Monism

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https://en.wikipedia.org/wiki/Monism

The circled dot was used by the Pythagoreans and later Greeks to represent the first metaphysical being, the Monad or The Absolute

Monism attributes oneness or singleness (Greek: μόνος) to a concept e.g., existence. Various kinds of monism can be distinguished:

• Priority monism states that all existing things go back to a source that is distinct from them; e.g., in Neoplatonism everything is derived from The One. In this view only the One is ontologically basic or prior to everything else.
• Existence monism posits that, strictly speaking, there exists only a single thing, the universe, which can only be artificially and arbitrarily divided into many things.
• Substance monism asserts that a variety of existing things can be explained in terms of a single reality or substance. Substance monism posits that only one kind of substance exists, although many things may be made up of this substance, e.g., matter or mind.
• Dual-aspect monism is the view that the mental and the physical are two aspects of, or perspectives on, the same substance.
• Neutral monism believes the fundamental nature of reality to be neither mental nor physical; in other words it is "neutral".

Definitions

There are two sorts of definitions for monism:

1. The wide definition: a philosophy is monistic if it postulates unity of the origin of all things; all existing things return to a source that is distinct from them.
2. The restricted definition: this requires not only unity of origin but also unity of substance and essence.

Although the term monism is derived from Western philosophy to typify positions in the mind–body problem, it has also been used to typify religious traditions. In modern Hinduism, the term "absolute monism" is used for Advaita Vedanta.

History

The term monism was introduced in the 18th century by Christian von Wolff in his work Logic (1728), to designate types of philosophical thought in which the attempt was made to eliminate the dichotomy of body and mind and explain all phenomena by one unifying principle, or as manifestations of a single substance.

The mind–body problem in philosophy examines the relationship between mind and matter, and in particular the relationship between consciousness and the brain. The problem was addressed by René Descartes in the 17th century, resulting in Cartesian dualism, and by pre-Aristotelian philosophers, in Avicennian philosophy, and in earlier Asian and more specifically Indian traditions.

It was later also applied to the theory of absolute identity set forth by Hegel and Schelling. Thereafter the term was more broadly used, for any theory postulating a unifying principle. The opponent thesis of dualism also was broadened, to include pluralism. According to Urmson, as a result of this extended use, the term is "systematically ambiguous".

According to Jonathan Schaffer, monism lost popularity due to the emergence of analytic philosophy in the early twentieth century, which revolted against the neo-Hegelians. Rudolf Carnap and A. J. Ayer, who were strong proponents of positivism, "ridiculed the whole question as incoherent mysticism".

The mind–body problem has reemerged in social psychology and related fields, with the interest in mind–body interaction and the rejection of Cartesian mind–body dualism in the identity thesis, a modern form of monism. Monism is also still relevant to the philosophy of mind, where various positions are defended.

Types

A diagram with neutral monism compared to Cartesian dualism, physicalism and idealism.

Different types of monism include:

1. Substance monism, "the view that the apparent plurality of substances is due to different states or appearances of a single substance"
2. Attributive monism, "the view that whatever the number of substances, they are of a single ultimate kind"
3. Partial monism, "within a given realm of being (however many there may be) there is only one substance"
4. Existence monism, "the view that there is only one concrete object token (The One, "Τὸ Ἕν" or the Monad)"
5. Priority monism, "the whole is prior to its parts" or "the world has parts, but the parts are dependent fragments of an integrated whole"
6. Property monism, "the view that all properties are of a single type (e.g., only physical properties exist)"
7. Genus monism, "the doctrine that there is a highest category; e.g., being"

Views contrasting with monism are:

• Metaphysical dualism, which asserts that there are two ultimately irreconcilable substances or realities such as Good and Evil, for example, Manichaeism.
• Metaphysical pluralism, which asserts three or more fundamental substances or realities.
• Metaphysical nihilism, negates any of the above categories (substances, properties, concrete objects, etc.).

Monism in modern philosophy of mind can be divided into three broad categories:

1. Idealist, mentalistic monism, which holds that only mind or spirit exists
2. Neutral monism, which holds that one sort of thing fundamentally exists, to which both the mental and the physical can be reduced
3. Material monism (also called Physicalism and materialism), which holds that the material world is primary, and consciousness arises through the interaction with the material world
   1. Eliminative Materialism, according to which everything is physical and mental things do not exist
   2. Reductive physicalism, according to which mental things do exist and are a kind of physical thing

Certain positions do not fit easily into the above categories, such as functionalism, anomalous monism, and reflexive monism. Moreover, they do not define the meaning of "real".

