Maren et al. , 1996; Gewirtz and Davis, 1997).Synaptic plasticity in this area is thought to underlie the learning process when afferent sensory information elicited by the conditioned stimulus is paired with afferent pain information elicited by the unconditioned stimulus (Fanselow and LeDoux, 1999). Extinction is de? ned as a reduction in conditioned fear when the conditioned stimulus (CS) is presented repeatedly in the absence of the unconditioned stimulus (US). Many studies show that extinction is not the result of forgetting or memory erasure but results from formation of new associations that compete with prior fear-conditioned associations (Falls and Davis, 1995; Davis et al. , 2000). Similar to acquisition, extinction is also blocked by glutamate NMDA receptor antagon ists either given systemically (Cox and Westbrook, 1994; Baker and Azorlosa, 1996; Kehoe et al. 1996) or locally infused into the BLA (Falls and Davis, 1992). The glycine modulatory site of the NMDA receptor provides a critical regulatory role. Whereas direct NMDA agonists may be neurotoxic due to unregulated calcium entry, partial agonists can facilitate glutamatergic NMDA activity in a more limited fashion (Lawler and Davis, 1992; Olney, 1994). Recent results showed that partial agonists acting at the glycine modulatory site of the NMDA receptor, such as D-cycloserine (DCS), enhance learning and memory in several animal models (Thompson and Disterhoft, 1997; Pussinen et al. , 1997; Matsuoka and Aigner, 1996; Land and Riccio, 1999; Walker et al. , 2002; 247 248 Y. L. Yang and K. T.Lu / Neuroscience 134 (2005) 247–260 extinction test, an extinction training and a post-extinction test (see Fig. 1A). Acclimation. On each of 3 consecutive days, rats were placed in the test chamb ers for 10 min and then returned to their home cages. Baseline startle test. On each of the next 2 consecutive days, animals were placed in the test chambers and presented with 30 95-dB startle stimuli at a 30-s interstimulus interval (ISI). Animals whose baseline startle response was 1% of the measurable level were not included in later analysis. Fear conditioning. Twenty-four hours later, rats were returned to the test chambers and after 5 min were given the ? rst of 10 light-footshock pairings.The shock (US) was delivered during the last 0. 5 s of the 3. 7 s light (CS). The average intertrial interval was 4 min (range 3–5 min) and the shock intensity was 0. 6 mA. Pre-extinction test. Twenty-four hours after fear conditioning, rats were returned to the test chambers and 5 min later presented with 30 startle-eliciting noise bursts (95 dB, 30 s ISI). These initial startle stimuli were used to habituate the startle response to a stable baseline prior to the light-noise test tr ials that followed. Thirty seconds later a total of 20 startle-eliciting noise bursts were presented, 10 in darkness (noise alone) and 10 3. 2 s after onset of the 3. s light (light-noise) in a balanced, irregular order at a 30-s ISI. Percent fear-potentiated startle was computed as [(startle amplitude on light-noise noise-alone trials)/noisealone trials] 100. Rats were then divided into equal size groups of comparable mean levels of percent fear-potentiated startle. Rats with less than 50% fear-potentiated startle during the pre-extinction test were not used. Extinction training. Extinction training (cue exposure) is de? ned as the repetitive exposure to the CS cue (light) in the absence of the US (shock). Twenty-four hours after the preextinction test, rats were returned to the test chamber. After 5 min, they were presented with 30, 3. s light exposures at a 30-s ISI. Context control groups (context exposure) remained in the test cages for the same amount of time but did not recei ve light presentations. Extinction training was performed for varying numbers of consecutive days (2 days for experiment 1 and 1 day for subsequent experiments). Post-extinction test-1. Twenty-four hours after the last extinction training, rats were returned to the test chamber. After 5 min, they were presented with 30 95-dB leader stimuli for a habituated startle baseline. This was followed by a total of 60 startle-eliciting noise bursts, 30 in darkness (noise alone) and 30 presented 3. 2 s after onset of the 3. s light (light-noise) in a balanced, irregular order at a 30-s ISI. Results were evaluated the same way as pre-extinction test. Post-extinction test-2. Twenty-four hours after the extend extinction training period, rats were returned to the test chamber and process the post-extinction test described above. Fear-potentiated startle test. Twenty-four hours after fear conditioning, rats were returned to the test chamber and testing for fear-potentiated startle using the post-e xtinction test-1 described above. Ledgerwood et al. , 2003; Richardson et al. , 2004). In addition, ( )-HA966, a competitive antagonist at the glycine regulatory site on the NMDA receptor, reversed the DCS effect (Walker et al. , 2002).Clinical studies have shown that DCS can sometimes enhance implicit memory and improve cognition in patients with Alzheimer’s disease (Schwartz et al. , 1996; Tsai et al. , 1998, 1999). It can also counter cognitive de? cits in schizophrenia (Javitt et al. , 1994; Goff et al. , 1999). Furthermore, systemic administration of DCS also proved to facilitate extinction of conditioned fear (Walker et al. , 2002; Ledgerwood et al. , 2003, 2004; Ressler et al. , 2004). Numerous signaling cascades including mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI-3K) and calcineurin, are involved in the extinction of conditioned fear (Lu et al. , 2001; Lin et al. , 2003).Similar mechanisms may also be involved in the facilitation effec t of DCS. This study was designed to clarify the relationship between amygdaloid NMDA receptors, MAPK and PI-3K signal cascades on the extinction of conditioned fear. EXPERIMENTAL PROCEDURES Animals Adult male Sprague–Dawley (SD) rats (obtained from the animal center of National Taiwan University Taipei, Taiwan) weighing between 250 and 350 g were used. Animals were housed in groups of four rats in a temperature (24  °C) -controlled animal colony with continuous access to food and water. Rats were kept on a 12-h light/dark cycle with lights on at 07:00 h. All behavioral procedures took place during the light cycle.All procedures were conducted in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals and the guidelines set forth by the Institutional Animal Care and Use Committee at the National Taiwan Normal University. In all experimental procedures involving animals, all efforts were made to minimize pain and the number of animals u sed. Surgery All surgeries were carried out under sodium pentobarbital (50 mg/ kg, i. p. ) anesthesia. Once anesthetized, the rat was placed in a Kopf stereotaxic instrument, the skull was exposed, and 22 gauge guide cannula (model C313G, Plastic-one Products, Roanoke, VA, USA) were implanted bilaterally into the BLA (AP, 2. ; DV, 9. 0, ML, 5. 0 from bregma (Paxinos and Watson, 1997)). Size 0 insect pins (Carolina Biological Supply, Burlington, NC, USA) were inserted into each cannula to prevent clogging. These extended about 2 mm past the end of the guide cannula. Screws were anchored to the skull and the assembly was cemented in place using dental cement (Plastic-one Products). Rats received an antibiotic (penicillin) once every day for the ? rst 3 days after the surgery to reduce the risk of infection. General behavioral procedures Fear conditioning was measured using the potentiated startle paradigm (Cassella and Davis, 1986; Lu et al. , 2001; Walker et al. , 2002).The rats were trained and tested in a startle chamber (San Diego Instruments, San Diego, CA, USA) in which cage movement resulted in the displacement of an accelerometer. Startle amplitude was de? ned as peak accelerometer voltage within 200 ms after startle stimulus onset. The behavioral procedures common to all experiments consisted of an acclimation phase, a baseline startle test phase, a fear conditioning phase, a pre- Drug injection DCS (Sigma) was freshly dissolved in saline. DCS (15 mg/kg, i. p. ) or saline was injected intraperitoneally 15 min prior to extinction training with a 26 gauge injection needle connected to a 1 ml syringe (Walker et al. , 2002; Ledgerwood et al. , 2003) (experiments 1– 8).MAPK inhibitor PD98059 (500 ng in 1 l of 20% DMSO; Calbiochem) (Lu et al. , 2001) or U0-126 (50 ng/side; Sigma) (Lin et al. , 2003) or 20% DMSO was infused into the BLA Y. L. Yang and K. T. Lu / Neuroscience 134 (2005) 247–260 249 Fig. 1. Systemic administration of DCS accelerate d extinction of conditioned fear. (A) Timeline of behavioral procedures for experiment 1. (B) Percent fear-potentiated startle measured 24 h before (pre-extinction test) and 24 h after extinction training (post-extinction test). Rats in each group were treated with either DCS or saline prior to a single session of extinction training. (C) To test for toxicity, after 24 h all animals of experiment 1 were retrained.They were tested for fear-potentiated startle response in the absence of drugs 24 h later (fear-potentiated startle test) (values are mean SEM, * P 0. 05 versus control group; # P 0. 05 versus the group with 1 day extinction and saline injection). 250 Y. L. Yang and K. T. Lu / Neuroscience 134 (2005) 247–260 10 min prior to saline or DCS injection (experiments 2 and 8). PI-3K inhibitor (wortmannin, 5 g/side) (Lin et al. , 2003) or vehicle was administrated to the BLA 10 min prior to saline or DCS injection (experiment 3). Transcription inhibitor actinomycin D (10 g d issolved in 1. 6 l vehicle; 0. 8 l per side) or translation inhibitor (anisomycin, 125 g dissolved in 1. 6 l vehicle; 0. 8 l per side) or vehicle (Lin et al. 2003) was administrated to the BLA 10 min prior to DCS or saline injection (experiment 4) or 25 min prior to fear-potentiated startle test (experiment 6). In the control experiment, PD98059, U0-126, wortmannin, actinomycin D, and anisomycin were injected 25 min prior to the fear-potentiated startle test. Injections were made through 28-gauge injection cannula (model C313I, Plastic-one Products) connected to a Hamilton micro-syringe via polyethylene tubing. Infusion speed was 0. 25 l/ min. The total volume of injection was 0. 8 l per side. Western blot analysis Animals were killed by decapitation 10 min after extinction training. The lateral and basolateral subregions of the amygdala were collected and sonicated brie? y in ice-cold buffer: 50 mM Tris–HCl (pH 7. ), 50 mM NaCl, 10 mM EGTA, 5 mM EDTA, 2 mM sodium pyrophospha te, 4 mM para-nitrophenylphosphate, 1 mM sodium orthovanadate, 1 mM phenylmethylsulfonyl ? uoride (PMSF), 20 ng/ml leupeptin, and 4 ng/ml aprotinin. Following sonication, the soluble extract was obtained after pelleting the crude membrane fraction in a centrifuge at 50,000 g at 4  °C. Protein concentration in the soluble fraction was then measured using a Bradford assay with bovine serum albumin as the standard. Equivalent amounts of protein for each sample were resolved in 10% sodium dodecyl sulfate (SDS)–polyacrylamide gels, blotted electrophoretically to PVDF membranes and blocked overnight in 5% skim milk (Cell Signaling Technology, Inc. , USA).Blots were incubated with antiphospho-ERK antibody (New England Biolabs, USA), anti-ERK antibody (BD Transduction Laboratories, USA), anti-phospho-Akt antibody (New England Biolabs) or anti-pan-Akt (BD Transduction Laboratories). Band detection was performed with an enhanced chemiluminescence Western blotting analysis system (RPN 2108; Amersham International, Amersham, UK). fear-potentiated startle during the pre-extinction test. The ? nal 30 rats were assigned into ? ve groups of six animals based on their level of fear-potentiated startle in the preextinction test. Twenty-four hours after the pre-extinction test, each rat received 1 or 2 consecutive days of extinction training with DCS (15 mg/kg, i. p. ) or saline. Saline or DCS was injected 15 min prior to the extinction training.An additional control group was tested 2 days after the pre-extinction training without intervening exposures to visual CS. Fig. 1B shows that DCS accelerated extinction of conditioned fear. A two way ANOVA for differences in treatment (DCS vs saline) and days (one or two extinction sessions) between-subjects indicated a signi? cant treatment effect (F(1,20) 9. 