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Friday, May 11, 2018

Existentialism

From Wikipedia, the free encyclopedia



Existentialism (/ɛɡzɪˈstɛnʃəlɪzəm/)[1] is a tradition of philosophical inquiry associated mainly with certain 19th and 20th-century European philosophers who, despite profound doctrinal differences,[2][3][4] shared the belief that philosophical thinking begins with the human subject—not merely the thinking subject, but the acting, feeling, living human individual.[5] While the predominant value of existentialist thought is commonly acknowledged to be freedom, its primary virtue is authenticity.[6] In the view of the existentialist, the individual's starting point is characterized by what has been called "the existential attitude", or a sense of disorientation, confusion, or dread in the face of an apparently meaningless or absurd world.[7] Many existentialists have also regarded traditional systematic or academic philosophies, in both style and content, as too abstract and remote from concrete human experience.[8][9]

Søren Kierkegaard is generally considered to have been the first existentialist philosopher,[2][10][11] though he did not use the term existentialism.[12] He proposed that each individual—not society or religion—is solely responsible for giving meaning to life and living it passionately and sincerely, or "authentically".[13][14] Existentialism became popular in the years following World War II, and strongly influenced many disciplines besides philosophy, including theology, drama, art, literature, and psychology.[15]

Definitional issues and background

The term is often seen as a historical convenience as it was first applied to many philosophers in hindsight, long after they had died. In fact, while existentialism is generally considered to have originated with Kierkegaard, the first prominent existentialist philosopher to adopt the term as a self-description was Jean-Paul Sartre. Sartre posits the idea that "what all existentialists have in common is the fundamental doctrine that existence precedes essence", as scholar Frederick Copleston explains.[16] According to philosopher Steven Crowell, defining existentialism has been relatively difficult, and he argues that it is better understood as a general approach used to reject certain systematic philosophies rather than as a systematic philosophy itself.[2] Sartre himself, in a lecture delivered in 1945, described existentialism as "the attempt to draw all the consequences from a position of consistent atheism".[17]

Although many outside Scandinavia consider the term existentialism to have originated from Kierkegaard himself, it is more likely that Kierkegaard adopted this term (or at least the term "existential" as a description of his philosophy) from the Norwegian poet and literary critic Johan Sebastian Cammermeyer Welhaven.[18] This assertion comes from two sources. The Norwegian philosopher Erik Lundestad refers to the Danish philosopher Fredrik Christian Sibbern. Sibbern is supposed to have had two conversations in 1841, the first with Welhaven and the second with Kierkegaard. It is in the first conversation that it is believed that Welhaven came up with "a word that he said covered a certain thinking, which had a close and positive attitude to life, a relationship he described as existential".[19] This was then brought to Kierkegaard by Sibbern.

The second claim comes from the Norwegian historian Rune Slagstad, who claims to prove that Kierkegaard himself said the term "existential" was borrowed from the poet. He strongly believes that it was Kierkegaard himself who said that "Hegelians do not study philosophy 'existentially'; to use a phrase by Welhaven from one time when I spoke with him about philosophy".[20]

Concepts

Existence precedes essence

Sartre claimed that a central proposition of Existentialism is that existence precedes essence, which means that the most important consideration for individuals is that they are individuals—independently acting and responsible, conscious beings ("existence")—rather than what labels, roles, stereotypes, definitions, or other preconceived categories the individuals fit ("essence"). The actual life of the individuals is what constitutes what could be called their "true essence" instead of there being an arbitrarily attributed essence others use to define them. Thus, human beings, through their own consciousness, create their own values and determine a meaning to their life.[21] Although it was Sartre who explicitly coined the phrase, similar notions can be found in the thought of existentialist philosophers such as Heidegger, and Kierkegaard:
"The subjective thinker’s form, the form of his communication, is his style. His form must be just as manifold as are the opposites that he holds together. The systematic eins, zwei, drei is an abstract form that also must inevitably run into trouble whenever it is to be applied to the concrete. To the same degree as the subjective thinker is concrete, to the same degree his form must also be concretely dialectical. But just as he himself is not a poet, not an ethicist, not a dialectician, so also his form is none of these directly. His form must first and last be related to existence, and in this regard he must have at his disposal the poetic, the ethical, the dialectical, the religious. Subordinate character, setting, etc., which belong to the well-balanced character of the esthetic production, are in themselves breadth; the subjective thinker has only one setting—existence—and has nothing to do with localities and such things. The setting is not the fairyland of the imagination, where poetry produces consummation, nor is the setting laid in England, and historical accuracy is not a concern. The setting is inwardness in existing as a human being; the concretion is the relation of the existence-categories to one another. Historical accuracy and historical actuality are breadth." Søren Kierkegaard (Concluding Postscript, Hong pp. 357–58)
Some interpret the imperative to define oneself as meaning that anyone can wish to be anything. However, an existentialist philosopher would say such a wish constitutes an inauthentic existence - what Sartre would call 'bad faith'. Instead, the phrase should be taken to say that people are (1) defined only insofar as they act and (2) that they are responsible for their actions. For example, someone who acts cruelly towards other people is, by that act, defined as a cruel person. Furthermore, by this action of cruelty, such persons are themselves responsible for their new identity (cruel persons). This is as opposed to their genes, or human nature, bearing the blame.

As Sartre says in his lecture Existentialism is a Humanism: "... man first of all exists, encounters himself, surges up in the world—and defines himself afterwards". The more positive, therapeutic aspect of this is also implied: A person can choose to act in a different way, and to be a good person instead of a cruel person. Here it is also clear that since humans can choose to be either cruel or good, they are, in fact, neither of these things essentially.[22]

Sartre's definition of existentialism was based on Heidegger's magnum opus "Being and Time". In a set of letters, Heidegger implies that Sartre misunderstood him for his own purposes of subjectivism, and that he did not mean that actions take precedence over being so long as those actions were not reflected upon. This way of living, Heidegger called "average everydayness".

The Absurd

The notion of the Absurd contains the idea that there is no meaning in the world beyond what meaning we give it. This meaninglessness also encompasses the amorality or "unfairness" of the world. This contrasts with the notion that "bad things don't happen to good people"; to the world, metaphorically speaking, there is no such thing as a good person or a bad person; what happens happens, and it may just as well happen to a "good" person as to a "bad" person.[23]

Because of the world's absurdity, at any point in time, anything can happen to anyone, and a tragic event could plummet someone into direct confrontation with the Absurd. The notion of the Absurd has been prominent in literature throughout history. Many of the literary works of Søren Kierkegaard, Samuel Beckett, Franz Kafka, Fyodor Dostoyevsky, Eugène Ionesco, Miguel de Unamuno, Luigi Pirandello,[24][25][26][27] Jean-Paul Sartre, Joseph Heller and Albert Camus contain descriptions of people who encounter the absurdity of the world.

It is in relation to the concept of the devastating awareness of meaninglessness that Albert Camus claimed that "there is only one truly serious philosophical problem, and that is suicide" in his The Myth of Sisyphus. Although "prescriptions" against the possibly deleterious consequences of these kinds of encounters vary, from Kierkegaard's religious "stage" to Camus' insistence on persevering in spite of absurdity, the concern with helping people avoid living their lives in ways that put them in the perpetual danger of having everything meaningful break down is common to most existentialist philosophers. The possibility of having everything meaningful break down poses a threat of quietism, which is inherently against the existentialist philosophy.[28] It has been said that the possibility of suicide makes all humans existentialists. The ultimate hero of absurdism is to live without meaning and face suicide without succumbing to it.[29]

Facticity

Facticity is a concept defined by Sartre in Being and Nothingness as the in-itself, which delineates for humans the modalities of being and not being. This can be more easily understood when considering facticity in relation to the temporal dimension of our past: one's past is what one is, in the sense that it co-constitutes oneself. However, to say that one is only one's past would be to ignore a significant part of reality (the present and the future), while saying that one's past is only what one was, would entirely detach it from oneself now. A denial of one's own concrete past constitutes an inauthentic lifestyle, and the same goes for all other kinds of facticity (having a human body — e.g., one that doesn't allow a person to run faster than the speed of sound — identity, values, etc.).[30]

Facticity is both a limitation and a condition of freedom. It is a limitation in that a large part of one's facticity consists of things one couldn't have chosen (birthplace, etc.), but a condition of freedom in the sense that one's values most likely depend on it. However, even though one's facticity is "set in stone" (as being past, for instance), it cannot determine a person: The value ascribed to one's facticity is still ascribed to it freely by that person. As an example, consider two men, one of whom has no memory of his past and the other who remembers everything. They both have committed many crimes, but the first man, knowing nothing about this, leads a rather normal life while the second man, feeling trapped by his own past, continues a life of crime, blaming his own past for "trapping" him in this life. There is nothing essential about his committing crimes, but he ascribes this meaning to his past.

However, to disregard one's facticity when, in the continual process of self-making, one projects oneself into the future, that would be to put oneself in denial of oneself, and thus would be inauthentic. In other words, the origin of one's projection must still be one's facticity, though in the mode of not being it (essentially). An example of one focusing solely on one's possible projects without reflecting on one's current facticity:[30] if one continually thinks about future possibilities related to being rich (e.g. a better car, bigger house, better quality of life, etc.) without considering the facticity of not currently having the financial means to do so. In this example, considering both facticity and transcendence, an authentic mode of being would be considering future projects that might improve one's current finances (e.g. putting in extra hours, or investing savings) in order to arrive at a future-facticity of a modest pay rise, further leading to purchase of an affordable car.

Another aspect of facticity is that it entails angst, both in the sense that freedom "produces" angst when limited by facticity, and in the sense that the lack of the possibility of having facticity to "step in" for one to take responsibility for something one has done, also produces angst.