Monistic philosophers

Pre-Socratic

While the lack of information makes it difficult in some cases to be sure of the details, the following pre-Socratic philosophers thought in monistic terms:

• Thales: Water
• Anaximander: Apeiron (meaning 'the undefined infinite'). Reality is some, one thing, but we cannot know what.
• Anaximenes of Miletus: Air
• Heraclitus: Change, symbolized by fire (in that everything is in constant flux).
• Parmenides: Being or Reality is an unmoving perfect sphere, unchanging, undivided.

Post-Socrates

• Neopythagorians such as Apollonius of Tyana centered their cosmologies on the Monad or One.
• Stoics taught that there is only one substance, identified as God.
• Middle Platonism under such works as those by Numenius taught that the Universe emanates from the Monad or One.
• Neoplatonism is monistic. Plotinus taught that there was an ineffable transcendent god, 'The One,' of which subsequent realities were emanations. From The One emanates the Divine Mind (Nous), the Cosmic Soul (Psyche), and the World (Cosmos).

Modern

• Alexander Bogdanov
• F. H. Bradley
• Giordano Bruno
• Gilles Deleuze
• Friedrich Engels
• Johann Gottlieb Fichte
• Ernst Haeckel
• Georg Wilhelm Friedrich Hegel
• Christopher Langan
• Gottfried Wilhelm Leibniz
• Giacomo Leopardi
• Ernst Mach
• Karl Marx
• Wilhelm Ostwald
• Charles Sanders Peirce
• Georgi Plekhanov
• Michael Della Rocca
• Bertrand Russell
• Gilbert Ryle
• Jonathan Schaffer
• Friedrich Wilhelm Joseph Schelling
• Arthur Schopenhauer
• Rupert Sheldrake
• B.F. Skinner
• Herbert Spencer
• Baruch Spinoza
• Rudolf Steiner
• Alan Watts
• Alfred North Whitehead

Monistic neuroscientists

• György Buzsáki
• Francis Crick
• Karl Friston
• Eric Kandel
• Mark Solms
• Rodolfo Llinas
• Ivan Pavlov
• Roger Sperry

Religion

Pantheism

Main article: Pantheism

Pantheism is the belief that everything composes an all-encompassing, immanent God, or that the universe (or nature) is identical with divinity. Pantheists thus do not believe in a personal or anthropomorphic god, but believe that interpretations of the term differ.

Pantheism was popularized in the modern era as both a theology and philosophy based on the work of the 17th-century philosopher Baruch Spinoza, whose Ethics was an answer to Descartes' famous dualist theory that the body and spirit are separate. Spinoza held that the two are the same, and this monism is a fundamental quality of his philosophy. He was described as a "God-intoxicated man," and used the word God to describe the unity of all substance. Although the term pantheism was not coined until after his death, Spinoza is regarded as its most celebrated advocate.

H. P. Owen claimed that

Pantheists are "monists" ... they believe that there is only one Being, and that all other forms of reality are either modes (or appearances) of it or identical with it.

Pantheism is closely related to monism, as pantheists too believe all of reality is one substance, called Universe, God or Nature. Panentheism, a slightly different concept (explained below), however is dualistic. Some of the most famous pantheists are the Stoics, Giordano Bruno and Spinoza.

Panentheism

Main article: Panentheism

Panentheism (from Greek πᾶν (pân) "all"; ἐν (en) "in"; and θεός (theós) "God"; "all-in-God") is a belief system that posits that the divine (be it a monotheistic God, polytheistic gods, or an eternal cosmic animating force) interpenetrates every part of nature, but is not one with nature. Panentheism differentiates itself from pantheism, which holds that the divine is synonymous with the universe.

In panentheism, there are two types of substance, "pan" the universe and God. The universe and the divine are not ontologically equivalent. God is viewed as the eternal animating force within the universe. In some forms of panentheism, the cosmos exists within God, who in turn "transcends", "pervades" or is "in" the cosmos.