02) and a signi? cant treatment days interaction (F(2,20) 6. 68). Thus, the reduction of fear-potentiated startle after 1 day of extinction training was greater in the gr oup that received DCS than in the group that received saline (Fig. 1B). Individual comparisons between DCS- and saline-treated groups indicated signi? ant differences after 1 day of extinction sessions (t(10) 3. 86). Previous studies have shown that lesions of the BLA block expression of fear-potentiated startle (Campeau and Davis, 1995). DCS may have toxic effect on BLA, and resulting misinterpretation of its facilitation effects on extinction. To test for toxicity, all animals of experiment 1 were retrained and tested 24 h later. Under these conditions, animals previously injected with DCS or saline showed a signi? cant fear-potentiated startle (Fig. 1C). Thus, the facilitation effect of DCS observed during the post-extinction test 1 appeared to result from the acute drug effect rather than from a more permanent, perhaps toxic, action of DCS.Experiment 2: intra-amygdala infusion of MAPK inhibitors blocked the facilitation of extinction by DCS To test the possible role of MAPK-depe ndent signaling cascade in the DCS-enhanced effect on the extinction of condition fear, 48 rats received fear conditioning, extinction training, and testing for fear-potentiated startle. Initially, 58 rats were used, but 10 of them were excluded. Rats were randomly assigned to six different groups and received one of the following treatments: vehicle saline (VEH SAL), vehicle DCS (VEH DCS), PD98059 DCS (PD DCS), U0-126 DCS (U0 DCS), PD98059 saline (PD SAL) or U0-126 saline (U0 SAL). The MAPK inhibitors, PD98059, and U0-126 (or vehicle) were administrated to the BLA 10 min prior to the injection with DCS or saline. Animals were then returned to their cage.Fifteen minutes after injection, animals were subjected to a single session of extinction training. Previously, we show that a single day of extinction training with cue exposure led to about 35% decrease in fear-potentiated startle, whereas 2–3 days of extinction training led to near complete extinction (Lu et al. , 2001; Wa lker et al. , 2002). We concluded that the acceleration of extinction is best detected after a single session of extinction training. As shown in Fig. 2, DMSO, PD98059 (500 ng/side, bilaterally), or U0-126 (20 nM/per side, bilaterally) was given 10 min prior to saline or DCS injection; rats were returned to their cages for 30 min before a single HistologyRats were overdosed with chloral hydrate and perfused intracardially with 0. 9% saline followed by 10% formalin. The brains were removed and immersed in a 30% sucrose-formalin solution for at least 3 day. Coronal sections (30 M) were cut through the area of interest, stained with Cresyl Violet, and examined under light microscope for cannula placement. Animals with misplaced cannula were not included in later analysis. Statistical analysis The mean startle amplitude across the 30 noise alone and 30 light-noise trials during the pre- and post-extinction tests was calculated for each animal. All results were analyzed using a score of percent fear-potentiated startle, as de? ned in the post-extinction tests above.ANOVA on scores was the primary statistical measure. Between-group comparisons were made using two-tailed t-tests for independent samples. The criterion for signi? cance for all comparisons was P 0. 05. RESULTS Experiment 1: systemic administration of DCS accelerated extinction of conditioned fear This experiment assessed the facilitation effect of DCS on different amounts of extinction training. Initially, 35 rats were used. Five were excluded for showing less than 50% Y. L. Yang and K. T. Lu / Neuroscience 134 (2005) 247–260 251 Fig. 2. Intra-amygdala infusion of MAPK inhibitors blocked facilitation effect of DCS on extinction. (A) Timeline of behavioral procedures for experiment 2. B) Cannula was placed in the BLA. Percent fear-potentiated startle measured 24 h before (pre-extinction test) and 24 h after extinction training (post-extinction test). Rats in each group underwent VEH SAL, VEH DCS, PD DCS, U0 DCS, PD SAL, or U0 SAL prior to a single session of extinction training. Twenty-four hours later, animals were tested for fear-potentiated startle in the absence of drugs (values are mean SEM, * P 0. 05 versus VEH SAL group; # P 0. 05 versus VEH DCS group). (C) Cannula tip placements transcribed onto atlas plates adapted from Paxinos and Watson (1997). 252 Y. L. Yang and K. T. Lu / Neuroscience 134 (2005) 247–260 session of extinction training.Twenty-four hours later, animals were tested for fear-potentiated startle in the absence of drugs. Results showed that there was a signi? cant overall difference between treatments (F(5,42) 11. 81). Fig. 2 shows that administration of DCS facilitated extinction of conditioned fear (VEH DCS) compared with the control group (VEH SAL) (t(14) 3. 12, P 0. 05). This effect was blocked by co-administration of MAPK inhibitor PD98059 (PD DCS) or U0-126 (U0 DCS) (t(14) 3. 08, P 0. 05 and t(14) 3. 29, P 0. 05, respectively) compared wit h the control (VEH DCS), treated with PD98059 only (PD SAL) or U0-126 only (U0 SAL) did not affect extinction (t(14) 0. 7 and t(14) 0. 