Another aspect of existential freedom is that one can change one's values. Thus, one is responsible for one's values, regardless of society's values. The focus on freedom in existentialism is related to the limits of the responsibility one bears, as a result of one's freedom: the relationship between freedom and responsibility is one of interdependency, and a clarification of freedom also clarifies that for which one is responsible.[31][32]

Authenticity

Many noted existentialist writers consider the theme of authentic existence important. Authentic existence involves the idea that one has to "create oneself" and then live in accordance with this self. What is meant by authenticity is that in acting, one should act as oneself, not as "one's acts" or as "one's genes" or any other essence requires. The authentic act is one that is in accordance with one's freedom. As a condition of freedom is facticity, this includes one's facticity, but not to the degree that this facticity can in any way determine one's transcendent choices (in the sense that one could then blame one's background [facticity] for making the choice one made [chosen project, from one's transcendence]). The role of facticity in relation to authenticity involves letting one's actual values come into play when one makes a choice (instead of, like Kierkegaard's Aesthete, "choosing" randomly), so that one also takes responsibility for the act instead of choosing either-or without allowing the options to have different values.[33]

In contrast to this, the inauthentic is the denial to live in accordance with one's freedom. This can take many forms, from pretending choices are meaningless or random, through convincing oneself that some form of determinism is true, to a sort of "mimicry" where one acts as "one should".

How "one should" act is often determined by an image one has, of how one such as oneself (say, a bank manager, lion tamer, prostitute, etc.) acts. In Being and Nothingness, Sartre relates an example of a "waiter" in bad faith: he merely takes part in the "act" of being a typical waiter, albeit very convincingly.[34] This image usually corresponds to some sort of social norm, but this does not mean that all acting in accordance with social norms is inauthentic: The main point is the attitude one takes to one's own freedom and responsibility, and the extent to which one acts in accordance with this freedom.

The Other and the Look

The Other (when written with a capital "O") is a concept more properly belonging to phenomenology and its account of intersubjectivity. However, the concept has seen widespread use in existentialist writings, and the conclusions drawn from it differ slightly from the phenomenological accounts. The experience of the Other is the experience of another free subject who inhabits the same world as a person does. In its most basic form, it is this experience of the Other that constitutes intersubjectivity and objectivity. To clarify, when one experiences someone else, and this Other person experiences the world (the same world that a person experiences)—only from "over there"—the world itself is constituted as objective in that it is something that is "there" as identical for both of the subjects; a person experiences the other person as experiencing the same things. This experience of the Other's look is what is termed the Look (sometimes the Gaze).[35]

While this experience, in its basic phenomenological sense, constitutes the world as objective, and oneself as objectively existing subjectivity (one experiences oneself as seen in the Other's Look in precisely the same way that one experiences the Other as seen by him, as subjectivity), in existentialism, it also acts as a kind of limitation of freedom. This is because the Look tends to objectify what it sees. As such, when one experiences oneself in the Look, one doesn't experience oneself as nothing (no thing), but as something. Sartre's own example of a man peeping at someone through a keyhole can help clarify this: at first, this man is entirely caught up in the situation he is in; he is in a pre-reflexive state where his entire consciousness is directed at what goes on in the room. Suddenly, he hears a creaking floorboard behind him, and he becomes aware of himself as seen by the Other. He is thus filled with shame for he perceives himself as he would perceive someone else doing what he was doing, as a Peeping Tom. The Look is then co-constitutive of one's facticity.

Another characteristic feature of the Look is that no Other really needs to have been there: It is quite possible that the creaking floorboard was nothing but the movement of an old house; the Look isn't some kind of mystical telepathic experience of the actual way the other sees one (there may also have been someone there, but he could have not noticed that the person was there). It is only one's perception of the way another might perceive him.

Angst and dread

"Existential angst", sometimes called existential dread, anxiety, or anguish, is a term that is common to many existentialist thinkers. It is generally held to be a negative feeling arising from the experience of human freedom and responsibility. The archetypical example is the experience one has when standing on a cliff where one not only fears falling off it, but also dreads the possibility of throwing oneself off. In this experience that "nothing is holding me back", one senses the lack of anything that predetermines one to either throw oneself off or to stand still, and one experiences one's own freedom. Angst, according to the modern existentialist, Adam Fong, is the sudden realization of a lack of meaning, often while one completes a task that initailly seems to have intrinsic meaning.[23]

It can also be seen in relation to the previous point how angst is before nothing, and this is what sets it apart from fear that has an object. While in the case of fear, one can take definitive measures to remove the object of fear, in the case of angst, no such "constructive" measures are possible. The use of the word "nothing" in this context relates both to the inherent insecurity about the consequences of one's actions, and to the fact that, in experiencing freedom as angst, one also realizes that one is fully responsible for these consequences. There is nothing in people (genetically, for instance) that acts in their stead—that they can blame if something goes wrong. Therefore, not every choice is perceived as having dreadful possible consequences (and, it can be claimed, human lives would be unbearable if every choice facilitated dread). However, this doesn't change the fact that freedom remains a condition of every action.

Despair

Despair, in existentialism, is generally defined as a loss of hope.[36] More specifically, it is a loss of hope in reaction to a breakdown in one or more of the defining qualities of one's self or identity. If a person is invested in being a particular thing, such as a bus driver or an upstanding citizen, and then finds their being-thing compromised, they would normally be found in a state of despair—a hopeless state. For example, a singer who loses the ability to sing may despair if they have nothing else to fall back on—nothing to rely on for their identity. They find themselves unable to be what defined their being.

What sets the existentialist notion of despair apart from the conventional definition is that existentialist despair is a state one is in even when they aren't overtly in despair. So long as a person's identity depends on qualities that can crumble, they are in perpetual despair—and as there is, in Sartrean terms, no human essence found in conventional reality on which to constitute the individual's sense of identity, despair is a universal human condition. As Kierkegaard defines it in Either/Or: "Let each one learn what he can; both of us can learn that a person’s unhappiness never lies in his lack of control over external conditions, since this would only make him completely unhappy."[37] In Works of Love, he said:
When the God-forsaken worldliness of earthly life shuts itself in complacency, the confined air develops poison, the moment gets stuck and stands still, the prospect is lost, a need is felt for a refreshing, enlivening breeze to cleanse the air and dispel the poisonous vapors lest we suffocate in worldliness. ... Lovingly to hope all things is the opposite of despairingly to hope nothing at all. Love hopes all things—yet is never put to shame. To relate oneself expectantly to the possibility of the good is to hope. To relate oneself expectantly to the possibility of evil is to fear. By the decision to choose hope one decides infinitely more than it seems, because it is an eternal decision. pp. 246–50

Opposition to positivism and rationalism

Existentialists oppose definitions of human beings as primarily rational, and, therefore, oppose positivism and rationalism. Existentialism asserts that people actually make decisions based on subjective meaning rather than pure rationality. The rejection of reason as the source of meaning is a common theme of existentialist thought, as is the focus on the feelings of anxiety and dread that we feel in the face of our own radical freedom and our awareness of death. Kierkegaard advocated rationality as a means to interact with the objective world (e.g., in the natural sciences), but when it comes to existential problems, reason is insufficient: "Human reason has boundaries".[38]

Like Kierkegaard, Sartre saw problems with rationality, calling it a form of "bad faith", an attempt by the self to impose structure on a world of phenomena—"the Other"—that is fundamentally irrational and random. According to Sartre, rationality and other forms of bad faith hinder people from finding meaning in freedom. To try to suppress their feelings of anxiety and dread, people confine themselves within everyday experience, Sartre asserts, thereby relinquishing their freedom and acquiescing to being possessed in one form or another by "the Look" of "the Other" (i.e., possessed by another person—or at least one's idea of that other person).

Religion

An existentialist reading of the Bible would demand that the reader recognize that (s)he is an existing subject studying the words more as a recollection of events. This is in contrast to looking at a collection of "truths" that are outside and unrelated to the reader, but may develop a sense of reality/God. Such a reader is not obligated to follow the commandments as if an external agent is forcing them upon her/him, but as though they are inside her/him and guiding her/him from inside. This is the task Kierkegaard takes up when he asks: "Who has the more difficult task: the teacher who lectures on earnest things a meteor's distance from everyday life - or the learner who should put it to use?"[39]

Confusion with nihilism

Although nihilism and existentialism are distinct philosophies, they are often confused with one another. A primary cause of confusion is that Friedrich Nietzsche is an important philosopher in both fields, but also the existentialist insistence on the inherent meaninglessness of the world. Existentialist philosophers often stress the importance of Angst as signifying the absolute lack of any objective ground for action, a move that is often reduced to a moral or an existential nihilism. A pervasive theme in the works of existentialist philosophy, however, is to persist through encounters with the absurd, as seen in Camus' The Myth of Sisyphus ("One must imagine Sisyphus happy"),[40] and it is only very rarely that existentialist philosophers dismiss morality or one's self-created meaning: Kierkegaard regained a sort of morality in the religious (although he wouldn't himself agree that it was ethical; the religious suspends the ethical), and Sartre's final words in Being and Nothingness are "All these questions, which refer us to a pure and not an accessory (or impure) reflection, can find their reply only on the ethical plane. We shall devote to them a future work."[34]

Etymology

The term "existentialism" was coined by the French Catholic philosopher Gabriel Marcel in the mid-1940s.[41][42][43] At first, when Marcel applied the term to him at a colloquium in 1945, Jean-Paul Sartre rejected it.[44] Sartre subsequently changed his mind and, on October 29, 1945, publicly adopted the existentialist label in a lecture to the Club Maintenant in Paris. The lecture was published as L'existentialisme est un humanisme (Existentialism is a Humanism), a short book that did much to popularize existentialist thought.[45] Marcel later came to reject the label himself in favour of the term Neo-Socratic, in honor of Kierkegaard's essay "On The Concept of Irony".

Some scholars argue that the term should be used only to refer to the cultural movement in Europe in the 1940s and 1950s associated with the works of the philosophers Jean-Paul Sartre, Simone de Beauvoir, Maurice Merleau-Ponty, and Albert Camus.[2] Other scholars extend the term to Kierkegaard, and yet others extend it as far back as Socrates.[46] However, the term is often identified with the philosophical views of Jean-Paul Sartre.[2]

History

19th century

Kierkegaard and Nietzsche

Søren Kierkegaard and Friedrich Nietzsche were two of the first philosophers considered fundamental to the existentialist movement, though neither used the term "existentialism" and it is unclear whether they would have supported the existentialism of the 20th century. They focused on subjective human experience rather than the objective truths of mathematics and science, which they believed were too detached or observational to truly get at the human experience. Like Pascal, they were interested in people's quiet struggle with the apparent meaninglessness of life and the use of diversion to escape from boredom. Unlike Pascal, Kierkegaard and Nietzsche also considered the role of making free choices, particularly regarding fundamental values and beliefs, and how such choices change the nature and identity of the chooser.[47] Kierkegaard's knight of faith and Nietzsche's Übermensch are representative of people who exhibit Freedom, in that they define the nature of their own existence. Nietzsche's idealized individual invents his own values and creates the very terms they excel under. By contrast, Kierkegaard, opposed to the level of abstraction in Hegel, and not nearly as hostile (actually welcoming) to Christianity as Nietzsche, argues through a pseudonym that the objective certainty of religious truths (specifically Christian) is not only impossible, but even founded on logical paradoxes. Yet he continues to imply that a leap of faith is a possible means for an individual to reach a higher stage of existence that transcends and contains both an aesthetic and ethical value of life. Kierkegaard and Nietzsche were also precursors to other intellectual movements, including postmodernism, and various strands of psychotherapy. However, Kierkegaard believed that individuals should live in accordance with their thinking.