While pantheism asserts that 'All is God', panentheism claims that God animates all of the universe, and also transcends the universe. In addition, some forms indicate that the universe is contained within God, like in the Judaic concept of Tzimtzum. Much Hindu thought is highly characterized by panentheism and pantheism.

Paul Tillich has argued for such a concept within Christian theology, as has liberal biblical scholar Marcus Borg and mystical theologian Matthew Fox, an Episcopal priest.

Pandeism

Main article: Pandeism

Pandeism or pan-deism (from Ancient Greek: πᾶν, romanized: pan, lit. 'all' and Latin: deus meaning "god" in the sense of deism), is a term describing beliefs coherently incorporating or mixing logically reconcilable elements of pantheism (that "God", or a metaphysically equivalent creator deity, is identical to Nature) and classical deism (that the creator-god who designed the universe no longer exists in a status where it can be reached, and can instead be confirmed only by reason). It is therefore most particularly the belief that the creator of the universe actually became the universe, and so ceased to exist as a separate entity.

Through this synergy pandeism claims to answer primary objections to deism (why would God create and then not interact with the universe?) and to pantheism (how did the universe originate and what is its purpose?).

Indian religions

Characteristics

The central problem in Asian (religious) philosophy is not the body-mind problem, but the search for an unchanging Real or Absolute beyond the world of appearances and changing phenomena, and the search for liberation from dukkha and the liberation from the cycle of rebirth. In Hinduism, substance-ontology prevails, seeing Brahman as the unchanging real beyond the world of appearances. In Buddhism, process ontology is prevalent, seeing reality as empty of an unchanging essence.

Characteristic for various Asian religions is the discernment of levels of truth, an emphasis on intuitive-experiential understanding of the Absolute such as jnana, bodhi and kensho, and an emphasis on the integration of these levels of truth and its understanding.

Hinduism

Main articles: Hinduism, Hindu philosophy, and Hindu denominations

Vedanta

Main article: Vedanta

 

Adi Shankara with Disciples, by Raja Ravi Varma (1904)

Vedanta is the inquiry into and systematisation of the Vedas and Upanishads, to harmonise the various and contrasting ideas that can be found in those texts. Within Vedanta, different schools exist:

• Advaita Vedanta, absolute monism, of which Adi Shankara is the best-known representative;
• Vishishtadvaita, qualified monism, is from the school of Ramanuja;
• Shuddhadvaita, in-essence monism, is the school of Vallabha;
• Dvaitadvaita, differential monism, is a school founded by Nimbarka;
• Dvaita, dualism, is a school founded by Madhvacharya is probably the only Vedantic System that is opposed to all types of monism. It believes that God is eternally different from souls and matter in both form and essence.
• Achintya Bheda Abheda, a school of Vedanta founded by Chaitanya Mahaprabhu representing the philosophy of inconceivable one-ness and difference. It can be understood as an integration of the strict dualist (dvaita) theology of Madhvacharya and the qualified monism (vishishtadvaita) of Ramanuja.

Advaita Vedanta

Main article: Advaita Vedanta

Monism is most clearly identified in Advaita Vedanta, though Renard points out that this may be a western interpretation, bypassing the intuitive understanding of a nondual reality.

In Advaita Vedanta, Brahman is the eternal, unchanging, infinite, immanent, and transcendent reality which is the Divine Ground of all matter, energy, time, space, being, and everything beyond in this Universe. The nature of Brahman is described as transpersonal, personal and impersonal by different philosophical schools.

Advaita Vedanta gives an elaborate path to attain moksha. It entails more than self-inquiry or bare insight into one's real nature. Practice, especially Jnana Yoga, is needed to "destroy one's tendencies (vāasanā-s)" before real insight can be attained.

Advaita took over from the Madhyamika the idea of levels of reality. Usually two levels are being mentioned, but Shankara uses sublation as the criterion to postulate an ontological hierarchy of three levels:

• Pāramārthika (paramartha, absolute), the absolute level, "which is absolutely real and into which both other reality levels can be resolved". This experience can't be sublated by any other experience.
• Vyāvahārika (vyavahara), or samvriti-saya (empirical or pragmatical), "our world of experience, the phenomenal world that we handle every day when we are awake". It is the level in which both jiva (living creatures or individual souls) and Iswara are true; here, the material world is also true.
• Prāthibhāṣika (pratibhashika, apparent reality, unreality), "reality based on imagination alone". It is the level in which appearances are actually false, like the illusion of a snake over a rope, or a dream.