36, respectively). These results indicated that the MAPK dependent signaling cascade most likely mediated the facilitation effect of DCS. Experiment 3: intra-amygdala infusion of the PI-3K inhibitor blocked facilitation of extinction by DCS Previous ? ndings have shown that PI-3K inhibitors retard acquisition in a variety of learning paradigms (Lin et al. , 2003). To evaluate the possible role of PI-3K signaling cascade in the DCS enhancement of extinction of conditioned fear, 32 rats received fear conditioning, extinction training, and testing for fear-potentiated startle. Although 38 rats were used initially, six were excluded.They were then randomly assigned to four different groups and received one of the following treatments: VEH SAL, VEH DCS, wortmannin DCS (WH DCS) and wortmannin saline (WH SAL). The PI-3K inhibitor (wortmannin, 5 g/side, bila terally) was infused to the BLA 10 min prior to the injection of saline or DCS. Then rats were returned to their cages for 15 min before being subjected to a single session of extinction training. Twenty-four hours later, animals were tested for fear-potentiated startle in the absence of drugs. Results showed that there was a signi? cant overall difference between treatments (F(4,28) 12. 17). As shown in Fig. 3, the facilitation effect of DCS (VEH DCS) on extinction was blocked by co-administration of PI-3K inhibitor (WH DCS) (t(14) 2. 98, P 0. 05).With the single extinction training session used in this experiment, this dose of wortmannin alone (WH SAL) at this dose had no effect on the extinction of fear-potentiated startle compared with control group (VEH SAL) (t(14) 0. 19). These results suggest that the PI-3K signaling cascade was involved in the DCS facilitation of extinction. Experiment 4: DCS enhanced the extinction training induced MAPK and PI-3K phosphorylation According t o the results of the above experiments, the DCS facilitation effect on extinction was prevented by coadministration of MAPK or PI-3K inhibitor. Previous studies have shown that infusion of these same inhibitors blocks extinction (Lu et al. , 2001; Lin et al. , 2003). Therefore, these treatments in conjunction with DCS must result in no extinction and resulting misinterpretation of its blockage effects on DCS.To show the MAPK and PI-3K signaling pathways are essential for the facilitation effect of DCS, we used Western blot to evaluate the DCS effect on the extinction training induced MAPK and PI-3K phosphorylation. Additional amygdala-cannulated rats received fear conditioning, extinction training, and testing for fear-potentiated startle. Then PD98059 or wortmannin was infused to the BLA 10 min prior to the injection of saline or DCS. Rats were returned to their cages. Fifteen minutes after DCS or saline injection, animals were subjected to a single session of extinction training. Animals were killed by decapitation 10 min after extinction training.The lateral and basolateral sub-regions of the amygdala were tested with Western blot analysis. Compared with control group, MAPK phosphorylation was signi? cantly elevated in BLA after extinction training (Fig. 4A, lane 2). Administration of DCS enhanced the effect of extinction training on MAPK phosphorylation (Fig. 4A, lane 3). The MAPK inhibitor PD98059 blocked the effect of DCS (Fig. 4A, lane 4). In addition, we measured the state of Akt phosphorylation as an index of PI-3K activity (Lin et al. , 2001). Fig. 4B showed that administration of DCS enhanced the effect of extinction training on Akt phosphorylation (Fig. 4B, lane 3). The PI-3K inhibitor, wortmannin, blocked the enhancement effect of DCS (Fig. 4b, lane 4).These results raise the possibility that DCS enhancement effect of extinction of conditioned fear is mediated by the amygdaloid MAPK and PI-3K dependent signaling cascades. Experiment 5: intra-amygd ala infusion of the transcription inhibitor or translation inhibitor blocked DCS facilitation of extinction The MAPK pathway participates in the synthesis of proteins important for the long-term stabilization and storage of fear memories. According to the result of experiment 2, the facilitation effect of DCS on extinction is mediated by the MAPK dependent signaling cascade. We predicted that the facilitation effect of DCS required new protein synthesis in the BLA.To test this hypothesis, 48 rats received fear conditioning, extinction training, and testing for fear-potentiated startle. Initially, 56 rats were used but eight of them were excluded. Rats were then randomly assigned to six different groups and received one of the following treatments: VEH SAL, VEH DCS, actinomycin D DCS (ACT DCS), anisomycin DCS (ANI DCS), actinomycin D saline (ACT SAL), and anisomycin saline (ANI SAL). Transcription inhibitor (actinomycin D, 10 g dissolved in 1. 6 l vehicle; 0. 8 l per side) and transl ation inhibitor (anisomycin, 125 g dissolved in 1. 6 l vehicle; 0. 8 l per side) were administered to the BLA 10 min prior to saline or DCS injection. Then rats were returned to their cages. Fifteen minutes later, nimals were subjected to a single session of extinction training. Twenty-four hours later, animals were tested for fear-potentiated startle in the absence of drugs. Results showed that there was a significant overall difference between treatments (F(5,42) 10. 17). As shown in Fig. 5, actinomycin D and anisomycin completely blocked the facilitation effect of DCS (t(14) 3. 11 and t(14) 2. 96, respectively) compared with the VEH DCS group. With a single extinction training session used in this experiment, actinomycin alone (ACT SAL) or anisomycin alone (ANI SAL) did not affect the extinction of fear-potentiated startle compared with control Y. L. Yang and K. T.Lu / Neuroscience 134 (2005) 247–260 253 Fig. 3. Intra-amygdala infusion of the PI-3K inhibitor blocked the fa cilitation effect of DCS on extinction. (A) Timeline of behavioral procedures for experiment 3. (B) Cannula was placed in the BLA. Percent fear-potentiated startle measured 24 h before (pre-extinction test) and 24 h after (post-extinction test) extinction training. Rats in each group were treated with VEH SAL, VEH DCS, WH DCS, or WH SAL prior to a single session of extinction training. Twenty-four hours later, animals were tested for fear-potentiated startle in the absence of drugs (values are mean SEM, * P 0. 