Dostoyevsky

The first important literary author also important to existentialism was the Russian Fyodor Dostoyevsky.[48] Dostoyevsky's Notes from Underground portrays a man unable to fit into society and unhappy with the identities he creates for himself. Jean-Paul Sartre, in his book on existentialism Existentialism is a Humanism, quoted Dostoyevsky's The Brothers Karamazov as an example of existential crisis. Sartre attributes Ivan Karamazov's claim, "If God did not exist, everything would be permitted"[49] to Dostoyevsky himself, though this quote does not appear in the novel.[50] However, a similar sentiment is explicitly stated when Alyosha visits Dimitri in prison. Dimitri mentions his conversations with Rakitin in which the idea that "Then, if He doesn't exist, man is king of the earth, of the universe" allowing the inference contained in Sartre's attribution to remain a valid idea contested within the novel.[51] Other Dostoyevsky novels covered issues raised in existentialist philosophy while presenting story lines divergent from secular existentialism: for example, in Crime and Punishment, the protagonist Raskolnikov experiences an existential crisis and then moves toward a Christian Orthodox worldview similar to that advocated by Dostoyevsky himself.[52]

Early 20th century

In the first decades of the 20th century, a number of philosophers and writers explored existentialist ideas. The Spanish philosopher Miguel de Unamuno y Jugo, in his 1913 book The Tragic Sense of Life in Men and Nations, emphasized the life of "flesh and bone" as opposed to that of abstract rationalism. Unamuno rejected systematic philosophy in favor of the individual's quest for faith. He retained a sense of the tragic, even absurd nature of the quest, symbolized by his enduring interest in Cervantes' fictional character Don Quixote. A novelist, poet and dramatist as well as philosophy professor at the University of Salamanca, Unamuno wrote a short story about a priest's crisis of faith, Saint Manuel the Good, Martyr, which has been collected in anthologies of existentialist fiction. Another Spanish thinker, Ortega y Gasset, writing in 1914, held that human existence must always be defined as the individual person combined with the concrete circumstances of his life: "Yo soy yo y mi circunstancia" ("I am myself and my circumstances"). Sartre likewise believed that human existence is not an abstract matter, but is always situated ("en situation").

Although Martin Buber wrote his major philosophical works in German, and studied and taught at the Universities of Berlin and Frankfurt, he stands apart from the mainstream of German philosophy. Born into a Jewish family in Vienna in 1878, he was also a scholar of Jewish culture and involved at various times in Zionism and Hasidism. In 1938, he moved permanently to Jerusalem. His best-known philosophical work was the short book I and Thou, published in 1922. For Buber, the fundamental fact of human existence, too readily overlooked by scientific rationalism and abstract philosophical thought, is "man with man", a dialogue that takes place in the so-called "sphere of between" ("das Zwischenmenschliche").[53]

Two Russian thinkers, Lev Shestov and Nikolai Berdyaev, became well known as existentialist thinkers during their post-Revolutionary exiles in Paris. Shestov, born into a Ukrainian-Jewish family in Kiev, had launched an attack on rationalism and systematization in philosophy as early as 1905 in his book of aphorisms All Things Are Possible.

Berdyaev, also from Kiev but with a background in the Eastern Orthodox Church, drew a radical distinction between the world of spirit and the everyday world of objects. Human freedom, for Berdyaev, is rooted in the realm of spirit, a realm independent of scientific notions of causation. To the extent the individual human being lives in the objective world, he is estranged from authentic spiritual freedom. "Man" is not to be interpreted naturalistically, but as a being created in God's image, an originator of free, creative acts.[54] He published a major work on these themes, The Destiny of Man, in 1931.

Gabriel Marcel, long before coining the term "existentialism", introduced important existentialist themes to a French audience in his early essay "Existence and Objectivity" (1925) and in his Metaphysical Journal (1927).[55] A dramatist as well as a philosopher, Marcel found his philosophical starting point in a condition of metaphysical alienation: the human individual searching for harmony in a transient life. Harmony, for Marcel, was to be sought through "secondary reflection", a "dialogical" rather than "dialectical" approach to the world, characterized by "wonder and astonishment" and open to the "presence" of other people and of God rather than merely to "information" about them. For Marcel, such presence implied more than simply being there (as one thing might be in the presence of another thing); it connoted "extravagant" availability, and the willingness to put oneself at the disposal of the other.[56]

Marcel contrasted secondary reflection with abstract, scientific-technical primary reflection, which he associated with the activity of the abstract Cartesian ego. For Marcel, philosophy was a concrete activity undertaken by a sensing, feeling human being incarnate—embodied—in a concrete world.[55][57] Although Jean-Paul Sartre adopted the term "existentialism" for his own philosophy in the 1940s, Marcel's thought has been described as "almost diametrically opposed" to that of Sartre.[55] Unlike Sartre, Marcel was a Christian, and became a Catholic convert in 1929.

In Germany, the psychologist and philosopher Karl Jaspers—who later described existentialism as a "phantom" created by the public[58]—called his own thought, heavily influenced by Kierkegaard and Nietzsche, Existenzphilosophie. For Jaspers, "Existenz-philosophy is the way of thought by means of which man seeks to become himself...This way of thought does not cognize objects, but elucidates and makes actual the being of the thinker".[59]

Jaspers, a professor at the University of Heidelberg, was acquainted with Martin Heidegger, who held a professorship at Marburg before acceding to Husserl's chair at Freiburg in 1928. They held many philosophical discussions, but later became estranged over Heidegger's support of National Socialism (Nazism). They shared an admiration for Kierkegaard,[60] and in the 1930s, Heidegger lectured extensively on Nietzsche. Nevertheless, the extent to which Heidegger should be considered an existentialist is debatable. In Being and Time he presented a method of rooting philosophical explanations in human existence (Dasein) to be analysed in terms of existential categories (existentiale); and this has led many commentators to treat him as an important figure in the existentialist movement.

After the Second World War

Following the Second World War, existentialism became a well-known and significant philosophical and cultural movement, mainly through the public prominence of two French writers, Jean-Paul Sartre and Albert Camus, who wrote best-selling novels, plays and widely read journalism as well as theoretical texts.[61] These years also saw the growing reputation of Heidegger's book Being and Time outside Germany.


French philosophers Jean-Paul Sartre and Simone de Beauvoir

Sartre dealt with existentialist themes in his 1938 novel Nausea and the short stories in his 1939 collection The Wall, and had published his treatise on existentialism, Being and Nothingness, in 1943, but it was in the two years following the liberation of Paris from the German occupying forces that he and his close associates—Camus, Simone de Beauvoir, Maurice Merleau-Ponty, and others—became internationally famous as the leading figures of a movement known as existentialism.[62] In a very short period of time, Camus and Sartre in particular became the leading public intellectuals of post-war France, achieving by the end of 1945 "a fame that reached across all audiences."[63] Camus was an editor of the most popular leftist (former French Resistance) newspaper Combat; Sartre launched his journal of leftist thought, Les Temps Modernes, and two weeks later gave the widely reported lecture on existentialism and secular humanism to a packed meeting of the Club Maintenant. Beauvoir wrote that "not a week passed without the newspapers discussing us";[64] existentialism became "the first media craze of the postwar era."[65]

By the end of 1947, Camus' earlier fiction and plays had been reprinted, his new play Caligula had been performed and his novel The Plague published; the first two novels of Sartre's The Roads to Freedom trilogy had appeared, as had Beauvoir's novel The Blood of Others. Works by Camus and Sartre were already appearing in foreign editions. The Paris-based existentialists had become famous.[62]

Sartre had traveled to Germany in 1930 to study the phenomenology of Edmund Husserl and Martin Heidegger,[66] and he included critical comments on their work in his major treatise Being and Nothingness. Heidegger's thought had also become known in French philosophical circles through its use by Alexandre Kojève in explicating Hegel in a series of lectures given in Paris in the 1930s.[67] The lectures were highly influential; members of the audience included not only Sartre and Merleau-Ponty, but Raymond Queneau, Georges Bataille, Louis Althusser, André Breton, and Jacques Lacan.[68] A selection from Heidegger's Being and Time was published in French in 1938, and his essays began to appear in French philosophy journals.


French-Algerian philosopher, novelist, and playwright Albert Camus

Heidegger read Sartre's work and was initially impressed, commenting: "Here for the first time I encountered an independent thinker who, from the foundations up, has experienced the area out of which I think. Your work shows such an immediate comprehension of my philosophy as I have never before encountered."[69] Later, however, in response to a question posed by his French follower Jean Beaufret,[70] Heidegger distanced himself from Sartre's position and existentialism in general in his Letter on Humanism.[71] Heidegger's reputation continued to grow in France during the 1950s and 1960s. In the 1960s, Sartre attempted to reconcile existentialism and Marxism in his work Critique of Dialectical Reason. A major theme throughout his writings was freedom and responsibility.

Camus was a friend of Sartre, until their falling-out, and wrote several works with existential themes including The Rebel, Summer in Algiers, The Myth of Sisyphus, and The Stranger, the latter being "considered—to what would have been Camus's irritation—the exemplary existentialist novel."[72] Camus, like many others, rejected the existentialist label, and considered his works concerned with facing the absurd. In the titular book, Camus uses the analogy of the Greek myth of Sisyphus to demonstrate the futility of existence. In the myth, Sisyphus is condemned for eternity to roll a rock up a hill, but when he reaches the summit, the rock will roll to the bottom again. Camus believes that this existence is pointless but that Sisyphus ultimately finds meaning and purpose in his task, simply by continually applying himself to it. The first half of the book contains an extended rebuttal of what Camus took to be existentialist philosophy in the works of Kierkegaard, Shestov, Heidegger, and Jaspers.