Vaishnava

Main article: Vaishnavism

All Vaishnava schools are panentheistic and view the universe as part of Krishna or Narayana, but see a plurality of souls and substances within Brahman. Monistic theism, which includes the concept of a personal god as a universal, omnipotent Supreme Being who is both immanent and transcendent, is prevalent within many other schools of Hinduism as well.

Tantra

Main article: Tantra

Tantra sees the Divine as both immanent and transcendent. The Divine can be found in the concrete world. Practices are aimed at transforming the passions, instead of transcending them.

Modern Hinduism

Main article: Hindu reform movements

The colonisation of India by the British had a major impact on Hindu society. In response, leading Hindu intellectuals started to study western culture and philosophy, integrating several western notions into Hinduism. This modernised Hinduism, at its turn, has gained popularity in the west.

A major role was played in the 19th century by Swami Vivekananda in the revival of Hinduism, and the spread of Advaita Vedanta to the west via the Ramakrishna Mission. His interpretation of Advaita Vedanta has been called Neo-Vedanta. In Advaita, Shankara suggests meditation and Nirvikalpa Samadhi are means to gain knowledge of the already existing unity of Brahman and Atman, not the highest goal itself:

[Y]oga is a meditative exercise of withdrawal from the particular and identification with the universal, leading to contemplation of oneself as the most universal, namely, Consciousness. This approach is different from the classical Yoga of complete thought suppression.

Vivekananda, according to Gavin Flood, was "a figure of great importance in the development of a modern Hindu self-understanding and in formulating the West's view of Hinduism." Central to his philosophy is the idea that the divine exists in all beings, that all human beings can achieve union with this "innate divinity", and that seeing this divine as the essence of others will further love and social harmony. According to Vivekananda, there is an essential unity to Hinduism, which underlies the diversity of its many forms. According to Flood, Vivekananda's view of Hinduism is the most common among Hindus today. This monism, according to Flood, is at the foundation of earlier Upanishads, to theosophy in the later Vedanta tradition and in modern Neo-Hinduism.

Buddhism

Main articles: Buddhism and Middle Way

According to the Pāli Canon, both pluralism (nānatta) and monism (ekatta) are speculative views. A Theravada commentary notes that the former is similar to or associated with nihilism (ucchēdavāda), and the latter is similar to or associated with eternalism (sassatavada).

In the Madhyamaka school of Mahayana Buddhism, the ultimate nature of the world is described as Śūnyatā or "emptiness", which is inseparable from sensorial objects or anything else. That appears to be a monist position, but the Madhyamaka views – including variations like rangtong and shentong – will refrain from asserting any ultimately existent entity. They instead deconstruct any detailed or conceptual assertions about ultimate existence as resulting in absurd consequences. The Yogacara view, a minority school now only found among the Mahayana, also rejects monism.

Levels of truth

Within Buddhism, a rich variety of philosophical and pedagogical models can be found. Various schools of Buddhism discern levels of truth:

• The Two truths doctrine of the Madhyamaka
• The Three Natures of the Yogacara
• Essence-Function, or Absolute-relative in Chinese and Korean Buddhism
• The Trikaya-formule, consisting of
  • The Dharmakāya or Truth body which embodies the very principle of enlightenment and knows no limits or boundaries;
  • The Sambhogakāya or body of mutual enjoyment which is a body of bliss or clear light manifestation;
  • The Nirmāṇakāya or created body which manifests in time and space.

The Prajnaparamita-sutras and Madhyamaka emphasize the non-duality of form and emptiness: "form is emptiness, emptiness is form", as the heart sutra says. In Chinese Buddhism this was understood to mean that ultimate reality is not a transcendental realm, but equal to the daily world of relative reality. This idea fitted into the Chinese culture, which emphasized the mundane world and society. But this does not tell how the absolute is present in the relative world:

To deny the duality of samsara and nirvana, as the Perfection of Wisdom does, or to demonstrate logically the error of dichotomizing conceptualization, as Nagarjuna does, is not to address the question of the relationship between samsara and nirvana -or, in more philosophical terms, between phenomenal and ultimate reality [...] What, then, is the relationship between these two realms?

This question is answered in such schemata as the Five Ranks of Tozan, the Oxherding Pictures, and Hakuin's Four ways of knowing.