05 versus VEH SAL group). C) Cannula tip placements transcribed onto atlas plates adapted from Paxinos and Watson (1997). 254 Y. L. Yang and K. T. Lu / Neuroscience 134 (2005) 247–260 (VEH SAL) (t(14) 0. 88 and t(14) 0. 48, respectively). These results suggest that new protein synthesis within the BLA played an important role in DCS facilitation of extinction of conditioned fear. Experiment 6: the disruptive effect of intra-amygdala infusion of actinomycin D and anisomy cin was not attributed to lasting damage to the amygdala The active drugs used in the above experiments may have toxic effect within the amygdala. Previous work shows that infusion of PD98095 (Lu et al. , 2001) or wortmannin (Lin et al. 2003) into BLA did not appear to cause permanent impairment of amygdala function. To test for possible toxic effects of actinomycin D and anisomycin on the BLA, all animals of experiment 5 received an additional 2 days of drug free extinction training followed 24 h later by testing. Under these conditions, rats previously treated with actinomycin D (ACT DCS-treated group and ACT SALtreated group) or anisomycin (ANI DCS- and ANI SALtreated group) showed a signi? cant reduction of fearpotentiated startle between post-extinction test 1 and post-extinction test 2 (t(7) 3. 08 and t(7) 3. 32 for the ACT DCS-treated group and ACT SAL-treated group respectively) and (t(7) 2. 96 and t(7) 3. 1 for the ANI DCStreated group and ANI SAL-treated group respectively ) (Fig. 6B). Thus, the blockage of extinction observed during post-extinction test 1 appeared to result from an acute drug effect rather than from a more permanent and perhaps toxic action, of actinomycin D or anisomycin. Previous studies have shown that lesions of the BLA block fear-potentiated startle (Campeau and Davis, 1995), an outcome opposite from that obtained with infusion of actinomycin D or anisomycin. It is also important to note that actinomycin D or anisomycin may have long-term toxicity within the BLA. The extinction of fear would look the same as a gradual loss of ability to express or relearn fear.Experiment 7: the disruptive effect of intra-amygdala infusion of actinomycin D and anisomycin was not attributed to state dependency To evaluate the contribution of state-dependency effects to the results obtained in experiment 6, additional amygdala-cannulated rats were tested for extinction in a drug-free state and after receiving the same compound that they had receive d during extinction training. Results showed that there was a signi? cant overall difference between treatments in post-extinction test 2 (F(2,21) 32. 16). These results are shown in Fig. 7. Rats infused with actinomycin or anisomycin before postextinction test 2 showed a slight, but non-signi? cant, decrease in fear-potentiated startle from post-extinction test 1 to post-extinction test 2. For control rats (n 8), fear-potentiated startle was signi? cantly lower during post-extinction test 2 than post-extinction test 1 (t(7) 2. 455; P 0. 05). The lost of fear-potentiated startle in both groups probably re? cted incidental extinction produced by the 30 non-reinforced CS presentations of post-extinction test 1. The failure of rats infused before Fig. 4. MAPK and PI-3K inhibitors blocked extinction training activation of MAPK and PI-3K. (A) Representative Western blots and densitometric analysis of the activation of MAPK in the BLA under different treatments (values are mean SEM, * P 0 . 05 versus VEH SAL group). (B) Representative Western blots and densitometric analysis Akt phosphorylation as an index of PI-3K activity in the BLA under different treatments (values are mean SEM, * P 0. 05 versus VEH DCS group). Y. L. Yang and K. T. Lu / Neuroscience 134 (2005) 247–260 255 Fig. 5.Intra-amygdala infusion of the transcription inhibitor or translation inhibitor blocks the facilitation effect of DCS on extinction of conditioned fear. (A) Timeline of behavioral procedures for experiment 5. (B) Cannula was placed in the BLA. Percent fear-potentiated startle measured 24 h before (pre-extinction test) and 24 h after (post-extinction test 1) extinction training. Rats underwent treatment with VEH SAL, VEH DCS, ACT DCS, ANI DCS, ACT SAL, or ANI SAL prior to a single session of extinction training. Twenty-four hours later, animals were tested for fear-potentiated startle in the absence of drugs (values are mean SEM, * P 0. 05 comparing with the VEH SAL group; # P 0. 05 compared with the VEH DCS group). C) Cannula tip placements transcribed onto atlas plates adapted from Paxinos and Watson (1997). 256 Y. L. Yang and K. T. Lu / Neuroscience 134 (2005) 247–260 Fig. 6. The disruptive effects of intra-amygdala infusion of actinomycin D and anisomycin on extinction were not attributed to lasting damage to the BLA. (A) Timeline of behavioral procedures for experiment 6. The same animals used in experiment 3 were subjected for two more trials of extinction training. (B) Twenty-four hours after the last extinction training, animals were tested for fear-potentiated startle in the absence of drugs (post-extinction test-2) (values are mean SEM, * P 0. 