Simone de Beauvoir, an important existentialist who spent much of her life as Sartre's partner, wrote about feminist and existentialist ethics in her works, including The Second Sex and The Ethics of Ambiguity. Although often overlooked due to her relationship with Sartre,[73] de Beauvoir integrated existentialism with other forms of thinking such as feminism, unheard of at the time, resulting in alienation from fellow writers such as Camus.[52]

Paul Tillich, an important existentialist theologian following Kierkegaard and Karl Barth, applied existentialist concepts to Christian theology, and helped introduce existential theology to the general public. His seminal work The Courage to Be follows Kierkegaard's analysis of anxiety and life's absurdity, but puts forward the thesis that modern humans must, via God, achieve selfhood in spite of life's absurdity. Rudolf Bultmann used Kierkegaard's and Heidegger's philosophy of existence to demythologize Christianity by interpreting Christian mythical concepts into existentialist concepts.

Maurice Merleau-Ponty, an existential phenomenologist, was for a time a companion of Sartre. Merleau-Ponty's Phenomenology of Perception (1945) was recognized as a major statement of French existentialism.[74] It has been said that Merleau-Ponty's work Humanism and Terror greatly influenced Sartre. However, in later years they were to disagree irreparably, dividing many existentialists such as de Beauvoir,[52] who sided with Sartre.

Colin Wilson, an English writer, published his study The Outsider in 1956, initially to critical acclaim. In this book and others (e.g. Introduction to the New Existentialism), he attempted to reinvigorate what he perceived as a pessimistic philosophy and bring it to a wider audience. He was not, however, academically trained, and his work was attacked by professional philosophers for lack of rigor and critical standards.[75]

Influence outside philosophy

Art

Film and television

Stanley Kubrick's 1957 anti-war film Paths of Glory "illustrates, and even illuminates...existentialism" by examining the "necessary absurdity of the human condition" and the "horror of war".[76] The film tells the story of a fictional World War I French army regiment ordered to attack an impregnable German stronghold; when the attack fails, three soldiers are chosen at random, court-martialed by a "kangaroo court", and executed by firing squad. The film examines existentialist ethics, such as the issue of whether objectivity is possible and the "problem of authenticity".[76] Orson Welles' 1962 film The Trial, based upon Franz Kafka's book of the same name (Der Process), is characteristic of both existentialist and absurdist themes in its depiction of a man (Joseph K.) arrested for a crime for which the charges are neither revealed to him nor to the reader.

Neon Genesis Evangelion is a Japanese science fiction animation series created by the anime studio Gainax and was both directed and written by Hideaki Anno. Existential themes of individuality, consciousness, freedom, choice, and responsibility are heavily relied upon throughout the entire series, particularly through the philosophies of Jean-Paul Sartre and Søren Kierkegaard. Episode 16's title, "The Sickness Unto Death, And…" (死に至る病、そして Shi ni itaru yamai, soshite) is a reference to Kierkegaard's book, The Sickness Unto Death. Some contemporary films dealing with existentialist issues include Melancholia, Fight Club, I Heart Huckabees, Waking Life, The Matrix, Ordinary People, and Life in a Day.[77] Likewise, films throughout the 20th century such as The Seventh Seal, Ikiru, Taxi Driver, the Toy Story films, The Great Silence, Ghost in the Shell, Harold and Maude, High Noon, Easy Rider, One Flew Over the Cuckoo's Nest, A Clockwork Orange, Groundhog Day, Apocalypse Now, Badlands, and Blade Runner also have existentialist qualities.[78]

Notable directors known for their existentialist films include Ingmar Bergman, François Truffaut, Jean-Luc Godard, Michelangelo Antonioni, Akira Kurosawa, Terrence Malick, Stanley Kubrick, Andrei Tarkovsky, Hideaki Anno, Wes Anderson, Gaspar Noé, Woody Allen, and Christopher Nolan.[79] Charlie Kaufman's Synecdoche, New York focuses on the protagonist's desire to find existential meaning.[80] Similarly, in Kurosawa's Red Beard, the protagonist's experiences as an intern in a rural health clinic in Japan lead him to an existential crisis whereby he questions his reason for being. This, in turn, leads him to a better understanding of humanity. The French film, Mood Indigo (directed by Michel Gondry) embraced various elements of existentialism.[citation needed] The film The Shawshank Redemption, released in 1994, depicts life in a prison in Maine, United States to explore several existentialist concepts.[81]

Literature

Existential perspectives are also found in modern literature to varying degrees, especially since the 1920s. Louis-Ferdinand Céline's Journey to the End of the Night (Voyage au bout de la nuit, 1932) celebrated by both Sartre and Beauvoir, contained many of the themes that would be found in later existential literature, and is in some ways, the proto-existential novel. Jean-Paul Sartre's 1938 novel Nausea[82] was "steeped in Existential ideas", and is considered an accessible way of grasping his philosophical stance.[83] Between 1900 and 1960, other authors such as Albert Camus, Franz Kafka, Rainer Maria Rilke, T.S. Eliot, Herman Hesse, Luigi Pirandello,[24][25][27][84][85][86] Ralph Ellison,[87][88][89][90] and Jack Kerouac, composed literature or poetry that contained, to varying degrees, elements of existential or proto-existential thought. The philosophy's influence even reached pulp literature shortly after the turn of the 20th century, as seen in the existential disparity witnessed in Man's lack of control of his fate in the works of H.P. Lovecraft.[91] Since the late 1960s, a great deal of cultural activity in literature contains postmodernist as well as existential elements. Books such as Do Androids Dream of Electric Sheep? (1968) (now republished as Blade Runner) by Philip K. Dick, Slaughterhouse-Five by Kurt Vonnegut, Fight Club by Chuck Palahniuk and Formless Meanderings by Bharath Srinivasan[92] all distort the line between reality and appearance while simultaneously espousing existential themes.

Theatre

Jean-Paul Sartre wrote No Exit in 1944, an existentialist play originally published in French as Huis Clos (meaning In Camera or "behind closed doors"), which is the source of the popular quote, "Hell is other people." (In French, "L'enfer, c'est les autres"). The play begins with a Valet leading a man into a room that the audience soon realizes is in hell. Eventually he is joined by two women. After their entry, the Valet leaves and the door is shut and locked. All three expect to be tortured, but no torturer arrives. Instead, they realize they are there to torture each other, which they do effectively by probing each other's sins, desires, and unpleasant memories.

Existentialist themes are displayed in the Theatre of the Absurd, notably in Samuel Beckett's Waiting for Godot, in which two men divert themselves while they wait expectantly for someone (or something) named Godot who never arrives. They claim Godot is an acquaintance, but in fact, hardly know him, admitting they would not recognize him if they saw him. Samuel Beckett, once asked who or what Godot is, replied, "If I knew, I would have said so in the play." To occupy themselves, the men eat, sleep, talk, argue, sing, play games, exercise, swap hats, and contemplate suicide—anything "to hold the terrible silence at bay".[93] The play "exploits several archetypal forms and situations, all of which lend themselves to both comedy and pathos."[94] The play also illustrates an attitude toward human experience on earth: the poignancy, oppression, camaraderie, hope, corruption, and bewilderment of human experience that can be reconciled only in the mind and art of the absurdist. The play examines questions such as death, the meaning of human existence and the place of God in human existence.

Tom Stoppard's Rosencrantz & Guildenstern Are Dead is an absurdist tragicomedy first staged at the Edinburgh Festival Fringe in 1966.[95] The play expands upon the exploits of two minor characters from Shakespeare's Hamlet. Comparisons have also been drawn to Samuel Beckett's Waiting For Godot, for the presence of two central characters who appear almost as two halves of a single character. Many plot features are similar as well: the characters pass time by playing Questions, impersonating other characters, and interrupting each other or remaining silent for long periods of time. The two characters are portrayed as two clowns or fools in a world beyond their understanding. They stumble through philosophical arguments while not realizing the implications, and muse on the irrationality and randomness of the world.

Jean Anouilh's Antigone also presents arguments founded on existentialist ideas.[96] It is a tragedy inspired by Greek mythology and the play of the same name (Antigone, by Sophocles) from the 5th century BC. In English, it is often distinguished from its antecedent by being pronounced in its original French form, approximately "Ante-GŌN." The play was first performed in Paris on 6 February 1944, during the Nazi occupation of France. Produced under Nazi censorship, the play is purposefully ambiguous with regards to the rejection of authority (represented by Antigone) and the acceptance of it (represented by Creon). The parallels to the French Resistance and the Nazi occupation have been drawn. Antigone rejects life as desperately meaningless but without affirmatively choosing a noble death. The crux of the play is the lengthy dialogue concerning the nature of power, fate, and choice, during which Antigone says that she is, "... disgusted with [the]...promise of a humdrum happiness." She states that she would rather die than live a mediocre existence.

Critic Martin Esslin in his book Theatre of the Absurd pointed out how many contemporary playwrights such as Samuel Beckett, Eugène Ionesco, Jean Genet, and Arthur Adamov wove into their plays the existentialist belief that we are absurd beings loose in a universe empty of real meaning. Esslin noted that many of these playwrights demonstrated the philosophy better than did the plays by Sartre and Camus. Though most of such playwrights, subsequently labeled "Absurdist" (based on Esslin's book), denied affiliations with existentialism and were often staunchly anti-philosophical (for example Ionesco often claimed he identified more with 'Pataphysics or with Surrealism than with existentialism), the playwrights are often linked to existentialism based on Esslin's observation.[97]

Psychoanalysis and psychotherapy

A major offshoot of existentialism as a philosophy is existentialist psychology and psychoanalysis, which first crystallized in the work of Otto Rank, Freud's closest associate for 20 years. Without awareness of the writings of Rank, Ludwig Binswanger was influenced by Freud, Edmund Husserl, Heidegger, and Sartre. A later figure was Viktor Frankl, who briefly met Freud and studied with Jung as a young man.[98] His logotherapy can be regarded as a form of existentialist therapy. The existentialists would also influence social psychology, antipositivist micro-sociology, symbolic interactionism, and post-structuralism, with the work of thinkers such as Georg Simmel[99] and Michel Foucault. Foucault was a great reader of Kierkegaard even though he almost never refers this author, who nonetheless had for him an importance as secret as it was decisive.[100]

An early contributor to existentialist psychology in the United States was Rollo May, who was strongly influenced by Kierkegaard and Otto Rank. One of the most prolific writers on techniques and theory of existentialist psychology in the USA is Irvin D. Yalom. Yalom states that
Aside from their reaction against Freud's mechanistic, deterministic model of the mind and their assumption of a phenomenological approach in therapy, the existentialist analysts have little in common and have never been regarded as a cohesive ideological school. These thinkers—who include Ludwig Binswanger, Medard Boss, Eugène Minkowski, V.E. Gebsattel, Roland Kuhn, G. Caruso, F.T. Buytendijk, G. Bally and Victor Frankl—were almost entirely unknown to the American psychotherapeutic community until Rollo May's highly influential 1985 book Existence—and especially his introductory essay—introduced their work into this country.[101]
A more recent contributor to the development of a European version of existentialist psychotherapy is the British-based Emmy van Deurzen.