05 versus the corresponding post-extinction test-2). esting with the transcription and translation inhibitors before testing to show a loss of fear-incidental extinction suggested that state dependency was not a major factor in the effects of actinomycin D and anisomycin. Experiment 8: effect of pretest PD98059, U0-126, wortmannin, actinomycin, and anisomycin administration on fear-potentiated startle This experiment was designed to evaluate whether the effect of the active drugs used has had a secondary effect on fear itself or on CS processing. For example, if MAPK inhibitor U0-126 reduced CS-elicited fear, this might attenuate extinction by decreasing the discrepancy between CS predictions and what actually occurred. If actinomycin D or anisomycin interfered with visual processing, this might block extinction produced by non-reinforced exposures to the visual CS.To evaluate these possibilities, 42 amygdala-cannulated rats received acclimation, baseline startle test, and fear conditioning. Initially, 50 rats were used, but eight of them were excluded. After 24 h, rats were infused with PD98059, U0-126, wortmannin, actinomycin, and anisomycin. At 25 min after the infusions, rats were tested for fear-potentiated startle. As shown in Fig. 8, none of the active drugs we used here sig ni? cantly in? uenced fearpotentiated startle (F(6,35) 0. 993). Thus, it is unlikely that these drugs in? uenced extinction by increasing fear or by disrupting CS processing. Y. L. Yang and K. T. Lu / Neuroscience 134 (2005) 247–260 57 Fig. 7. The disruptive effect of intra-amygdala infusion of actinomycin D and anisomycin were not attributed to state dependency. (A) Timeline of behavioral procedures for experiment 7. (B) Cannula was placed in the BLA. Percent fear-potentiated startle measured 24 h before (pre-extinction test), 24 h after (post-extinction test 1), and 48 h after (post-extinction test 2) extinction training. Rats in each group underwent VEH SAL, ACT DCS, or ANI DCS prior to a single session of extinction training and prior to post-extinction test 2. Animals were tested for fear-potentiated startle in the absence of drugs (values are mean SEM, * P 0. 05). C) Cannula tip placements transcribed onto atlas plates adapted from Paxinos and Watson (1997). 258 Y. L. Y ang and K. T. Lu / Neuroscience 134 (2005) 247–260 Fig. 8. Effect of pretest PD98059, U0-126, wortmannin, actinomycin, and anisomycin administration on fear-potentiated startle. (A) Timeline of behavioral procedures for experiment 8. (B) Cannula was placed in the BLA. Percent fear-potentiated startle was measured 24 h after fear conditioning. Rats were treated with DMSO, PD98059 (PD), U0-126 (U0), wortmannin (WH), vehicle (VEH), actinomycin (ACT), or anisomycin (ANI) 25 min prior to the fear-potentiated startle test (values are mean SEM). C) Cannula tip placements transcribed onto atlas plates adapted from Paxinos and Watson (1997). DISCUSSION We build on the previous ? ndings that DCS facilitated extinction of conditioned fear (Walker et al. , 2002; Ledgerwood et al. , 2003, 2004; Ressler et al. , 2004). Here, we show for the ? rst time that the DCS effect was prevented by co-administration of MAPK, PI-3K, transcription, and translation inhibitors. Control experiments indica ted that the blocking effects of actinomycin D and anisomycin on extinction were not due to lasting damage to the BLA or state dependency. In addition, none of active drugs we used in this study altered the expression of conditioned fear.These results suggest that PI-3K and MAPK-dependent signaling cascades and de novo protein synthesis within the BLA were important for DCS facilitation. Early behavioral studies by Pavlov (1927) and Konorski (1948) de? ned extinction as an active process involving formation of new inhibitory associations as opposed to forgetting previously conditioned associations. Numerous studies since have con? rmed and elaborated these early ? ndings (reviewed in Falls and Davis, 1995; Davis et al. , 2000). It is now well accepted that extinction occurs with repeated presentation of a CS in the absence of the pre- Y. L. Yang and K. T. Lu / Neuroscience 134 (2005) 247–260 259 viously paired US.This reduces the conditioned response elicited by the CS. In co ntrast to forgetting which implies the passive loss of memory, extinction implies active formation of new inhibitory associations competing with and overpowering original excitatory associations. Evidence is growing that extinction may involve circuits and use mechanisms of synaptic plasticity similar to those of conditioned fear learning (Falls and Davis, 1992; Cox and Westbrook, 1994; Baker and Azorlosa, 1996; Davis et al. , 2000). NMDA-dependent synaptic plasticity appears to mediate many forms of active learning (Morris, 1989; Staubli et al. , 1989; Flood et al. , 1990; Collinridge and Bliss, 1995).It is likely that conditioned fear learning depends on CS–US pairing mediated by NMDA receptors within the BLA (Miserendino et al. , 1990; Fanselow and LeDoux, 1999). Extinction also appears to require active, NMDA-dependent learning within the amygdala. This was demonstrated by blockage of extinction by microinjections of APV into the BLA in both fear-potentiated startle (Fall s and Davis, 1992) and freezing paradigms (Lee and Kim, 1998). Furthermore, systemic administration of a different NMDA antagonist, MK801, blocks the extinction process in a range of different learning paradigms (Cox and Westbrook, 1994; Baker and Azorlosa, 1996; Kehoe et al. , 1996).Recently, DCS, a partial agonist acting at the strychnine-insensitive glycine-recognition site of the NMDA receptor complex, has repeatedly been shown to facilitate learning in various cue and context association paradigms (Monahan et al. , 1989; Flood et al. , 1992; Thompson and Disterhoft, 1997). Walker et al. (2002) reported the ? rst evidence that DCS facilitates extinction of learned fear. Since then, further studies con? rmed and elaborated this early ? nding (Ledgerwood et al. , 2003, 2004; Ressler et al. , 2004). These studies reported that DCS is more effective at facilitating extinction when given after extinction training, rather than before. They interpret these ? dings as evidence that DCS facilitates the consolidation of a new memory acquired during extinction. It is important to note that although some studies have shown DCS to be effective in improving memory impairment due to Alzheimer’s disease (Schwartz et al. , 1996; Tsai et al. , 1999) and schizophrenia (Javitt et al. , 1994; Goff et al. , 1999), other studies found little or no improvement (Tsai et al. , 1998; van Berckel et al. , 1999). This may be related to the fact that acute treatment with DCS may have a more pronounced facilitation than chronic treatment (Quartermain et al. , 1994; Ledgerwood et al. , 2003; Richardson et al. , 2004). Ledgerwood et al. (2003, 2004) reported that DCStreated animals fail to exhibit reinstatement effects.That DCS enhances extinction may be through some processes different from extinction induced by repeat representation of CS. Lin et al. (2003) investigated the similarities and differences between consolidation of conditioning and consolidation of extinction. They fo und that both processes depend on activation of NMDA receptors, PI-3K, MAPK, and require synthesis of new proteins within the amygdala. They also found that different characteristics show differential sensitivity to the transcription inhibitor actinomycin D. Our results were consistent with the model that the extinc- tion process involved active learning of new inhibitory associations.Here we showed that DCS facilitation of extinction could be blocked by actinomycin D and anisomycin. These seemingly con? icting results could be attributable to our extinction protocol. Our protocol resembled betweensession extinction, presumably corresponding to long-term extinction memory. In addition, we used DCS to facilitate the extinction process and tested the animals in a drug free condition. Acquisition or consolidation of long-term memory requires activation of protein kinase, transcription of genes, new protein synthesis, and synapse formation (Schafe and LeDoux, 2000). Similar mechanisms w ere involved in the DCS facilitation of extinction. The DCS activated NMDA receptors, resulted in Ca2 in? x into the cell, and led to the PI-3K and MAPK activation. Activated MAPK can translocate to the nucleus, subsequently activating transcription factors to promote gene transcription and new protein synthesis. Thus, combinations of drugs and extinction training may weaken or erase original memory. There is increasing evidence that learning of CS–US associations involves synaptic plasticity within the BLA, leading to differential activation of this circuit by sensory afferents (Davis, 1997; Rogan et al. , 1997; Lee and Kim, 1998; Fanselow and LeDoux, 1999). Our results suggested that the extinction of conditioned fear also involved NMDA-dependent plasticity, but speci? inhibitory circuits may be activated by extinction learning. We hypothesize that this newly activated inhibitory circuit would oppose conditioned excitatory pathways normally leading to activation of the cent ral nucleus of the amygdala, resulting in the elicitation of fear responses. CONCLUSION This may be the ? rst study to show that PI-3K and MAPKdependent signaling cascade and de novo protein synthesis within the BLA were essential to the DCS facilitation of the extinction of conditioned fear. Acknowledgments—The work was supported by grants from the National Science Council (NSC 90-2320-B-003-007, NSC 902320-B-006-038, NSC 93-2320-B-003-003).Our gratitude (also) goes to the Academic Paper Editing Clinic, NTNU. REFERENCES Baker J, Azorlosa J (1996) The NMDA antagonist MK-801 blocks the extinction of Pavlovian fear conditioning. Behav Neurosci 110:618–620. 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Education and teaching philosophy Essay Example | Topics and Well Written Essays - 2500 words

Education and teaching philosophy - Essay Example The lines in particular are: At a reunion thirty years after high school graduation, an old teacher of Literature was moved to tears when asked by his classmate what he remembered about her teaching, he quoted a few lines from Omar Khayyam. He even explained how the latter’s words helped him survive while he was pursuing further studies in a university far from home. All this after a decade and a half, as though the class went through the lesson only yesterday. The boy who had turned into a man claimed that Omar Khayyan’s philosophy enabled him to survive while pursuing further studies in a university far from home. Reading, which is an integral part of language allows the reader to take in the human experience. Reading is a way to explore worlds and travel through time. A good teacher can introduce to her classes, great men of the past. These great personalities, perhaps no longer in our midst can still serve as role models for the young and inspire them to great deeds in the future. Students shouldn’t read books because they are forced to. Rather they should find deep personal meaning in a book and find themselves reflecting on it even after they’ve put it down. There should be books that change every student’s life. Here are some steps the students should take to gain background knowledge and become motivated to read. Then they actually read the text in which the readers develop a basic understanding. Then they re-read the text to extend their understanding, interpret, analyze and critique the selection (This second reading could be done orally during the lesson itself. The teacher allows the students to read orally certain paragraphs to justify their opinions with evidence from sources on the text itself.). Preview activities include brainstorming and anticipation guides. Teachers also show the students how to

Classical Literature Essay Example | Topics and Well Written Essays - 750 words