Anxiety's importance in existentialism makes it a popular topic in psychotherapy. Therapists often offer existentialist philosophy as an explanation for anxiety. The assertion is that anxiety is manifested of an individual's complete freedom to decide, and complete responsibility for the outcome of such decisions. Psychotherapists using an existentialist approach believe that a patient can harness his anxiety and use it constructively. Instead of suppressing anxiety, patients are advised to use it as grounds for change. By embracing anxiety as inevitable, a person can use it to achieve his full potential in life. Humanistic psychology also had major impetus from existentialist psychology and shares many of the fundamental tenets. Terror management theory, based on the writings of Ernest Becker and Otto Rank, is a developing area of study within the academic study of psychology. It looks at what researchers claim are implicit emotional reactions of people confronted with the knowledge that they will eventually die.

Also, Gerd B. Achenbach has refreshed the Socratic tradition with his own blend of philosophical counseling. So did Michel Weber with his Chromatiques Center in Belgium.

Criticisms

General criticisms

Walter Kaufmann criticized 'the profoundly unsound methods and the dangerous contempt for reason that have been so prominent in existentialism.'[102] Logical positivist philosophers, such as Rudolf Carnap and A. J. Ayer, assert that existentialists are often confused about the verb "to be" in their analyses of "being".[103] Specifically, they argue that the verb "is" is transitive and pre-fixed to a predicate (e.g., an apple is red) (without a predicate, the word "is" is meaningless), and that existentialists frequently misuse the term in this manner. Colin Wilson has stated in his book The Angry Years that existentialism has created many of its own difficulties: "we can see how this question of freedom of the will has been vitiated by post-romantic philosophy, with its inbuilt tendency to laziness and boredom, we can also see how it came about that existentialism found itself in a hole of its own digging, and how the philosophical developments since then have amounted to walking in circles round that hole".[104]

Sartre's philosophy

Many critics argue Jean-Paul Sartre's philosophy is contradictory. Specifically, they argue that Sartre makes metaphysical arguments despite his claiming that his philosophical views ignore metaphysics.
Herbert Marcuse criticized Sartre's 1943 Being and Nothingness for projecting anxiety and meaninglessness onto the nature of existence itself: "Insofar as Existentialism is a philosophical doctrine, it remains an idealistic doctrine: it hypostatizes specific historical conditions of human existence into ontological and metaphysical characteristics. Existentialism thus becomes part of the very ideology which it attacks, and its radicalism is illusory".[105]

In Letter on Humanism, Martin Heidegger criticized Sartre's existentialism:
Existentialism says existence precedes essence. In this statement he is taking existentia and essentia according to their metaphysical meaning, which, from Plato's time on, has said that essentia precedes existentia. Sartre reverses this statement. But the reversal of a metaphysical statement remains a metaphysical statement. With it, he stays with metaphysics, in oblivion of the truth of Being.[106]

Organ-on-a-chip

From Wikipedia, the free encyclopedia
 
An organ-on-a-chip (OOC) is a multi-channel 3-D microfluidic cell culture chip that simulates the activities, mechanics and physiological response of entire organs and organ systems, a type of artificial organ.[1] It constitutes the subject matter of significant biomedical engineering research, more precisely in bio-MEMS. The convergence of labs-on-chips (LOCs) and cell biology has permitted the study of human physiology in an organ-specific context, introducing a novel model of in vitro multicellular human organisms. One day, they will perhaps abolish the need for animals in drug development and toxin testing.

Although multiple publications claim to have translated organ functions onto this interface, the movement towards this microfluidic application is still in its infancy. Organs-on-chips will vary in design and approach between different researchers. As such, validation and optimization of these systems will likely be a long process. Organs that have been simulated by microfluidic devices include the heart, the lung, kidney, artery, bone, cartilage, skin and more.

Nevertheless, building valid artificial organs requires not only a precise cellular manipulation, but a detailed understanding of the human body’s fundamental intricate response to any event. A common concern with organs-on-chips lies in the isolation of organs during testing. "If you don’t use as close to the total physiological system that you can, you’re likely to run into troubles"[1] says William Haseltine, founder of Human Genome Sciences in Rockville, Maryland. Microfabrication, microelectronics and microfluidics offer the prospect of modeling sophisticated in vitro physiological responses under accurately simulated conditions.

Lab-on-chip

A lab-on-a-chip is a device that integrates one or several laboratory functions on a single chip that deals with handling particles in hollow microfluidic channels. It has been developed for over a decade. Advantages in handling particles at such a small scale include lowering fluid volume consumption (lower reagents costs, less waste), increasing portability of the devices, increasing process control (due to quicker thermo-chemical reactions) and decreasing fabrication costs. Additionally, microfluidic flow is entirely laminar (i.e., no turbulence). Consequently, there is virtually no mixing between neighboring streams in one hollow channel. In cellular biology convergence, this rare property in fluids has been leveraged to better study complex cell behaviors, such as cell motility in response to chemotactic stimuli, stem cell differentiation, axon guidance, subcellular propagation of biochemical signaling and embryonic development.[2]

Transitioning from 3D cell-culture models to OOCs

3D cell-culture models exceed 2D culture systems by promoting higher levels of cell differentiation and tissue organization. 3D culture systems are more successful because the flexibility of the ECM gels accommodates shape changes and cell-cell connections – formerly prohibited by rigid 2D culture substrates. Nevertheless, even the best 3D culture models fail to mimic an organ’s cellular properties in many aspects,[2] including tissue-to-tissue interfaces (e.g., epithelium and vascular endothelium), spatiotemporal gradients of chemicals, and the mechanically active microenvironments (e.g. arteries’ vasoconstriction and vasodilator responses to temperature differentials). The application of microfluidics in organs-on-chips enables the efficient transport and distribution of nutrients and other soluble cues throughout the viable 3D tissue constructs. Organs-on-chips are referred to as the next wave of 3D cell-culture models that mimic whole living organs’ biological activities, dynamic mechanical properties and biochemical functionalities.[1]

Organs

Lung-on-a-chip

Lung-on-a-chips are being designed in an effort to improve the physiological relevance of existing in vitro alveolar-capillary interface models.[3] Such a multifunctional microdevice can reproduce key structural, functional and mechanical properties of the human alveolar-capillary interface (i.e., the fundamental functional unit of the living lung).
Example
Dongeun Huh from Wyss Institute for Biologically Inspired Engineering at Harvard describes their fabrication of a system containing two closely apposed microchannels separated by a thin (10µm) porous flexible membrane made of PDMS.[4] The device largely comprises three microfluidic channels, and only the middle one holds the porous membrane. Culture cells were grown on either side of the membrane: human alveolar epithelial cells on one side, and human pulmonary microvascular endothelial cells on the other.
The compartmentalization of the channels facilitates not only the flow of air as a fluid which delivers cells and nutrients to the apical surface of the epithelium, but also allows for pressure differences to exist between the middle and side channels. During normal inspiration in a human’s respiratory cycle, intrapleural pressure decreases, triggering an expansion of the alveoli. As air is pulled into the lungs, alveolar epithelium and the coupled endothelium in the capillaries are stretched. Since a vacuum is connected to the side channels, a decrease in pressure will cause the middle channel to expand, thus stretching the porous membrane and subsequently, the entire alveolar-capillary interface. The pressure-driven dynamic motion behind the stretching of the membrane, also described as a cyclic mechanical strain (valued at approximately 10%), significantly increases the rate of nanoparticle translocation across the porous membrane, when compared to a static version of this device, and to a Transwell culture system.
In order to fully validate the biological accuracy of a device, its whole-organ responses must be evaluated. In this instance, researchers inflicted injuries to the cells:

Pulmonary inflammatory responses entail a multistep strategy, but alongside an increased production of epithelial cells and an early response release of cytokines, the interface should undergo an increased number of leukocyte adhesion molecules.[5] In Huh’s experiment, the pulmonary inflammation was simulated by introducing medium containing a potent proinflammatory mediator. Only hours after the injury was caused, the cells in the microfluidic device subjected to a cyclic strain reacted in accordance with the previously mentioned biological response.
  • Pulmonary infection
Living E-coli bacteria was used to demonstrate how the system can even mimic the innate cellular response to a bacterial pulmonary infection. The bacteria were introduced onto the apical surface of the alveolar epithelium. Within hours, neutrophils were detected in the alveolar compartment, meaning they had transmigrated from the vascular microchannel where the porous membrane had phagocytized the bacteria.
Additionally, researchers believe the potential value of this lung-on-a-chip system will aid in toxicology applications. By investigating the pulmonary response to nanoparticles, researchers hope to learn more about health risks in certain environments, and correct previously oversimplified in vitro models. Because a microfluidic lung-on-a-chip can more exactly reproduce the mechanical properties of a living human lung, its physiological responses will be quicker and more accurate than a Transwell culture system. Nevertheless, published studies admit that responses of a lung-on-a-chip don’t yet fully reproduce the responses of native alveolar epithelial cells.

Heart-on-a-chip

Past efforts to replicate in vivo cardiac tissue environments have proven to be challenging due to difficulties when mimicking contractility and electrophysiological responses. Such features would greatly increase the accuracy of in vitro experiments.