Classical Literature - Essay Example This is what will be dissertated in the following. Genesis is the first Bible verse of the first chapter in the Book of Genesis, and it contains the first words of the Bible. Two distinct stories of the creation of humanity in particular are given in Genesis, and these are: Genesis 1:27-30 "So God created man in his own image; male and female he created them. God blessed them and said to them, 'Be fruitful and increase, fill the earth and subdue it, rule over the fish in the sea, the birds of heaven, and every living thing that moves upon the earth'. God also said, 'I give you all plants that bear seed everywhere on the earth, and every tree bearing fruit which yields seed: they shall be yours for food'; and Genesis 2: 7-8 "Then the Lord God formed a man from the dust of the ground and breathed into his nostrils the breath of life. Thus the man became a living creature'. Without question the stories of Genesis are the most significant form of history in this regards, however although some of the events that are described re consiste nt with other historical records, there are many others - particularly those before the time of Saul and David - which cannot be tested for accuracy, and thus are considered by many to have been shaped to reflect certain persons' religious and political goals. "The history includes dramatic accounts of persecution, escape, exile, sacrifice, and global devastation by a great flood. It tells of a creator God who watches over his people, tests his people, and promises them great things if they honor his commandments. As any great story must, the history has its villains and it has heroes." (123). Then there is the Epic of Gilgamesh, which is considered by some as being the oldest written story on Earth, and which "was originally written on 12 clay tablets in cuneiform script. It is about the adventures of the historical King of Uruk (somewhere between 2750 and 2500 BCE)". (79). The Epic of Gilgamesh is an epic poem from Babylonia, one which includes a series of Sumerian legends and poems about the mythological hero-king Gilgamesh, who was thought to be a ruler of the 3rd millennium BC, and all of these legends and poems were then gathered together into a "longer Akkadian poem long afterward, with the most complete version extant today pressed on twelve clay tablets in the library collection of the 7th century BC Assyrian king Ashurbanipal" (101). In regards to the similarities and differences between the stories of Genesis and the Epic of Gilgamesh, there are many of both, and all of these must be taken into serious consideration. One of the most major similarities between the two is in regards to the fact of how they are both surrounded around their own leaders; Genesis to God and the Epic of Gilgamesh to the King of Uruk. Each basically describes the workings and actions of their supposed leader, and as well tells of the considered creations and works that took place during their own described eras. Another major similarity between the two i

Nintendo Wii for Women in the UAE Essay Example | Topics and Well Written Essays - 2500 words

Nintendo Wii for Women in the UAE - Essay Example This paper believes that Nintendo Wii should find a new market, especially in a foreign market where it is not doing well yet. This paper presents a marketing plan for introducing Nintendo Wii to women in the United Arab Emirates (UAE). The situation analyses will provide the information on why Emirati and non-national women are attractive new market segments for Nintendo Wii. SITUATION ANALYSIS This section will analyse the strengths, weaknesses, opportunities, and threats to Nintendo Wii. SWOT Analysis Strengths It is believed that Nintendo President and Director Satoru Iwata is a company strength because he has turned the company around with his support for innovations like Wii and DS (Schilling 2009). He is also a hardware innovator, which makes R&D in Nintendo a core competency also of Nintendo. Another company strength is its wide array of creative products. The company has led the video games industry since 2007, because of its intuitive and socially attractive games. Since 20 07, Nintendo has regained its top 1 market status because of â€Å"rethinking video gaming, making it more social, more intuitive, and physically engaging† (Deshpande and Chua 2008, p.22). Nintendo Wii has become a blockbuster product, because of its ability to physically engage players, embedding them into the gaming experience in intuitive ways. Nintendo has a strong multinational video gaming brand since its Mario Brothers times. With its phenomenal Wii and DS consoles, quality and creative gaming experience is already equated with Nintendo. This brand equity can easily spill over to other markets. Weaknesses Nintendo’s weakness is inventory shortage for its leading products Wii video game console and DS handheld... Center of discussion in this paper is Nintendo Wii and DS, the company's blockbuster products in the beginning of the twenty-first century. In 2006, Nintendo's revenues are $5 billion, but a year after that, it jumped to $9 billion, a rise of 80%. From 2006 to 2009, revenues have risen from $5 billion to $18 billion, which means that sales increased by 260%. For the past two years, however, sales are dipping as Wii, DS, and Dsi are approaching market saturation in the United States. In 2011, Nintendo sold 4.5 million Wii units, which is a far cry from its 2007 sales of 7 million-strong units, and which translates to a drop of 35%. This is not surprising also because of the short product lifecycle of video games consoles and gaming software, where new products, hardware and software alike, are produced every two to three years, sometimes even less. This paper believes that Nintendo Wii should find a new market, especially in a foreign market where it is not doing well yet. This paper presents a marketing plan for introducing Nintendo Wii to women in the United Arab Emirates (UAE). The situation analyses will provide the information on why Emirati and non-national women are attractive new market segments for Nintendo Wii. The main target markets are Emirati women, although other women are included. The Emiratis continue to have a conservative culture that keep women inside their homes, which hamper women's education, employment, and even exercise opportunities.