Microfluidics has already contributed to in vitro experiments on cardiomyocytes, which generate the electrical impulses that control the heart rate.[6] For instance, researchers have built an array of PDMS microchambers, aligned with sensors and stimulating electrodes as a tool that will electrochemically and optically monitor the cardiomyocytes’ metabolism.[7] Another lab-on-a-chip similarly combined a microfluidic network in PDMS with planar microelectrodes, this time to measure extracellular potentials from single adult murine cardiomyocytes.[8]
Example
Preparation of the Heart-on-a-chip substrate and contractility
test samples – After applying a stimulating the contraction of
the myocytes via the field electrodes, strips/teeth in the MTF
start to curl. Researchers have developed a correlation between
tissue stress and the radius of curvature of the MTF strips
during the contractile cycle, validating the demonstrated chip
as a heart-on-a-chip (in the realm of their respective needs).
A reported design of a heart-on-a-chip claims to have built "an efficient means of measuring structure-function relationships in constructs that replicate the hierarchical tissue architectures of laminar cardiac muscle."[9] This chip determines that the alignment of the myocytes in the contractile apparatus made of cardiac tissue and the gene expression profile (affected by shape and cell structure deformation) contributes to the force produced in cardiac contractility. This heart-on-a-chip is a biohybrid construct: an engineered anisotropic ventricular myocardium is an elastomeric thin film.
The design and fabrication process of this particular microfluidic device entails first covering the edges of a glass surface with tape (or any protective film) such as to contour the substrate’s desired shape. A spin coat layer of PNIPA is then applied. After its dissolution, the protective film is peeled away, resulting in a self-standing body of PNIPA. The final steps involve the spin coating of protective surface of PDMS over the cover slip and curing. Muscular thin films (MTF) enable cardiac muscle monolayers to be engineered on a thin flexible substrate of PDMS.[10] In order to properly seed the 2D cell culture, a microcontact printing technique was used to lay out a fibronectin "brick wall" pattern on the PDMS surface. Once the ventricular myocytes were seeded on the functionalized substrate, the fibronectin pattern oriented them to generate an anisotropic monolayer.
After the cutting of the thin films into two rows with rectangular teeth, and subsequent placement of the whole device in a bath, electrodes stimulate the contraction of the myocytes via a field-stimulation – thus curving the strips/teeth in the MTF. Researchers have developed a correlation between tissue stress and the radius of curvature of the MTF strips during the contractile cycle, validating the demonstrated chip as a "platform for quantification of stress, electrophysiology and cellular architecture."[9]

Kidney-on-a-chip

Renal cells and nephrons have already been simulated by microfluidic devices. "Such cell cultures can lead to new insights into cell and organ function and be used for drug screening".[11] A kidney-on-a-chip device has the potential to accelerate research encompassing artificial replacement for lost kidney function. Nowadays, dialysis requires patients to go to a clinic up to three times per week. A more transportable and accessible form of treatment would not only increase the patient’s overall health (by increasing frequency of treatment), but the whole process would become more efficient and tolerable.[12] Artificial kidney research is striving to bring transportability, wearability and perhaps implantation capability to the devices through innovative disciplines: microfluidics, miniaturization and nanotechnology.[13]
Example – nephron-on-a-chip
The nephron is the functional unit of the kidney and is composed of a glomerulus and a tubular component.[14] Researchers at MIT claim to have designed a bioartificial device that replicates the function of the nephron’s glomerulus, proximal convoluted tubule and loop of Henle.

Each part of the device has its unique design, generally consisting of two microfabricated layers separated by a membrane. The only inlet to the microfluidic device is designed for the entering blood sample. In the glomerulus’ section of the nephron, the membrane allows certain blood particles through its wall of capillary cells, composed by the endothelium, basement membrane and the epithelial podocytes. The fluid that is filtered from the capillary blood into Bowman’s space is called filtrate or primary urine.[15]

In the tubules, some substances are added to the filtrate as part of the urine formation, and some substances reabsorbed out of the filtrate and back into the blood. The first segment of these tubules is the proximal convoluted tubule. This is where the almost complete absorption of nutritionally important substances takes place. In the device, this section is merely a straight channel, but blood particles going to the filtrate have to cross the previously mentioned membrane and a layer of renal proximal tubule cells. The second segment of the tubules is the loop of Henle where the reabsorption of water and ions from the urine takes place. The device’s looping channels strives to simulate the countercurrent mechanism of the loop of Henle. Likewise, the loop of Henle requires a number of different cell types because each cell type has distinct transport properties and characteristics. These include the descending limb cells, thin ascending limb cells, thick ascending limb cells, cortical collecting duct cells and medullary collecting duct cells.[14]

One step towards validating the microfluidic device’s simulation of the full filtration and reabsorption behavior of a physiological nephron would include demonstrating that the transport properties between blood and filtrate are identical with regards to where they occur and what is being let in by the membrane. For example, the large majority of passive transport of water occurs in the proximal tubule and the descending thin limb, or the active transport of NaCl largely occurs in the proximal tubule and the thick ascending limb. The device’s design requirements would require the filtration fraction in the glomerulus to vary between 15–20%, or the filtration reabsorption in the proximal convoluted tubule to vary between 65–70%, and finally the urea concentration in urine (collected at one of the two outlets of the device) to vary between 200–400 mM.[16]

One recent report illustrates a biomimic nephron on hydrogel microfluidic devices with establishing the function of passive diffusion.[17] The complex physiological function of nephron is achieved on the basis of interactions between vessels and tubules (both are hollow channels).[18] However, conventional laboratory techniques usually focus on 2D structures, such as petri-dish that lacks capability to recapitulate real physiology that occurs in 3D. Therefore, the authors developed a new method to fabricate functional, cell-lining and perfusable microchannels inside 3D hydrogel. The vessel endothelial and renal epithelial cells are cultured inside hydrogel microchannel and form cellular coverage to mimic vessels and tubules, respectively. They employed confocal microscope to examine the passive diffusion of one small organic molecule (usually drugs) between the vessels and tubules in hydrogel. The study demonstrates the beneficial potential to mimic renal physiology for regenerative medicine and drug screening.

Artery-on-a-chip

Cardiovascular diseases are often caused by changes in structure and function of small blood vessels. For instance, self-reported rates of hypertension suggest that the rate is increasing, says a 2003 report from the National Health and Nutrition Examination Survey.[19] A microfluidic platform simulating the biological response of an artery could not only enable organ-based screens to occur more frequently throughout a drug development trial, but also yield a comprehensive understanding of the underlying mechanisms behind pathologic changes in small arteries and develop better treatment strategies. Axel Gunther from the University of Toronto argues that such MEMS-based devices could potentially help in the assessment of a patient’s microvascular status in a clinical setting (personalized medicine).[20]

Conventional methods used to examine intrinsic properties of isolated resistance vessels (arterioles and small arteries with diameters varying between 30 µm and 300 µm) include the pressure myography technique. However, such methods currently require manually skilled personnel and are not scalable. An artery-on-a-chip could overcome several of these limitations by accommodating an artery onto a platform which would be scalable, inexpensive and possibly automated in its manufacturing.
Example
An organ-based microfluidic platform has been developed as a lab-on-a-chip onto which a fragile blood vessel can be fixed, allowing for determinants of resistance artery malfunctions to be studied.

The artery microenvironment is characterized by surrounding temperature, transmural pressure, and luminal & abluminal drug concentrations. The multiple inputs from a microenvironment cause a wide range of mechanical or chemical stimuli on the smooth muscle cells (SMCs) and endothelial cells (ECs) that line the vessel’s outer and luminal walls, respectively. Endothelial cells are responsible for releasing vasoconstriction and vasodilator factors, thus modifying tone. Vascular tone is defined as the degree of constriction inside a blood vessel relative to its maximum diameter.[21] Pathogenic concepts currently believe that subtle changes to this microenvironment have pronounced effects on arterial tone and can severely alter peripheral vascular resistance. The engineers behind this design believe that a specific strength lies in its ability to control and simulate heterogeneous spatiotemporal influences found within the microenvironment, whereas myography protocols have, by virtue of their design, only established homogeneous microenvironments.[20] They proved that by delivering phenylephrine through only one of the two channels providing superfusion to the outer walls, the drug-facing side constricted much more than the drug opposing side.

The artery-on-a-chip is designed for reversible implantation of the sample. The device contains a microchannel network, an artery loading area and a separate artery inspection area. There is a microchannel used for loading the artery segment, and when the loading well is sealed, it is also used as a perfusion channel, to replicate the process of nutritive delivery of arterial blood to a capillary bed in the biological tissue.[22] Another pair of microchannels serves to fix the two ends of the arterial segment. Finally, the last pair of microchannels is used to provide superfusion flow rates, in order to maintain the physiological and metabolic activity of the organ by delivering a constant sustaining medium over the abluminal wall. A thermoelectric heater and a thermoresistor are connected to the chip and maintain physiological temperatures at the artery inspection area.

The protocol of loading and securing the tissue sample into the inspection zone helps understand how this approach acknowledges whole organ functions. After immersing the tissue segment into the loading well, the loading process is driven by a syringe withdrawing a constant flow rate of buffer solution at the far end of the loading channel. This causes the transport of the artery towards its dedicated position. This is done with closed fixation and superfusion in/outlet lines. After stopping the pump, sub-atmospheric pressure is applied through one of the fixation channels. Then after sealing the loading well shut, the second fixation channel is subjected to a sub-atmospheric pressure. Now the artery is symmetrically established in the inspection area, and a transmural pressure is felt by the segment. The remaining channels are opened and constant perfusion and superfusion are adjusted using separate syringe pumps.[20]

Skin-on-a-chip

A skin model on a biochip has been created by researchers at cellasys.[23]

Human-on-a-chip

Researchers are working towards building a multi-channel 3D microfluidic cell culture system that compartmentalizes microenvironments in which 3D cellular aggregates are cultured to mimic multiple organs in the body.[24] Most organ-on-a-chip models today only culture one cell type, so even though they may be valid models for studying whole organ functions, the systemic effect of a drug on the human body is not verified.

Conceptual schematic of a human-on-a-chip – Designing a
whole body biomimetic device will potentially correct one
of the most significant limitations on organs-on-chips: the
isolation of organs.

In particular, an integrated cell culture analog (µCCA) was developed and included lung cells, drug-metabolizing liver and fat cells. The cells were linked in a 2D fluidic network with culture medium circulating as a blood surrogate, thus efficiently providing a nutritional delivery transport system, while simultaneously removing wastes from the cells.[25] "The development of the µCCA laid the foundation for a realistic in vitro pharmacokinetic model and provided an integrated biomimetic system for culturing multiple cell types with high fidelity to in vivo situations", claim C. Zhang et al. They have developed a microfluidic human-on-a-chip, culturing four different cell types to mimic four human organs: liver, lung, kidney and fat.[26] They focused on developing a standard serum-free culture media that would be valuable to all cell types included in the device. Optimized standard media are generally targeted to one specific cell-type, whereas a human-on-a-chip will evidently require a common medium (CM). In fact, they claim to have identified a cell culture CM that, when used to perfuse all cell cultures in the microfluidic device, maintains the cells’ functional levels. Heightening the sensitivity of the in vitro cultured cells ensures the validity of the device, or that any drug injected into the microchannels will stimulate an identical physiological and metabolic reaction from the sample cells as whole organs in humans.

With more extensive development of this kind of chip, pharmaceutical companies will potentially be able to measure direct effects of one organ’s reaction on another. For instance, the delivery of biochemical substances would be screened to confirm that even though it may benefit one cell type, it does not compromise the functions of others. It is probably already possible to print these organs with 3D printers, but the cost is too high. Designing whole body biomimetic devices addresses a major reservation that pharmaceutical companies have towards organs-on-chips, namely the isolation of organs.[citation needed] As these devices become more and more accessible, the complexity of the design increases exponentially. Systems will soon have to simultaneously provide mechanical perturbation and fluid flow through a circulatory system. "Anything that requires dynamic control rather than just static control is a challenge", says Takayama from the University of Michigan.[27]

Replacing animal testing

In the early phase of drug development, animal models were the only way of obtaining in vivo data that would predict the human pharmacokinetic responses. However, experiments on animals are lengthy, expensive and controversial. For example, animal models are often subjected to mechanical or chemical techniques that simulate human injuries. There are also concerns with regards to the validity of such animal models, due to deficiency in cross-species extrapolation.[28] Moreover, animal models offer very limited control of individual variables and it can be cumbersome to harvest specific information.

Therefore, mimicking a human's physiological responses in an in vitro model needs to be made more affordable, and needs to offer cellular level control in biological experiments: biomimetic microfluidic systems could replace animal testing. The development of MEMS-based biochips that reproduce complex organ-level pathological responses could revolutionize many fields, including toxicology and the developmental process of pharmaceuticals and cosmetics that rely on animal testing and clinical trials.[29]

Recently, physiologically based perfusion in vitro systems have been developed to provide cell culture environment close to in vivo cell environment. A new testing platforms based on multi-compartmental perfused systems have gained a remarkable interest in pharmacology and toxicology. It aims to provide a cell culture environment close to the in vivo situation to reproduce more reliably in vivo mechanisms or ADME processes that involve its absorption, distribution, metabolism, and elimination. Perfused in vitro systems combined with kinetic modelling are promising tools for studying in vitro the different processes involved in the toxicokinetics of xenobiotics.

Efforts made toward the development of micro fabricated cell culture systems that aim to create models that replicate aspects of the human body as closely as possible and give examples that demonstrate their potential use in drug development, such as identifying synergistic drug interactions as well as simulating multi-organ metabolic interactions. Multi compartment micro fluidic-based devices, particularly those that are physical representations of physiologically based pharmacokinetic (PBPK) models that represent the mass transfer of compounds in compartmental models of the mammalian body, may contribute to improving the drug development process.

Mathematical pharmacokinetic (PK) models aim to estimate concentration-time profiles within each organ on the basis of the initial drug dose. Such mathematical models can be relatively simple, treating the body as a single compartment in which the drug distribution reaches a rapid equilibrium after administration. Mathematical models can be highly accurate when all parameters involved are known. Models that combine PK or PBPK models with PD models can predict the time-dependent pharmacological effects of a drug. We can nowadays predict with PBPK models the PK of about any chemical in humans, almost from first principles. These models can be either very simple, like statistical dose-response models, or sophisticated and based on systems biology, according to the goal pursued and the data available. All we need for those models are good parameter values for the molecule of interest.

Microfluidic cell culture systems such as micro cell culture analogs (μCCAs) could be used in conjunction with PBPK models. These μCCAs scaled-down devices, termed also body-on-a-chip devices, can simulate multi-tissue interactions under near-physiological fluid flow conditions and with realistic tissue-to-tissue size ratios . Data obtained with these systems may be used to test and refine mechanistic hypotheses. Microfabricating devices also allows us to custom-design them and scale the organs' compartments correctly with respect to one another.

Because the device can be used with both animal and human cells, it can facilitate cross-species extrapolation. Used in conjunction with PBPK models, the devices permit an estimation of effective concentrations that can be used for studies with animal models or predict the human response. In the development of multicompartment devices, representations of the human body such as those in used PBPK models can be used to guide the device design with regard to the arrangement of chambers and fluidic channel connections to augment the drug development process, resulting in increased success in clinical trials.

Molecular neuroscience

From Wikipedia, the free encyclopedia
 
Molecular neuroscience is a branch of neuroscience that observes concepts in molecular biology applied to the nervous systems of animals. The scope of this subject covers topics such as molecular neuroanatomy, mechanisms of molecular signaling in the nervous system, the effects of genetics and epigenetics on neuronal development, and the molecular basis for neuroplasticity and neurodegenerative diseases.[1] As with molecular biology, molecular neuroscience is a relatively new field that is considerably dynamic.

Locating neurotransmitters

In molecular biology, communication between neurons typically occurs by chemical transmission across gaps between the cells called synapses. The transmitted chemicals, known as neurotransmitters, regulate a significant fraction of vital body functions.[2] It is possible to anatomically locate neurotransmitters by labeling techniques. It is possible to chemically identify certain neurotransmitters such as catecholamines by fixing neural tissue sections with formaldehyde. This can give rise to formaldehyde-induced fluorescence when exposed to ultraviolet light. Dopamine, a catecholamine, was identified in the nematode C. elegans by using this technique.[3]  Immunocytochemistry, which involves raising antibodies against targeted chemical or biological entities, includes a few other techniques of interest. A targeted neurotransmitter could be specifically tagged by primary and secondary antibodies with radioactive labeling in order to identify the neurotransmitter by autoradiography. The presence of neurotransmitters (though not necessarily the location) can be observed in enzyme-linked immunocytochemistry or enzyme--linked immunosorbent assays (ELISA) in which substrate-binding in the enzymatic assays can induce precipitates, fluorophores, or chemiluminescence. In the event that neurotransmitters cannot be histochemically identified, an alternative method is to locate them by their neural uptake mechanisms.[1]

Voltage-gated ion channels

Structure of eukaryotic voltage-gated potassium ion channels

Excitable cells in living organisms have voltage-gated ion channels. These can be observed throughout the nervous system in neurons. The first ion channels to be characterized were the sodium and potassium ion channels by A.L. Hodgkin and A.F. Huxley in the 1950s upon studying the giant axon of the squid genus Loligo. Their research demonstrated the selective permeability of cellular membranes, dependent on physiological conditions, and the electrical effects that result from these permeabilities to produce action potentials.[4]

Sodium ion channels

Sodium channels were the first voltage-gated ion channels to be isolated in 1984 from the eel Electrophorus electricus by Shosaku Numa. The pufferfish toxin tetrodotoxin (TTX), a sodium channel blocker, was used to isolate the sodium channel protein by binding it using the column chromatography technique for chemical separation. The amino acid sequence of the protein was analyzed by Edman degradation and then used to construct a cDNA library which could be used to clone the channel protein. Cloning the channel itself allowed for applications such as identifying the same channels in other animals.[1] Sodium channels are known for working in concert with potassium channels during the development of graded potentials and action potentials. Sodium channels allow an influx of Na+ ions into a neuron, resulting in a depolarization from the resting membrane potential of a neuron to lead to a graded potential or action potential, depending on the degree of depolarization.[5]

Potassium ion channels

Potassium channels come in a variety of forms, are present in most eukaryotic cells, and typically tend to stabilize the cell membrane at the potassium equilibrium potential. As with sodium ions, graded potentials and action potentials are also dependent on potassium channels. While influx of Na+ ions into a neuron induce cellular depolarization, efflux of influx of K+ ions out of a neuron causes a cell to repolarize to resting membrane potential. The activation of potassium ion channels themselves are dependent on the depolarization resulting from Na+ influx during an action potential.[1] As with sodium channels, the potassium channels have their own toxins that block channel protein action. An example of such a toxin is the large cation, tetraethylammonium (TEA), but it is notable that the toxin does not have the same mechanism of action on all potassium channels, given the variety of channel types across species. The presence of potassium channels was first identified in Drosophila melanogaster mutant flies that shook uncontrollably upon anesthesia due to problems in cellular repolarization that led to abnormal neuron and muscle electrophysiology. Potassium channels were first identified by manipulating molecular genetics (of the flies) instead of performing channel protein purification because there were no known high-affinity ligands for potassium channels (such as TEA) at the time of discovery.[1][6]

Calcium ion channels

Calcium channels are important for certain cell-signaling cascades as well as neurotransmitter release at axon terminals. A variety of different types of calcium ion channels are found in excitable cells. As with sodium ion channels, calcium ion channels have been isolated and cloned by chromatographic purification techniques. It is notable, as with the case of neurotransmitter release, that calcium channels can interact with intracelluar proteins and plays a strong role in signaling, especially in locations such as the sarcoplasmic reticulum of muscle cells.[1]

Receptors

Various types of receptors can be used for cell signaling and communication and can include ionotropic receptors and metabotropic receptors. These cell surface receptor types are differentiated by the mechanism and duration of action with ionotropic receptors being associated with fast signal transmission and metabotropic receptors being associated with slow signal transmission. Metabotropic receptors happen to cover a wide variety of cell-surface receptors with notably different signaling cascades.[1][5]

Ionotropic receptors

Prototypical depiction of ionotropic receptor in the case of Ca2+ ion flow

Ionotropic receptors, otherwise known as ligand-gated ion channels, are fast acting receptors that mediate neural and physiological function by ion channel flow with ligand-binding. Nicotinic, GABA, and Glutamate receptors are among some of the cell surface receptors regulated by ligand-gated ion channel flow. GABA is the brain's main inhibitory neurotransmitter and glutamate is the brain's main excitatory neurotransmitter.[1]

GABA receptors

GABAA and GABAC receptors are known to be ionotropic, while the GABAB receptor is metabotropic. GABAA receptors mediate fast inhibitory responses in the central nervous system (CNS) and are found on neurons, glial cells, and adrenal medulla cells. It is responsible for inducing Cl ion influx into cells, thereby reducing the probability that membrane depolarization will occur upon the arrival of a graded potential or an action potential. GABA receptors can also interact with non-endogenous ligands to influence activity. For example, the compound diazepam (marketed as Valium) is an allosteric agonist which increases the affinity of the receptor for GABA. The increased physiological inhibitory effects resulting from increased GABA binding make diazepam a useful tranquilizer or anticonvulsant (antiepileptic drugs). On the other hand, GABA receptors can also be targeted by decreasing Cl cellular influx with the effect of convulsants like picrotoxin. The antagonistic mechanism of action for this compound is not directly on the GABA receptor, but there are other compounds that are capable of allosteric inactivation, including T-butylbicyclophorothionate (TBPS) and pentylenetetrazole (PZT). Compared with GABAA, GABAC receptors have a higher affinity for GABA, they are likely to be longer-lasting in activity, and their responses are likely to be generated by lower GABA concentrations.[1]

Glutamate receptors

Ionotropic glutamate receptors can include NMDA, AMPA, and kainate receptors. These receptors are named after agonists that facilitate glutamate activity. NMDA receptors are notable for their excitatory mechanisms to affect neuronal plasticity in learning and memory, as well as neuropathologies such as stroke and epilepsy. NDMA receptors have multiple binding sites just like ionotropic GABA receptors and can be influenced by co-agonists such the glycine neurotransmitter or phencyclidine (PCP). The NMDA receptors carry a current by Ca2+ ions and can be blocked by extracellular Mg2+ ions depending on voltage and membrane potential. This Ca2+ influx is increased by excitatory postsynaptic potentials (EPSPs) produced by NMDA receptors, activating Ca2+-based signaling cascades (such as neurotransmitter release). AMPA generate shorter and larger excitatory postsynaptic currents than other ionotropic glutamate receptors.[5]

Nicotinic ACh receptors

Nicotinic receptors bind the acetylcholine (ACh) neurotransmitter to produce non-selective cation channel flow that generates excitatory postsynaptic responses. Receptor activity, which can be influenced by nicotine consumption, produces feelings of euphoria, relaxation, and inevitably addiction in high levels.[5]

Metabotropic receptors

G-protein-linked receptor signaling cascade

Metabotropic receptors, are slow response receptors in postsynaptic cells. Typically these slow responses are characterized by more elaborate intracellular changes in biochemistry. Responses of neurotransmitter uptake by metabotropic receptors can result in the activation of intracellualar enzymes and cascades involving second messengers, as is the case with G protein-linked receptors. Various metabotropic receptors can include certain glutamate receptors, muscarinic ACh receptors, GABAB receptors, and receptor tyrosine kinases.

G protein-linked receptors

The G protein-linked signaling cascade can significantly amplify the signal of a particular neurotransmitter to produce hundreds to thousands of second messengers in a cell. The mechanism of action by which G protein-linked receptors cause a signaling cascade is as follows:
  1. Neurotransmitter binds to the receptor
  2. The receptor undergoes a conformational change to allow G-protein complex binding
  3. GDP is exchanged with GTP upon G protein complex binding to the receptor
  4. The α-subunit of the G protein complex is bound to GTP and separates to bind with a target protein such as adenylate cyclase
  5. The binding to the target protein either increases or decreases the rate of second messenger (such as cyclic AMP) production
  6. GTPase hydrolyzes the α-subunit so that is bound to GDP and the α-subunit returns to the G protein complex inactive

Neurotransmitter release

Structure of a synapse where neurotransmitter release and uptake occurs

Neurotransmitters are released in discrete packets known as quanta from the axon terminal of one neuron to the dendrites of another across a synapse. These quanta have been identified by electron microscopy as synaptic vesicles. Two types of vesicles are small synaptic vessicles (SSVs), which are about 40-60nm in diameter, and large dense-core vesicles (LDCVs), electron-dense vesicles approximately 120-200nm in diameter.[1] The former is derived from endosomes and houses neurotransmitters such as acetylcholine, glutamate, GABA, and glycine. The latter is derived from the Golgi apparatus and houses larger neurotransmitters such as catecholamines and other peptide neurotransmitters.[7] Neurotransmitters are released from an axon terminal and bind to postsynaptic dendrites in the following procession:[5]
  1. Mobilization/recruitment of synaptic vesicle from cytoskeleton
  2. Docking of vesicle (binding) to presynaptic membrane
  3. Priming of vesicle by ATP (relatively slow step)
  4. Fusion of primed vesicle with presynaptic membrane and exocytosis of the housed neurotransmitter
  5. Uptake of neurotransmitters in receptors of a postsynaptic cell
  6. Initiation or inhibition of action potential in postsynaptic cell depending on whether the neurotransmitters are excitatory or inhibitory (excitatory will result in depolarization of the postsynaptic membrane)

Neurotransmitter release is calcium-dependent

Neurotransmitter release is dependent on an external supply of Ca2+ ions which enter axon terminals via voltage-gated calcium channels. Vesicular fusion with the terminal membrane and release of the neurotransmitter is caused by the generation of Ca2+ gradients induced by incoming action potentials. The Ca2+ ions cause the mobilization of newly synthesized vesicles from a reserve pool to undergo this membrane fusion. This mechanism of action was discovered in squid giant axons.[8] Lowering intracellular Ca2+ ions provides a direct inhibitory effect on neurotransmitter release.[1] After release of the neurotransmitter occurs, vesicular membranes are recycled to their origins of production. Calcium ion channels can vary depending on the location of incidence. For example, the channels at an axon terminal differ from the typical calcium channels of a cell body (whether neural or not). Even at axon terminals, calcium ion channel types can vary, as is the case with P-type calcium channels located at the neuromuscular junction.[1]

Neuronal gene expression

Sex differences

Differences in sex determination are controlled by sex chromosomes. Sex hormonal releases have a significant effect on sexual dimorphisms (phenotypic differentiation of sexual characteristics) of the brain. Recent studies seem to suggest that regulating these dimorphisms has implications for understanding normal and abnormal brain function. Sexual dimorphisms may be significantly influenced by sex-based brain gene expression which varies from species to species.

Animal models such as rodents, Drosophila melanogaster, and Caenorhabditis elegans, have been used to observe the origins and/or extent of sex bias in the brain versus the hormone-producing gonads of an animal. With the rodents, studies on genetic manipulation of sex chromosomes resulted in an effect on one sex that was completely opposite of the effect in the other sex. For example, a knockout of a particular gene only resulted in anxiety-like effects in males. With studies on D. menlanogaster it was found that a large brain sex bias of expression occurred even after the gonads were removed, suggesting that sex bias could be independent of hormonal control in certain aspects.[9]

Observing sex-biased genes has the potential for clinical significance in observing brain physiology and the potential for related (whether directly or indirectly) neurological disorders. Examples of diseases with sex biases in development include Huntington's disease, cerebral ischemia, and Alzheimer's disease.[9]

Epigenetics of the brain

Many brain functions can be influenced at the cellular and molecular level by variations and changes in gene expression, without altering the sequence of DNA in an organism. This is otherwise known as epigenetic regulation. Examples of epigenetic mechanisms include histone modifications and DNA methylation. Such changes have been found to be strongly influential in the incidence of brain disease, mental illness, and addiction.[10] Epigenetic control has been shown to be involved in high levels of plasticity in early development, thereby defining its importance in the critical period of an organism.[11] Examples of how epigenetic changes can affect the human brain are as follows:
  • Higher methylation levels in rRNA genes in the hippocampus of the brain results in a lower production of proteins and thus limited hippocampal function can result in learning and memory impairment and resultant suicidal tendencies.[12]
  • In a study comparing genetic differences between healthy people and psychiatric patients 60 different epigenetic markers associated with brain cell signaling were found.[12]
  • Environmental factors such as child abuse appears to cause the expression of an epigenetic tag on glucocorticoid receptors (associated with stress responses) that was not found in suicide victims.[12] This is an example of experience-dependent plasticity.
  • Environmental enrichment in individuals is associated with increased hippocampal gene histone acetylation and thus improved memory consolidation (notably spatial memory).[11]

Molecular mechanisms of neurodegenerative diseases

Excitotoxicity and glutamate receptors

Excitotoxicity is phenomenon in which glutamate receptors are inappropriately activated. It can be caused by prolonged excitatory synaptic transmission in which high levels of glutamate neurotransmitter cause excessive activation in a postsynaptic neuron that can result in the death of the postsynaptic neuron. Following brain injury (such as from ischemia), it has been found that excitotoxicity is a significant cause of neuronal damage. This can be understandable in the case where sudden perfusion of blood after reduced blood flow to the brain can result in excessive synaptic activity caused by the presence of increased glutamate and aspartate during the period of ischemia.[5][13]

Alzheimer's disease

Alzheimer's disease is the most common neurodegenerative disease and is the most common form of dementia in the elderly. The disorder is characterized by progressive loss of memory and various cognitive functions. It is hypothesized that the deposition of amyloid-β peptide (40-42 amino acid residues) in the brain is integral in the incidence of Alzheimer's disease. Accumulation is purported to block hippocampal long-term potentiation. It is also possible that a receptor for amyloid-β oligomers could be a prion protein.[14]

Parkinson's disease

Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease. It is a hypokinetic movement basal ganglia disease caused by the loss of dopaminergic neurons in the substantia nigra of the human brain. The inhibitory outflow of the basal ganglia is thus not decreased, and so upper motor neurons, mediated by the thalamus, are not activated in a timely manner. Specific symptoms include rigidity, postural problems, slow movements, and tremors. Blocking GABA receptor input from medium spiny neurons to reticulata cells, causes inhibition of upper motor neurons similar to the inhibition that occurs in Parkinson's disease.[5]

Huntington's disease

Huntington's disease is a hyperkinetic movement basal ganglia disease caused by lack of normal inhibitory inputs from medium spiny neurons of the basal ganglia. This poses the opposite effects of those associated with Parkinson's disease, including inappropriate activation of upper motor neurons. As with the GABAergic mechanisms observed in relation to Parkinson's disease, a GABA agonist injected into the substantia nigra pars reticulata decreases inhibition of upper motor neurons, resulting in ballistic involuntary motor movements, similar to symptoms of Huntington's disease.[5]

Platinum group

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