Sikhism

Main article: God in Sikhism

Sikhism complies with the concept of Priority Monism. Sikh philosophy advocates that all that our senses comprehend is an illusion; God is the sole reality. Forms being subject to time shall pass away. God's Reality alone is eternal and abiding. The thought is that Atma (soul) is born from, and a reflection of, ParamAtma (Supreme Soul), and "will again merge into it", in the words of the fifth guru of Sikhs, Guru Arjan Dev Ji, "just as water merges back into the water."

ਜਿਉ ਜਲ ਮਹਿ ਜਲੁ ਆਇ ਖਟਾਨਾ ॥
Jio Jal Mehi Jal Aae Khattaanaa ||
As water comes to blend with water,

ਤਿਉ ਜੋਤੀ ਸੰਗਿ ਜੋਤਿ ਸਮਾਨਾ ॥
Thio Jothee Sang Joth Samaanaa ||
His light blends into the Light.

— SGGS. Pg 278, https://www.searchgurbani.com/guru-granth-sahib/ang-by-ang

God and Soul are fundamentally the same; identical in the same way as Fire and its sparks. "Atam meh Ram, Ram meh Atam" which means "The Ultimate Eternal reality resides in the Soul and the Soul is contained in Him". As from one stream, millions of waves arise and yet the waves, made of water, again become water; in the same way all souls have sprung from the Universal Being and would blend again into it.

Abrahamic faiths

Judaism

Main article: Judaism

Jewish thought considers God as separate from all physical, created things and as existing outside of time.

According to Maimonides, God is an incorporeal being that caused all other existence. According to Maimonides, to admit corporeality to God is tantamount to admitting complexity to God, which is a contradiction to God as the first cause and constitutes heresy. While Hasidic mystics considered the existence of the physical world a contradiction to God's simpleness, Maimonides saw no contradiction.

According to Hasidic thought (particularly as propounded by the 18th century, early 19th-century founder of Chabad, Shneur Zalman of Liadi), God is held to be immanent within creation for two interrelated reasons:

1. A very strong Jewish belief is that "[t]he Divine life-force which brings [the universe] into existence must constantly be present ... were this life-force to forsake [the universe] for even one brief moment, it would revert to a state of utter nothingness, as before the creation ..."
2. Simultaneously, Judaism holds as axiomatic that God is an absolute unity, and that he is perfectly simple, thus, if his sustaining power is within nature, then his essence is also within nature.

The Vilna Gaon was very much against this philosophy, for he felt that it would lead to pantheism and heresy. According to some this is the main reason for the Gaon's ban on Chasidism.

Christianity

See also: Christian anthropology

Creator–creature distinction

Christians maintain that God created the universe ex nihilo and not from his own substance, so that the creator is not to be confused with creation, but rather transcends it. There is a movement of "Christian Panentheism". Even more immanent concepts and theologies are to be defined together with God's omnipotence, omnipresence and omniscience, due to God's desire for intimate contact with his own creation (cf. Acts 17:27). Another use of the term "monism" is in Christian anthropology to refer to the innate nature of humankind as being holistic, as usually opposed to bipartite and tripartite views.

Rejection of radical dualism

In On Free Choice of the Will, Augustine argued, in the context of the problem of evil, that evil is not the opposite of good, but rather merely the absence of good, something that does not have existence in itself. Likewise, C. S. Lewis described evil as a "parasite" in Mere Christianity, as he viewed evil as something that cannot exist without good to provide it with existence. Lewis went on to argue against dualism from the basis of moral absolutism, and rejected the dualistic notion that God and Satan are opposites, arguing instead that God has no equal, hence no opposite. Lewis rather viewed Satan as the opposite of Michael the archangel. Due to this, Lewis instead argued for a more limited type of dualism. Other theologians, such as Greg Boyd, have argued in more depth that the Biblical authors held a "limited dualism", meaning that God and Satan do engage in real battle, but only due to free will given by God, for the duration that God allows.

Isaiah 45:5–7 (KJV) says:

I am the LORD, and there is none else, there is no God beside me: I girded thee, though thou hast not known me: That they may know from the rising of the sun, and from the west, that there is none beside me. I am the LORD, and there is none else. I form the light, and create darkness: I make peace, and create evil: I the LORD do all these things.

Theosis

In Roman Catholicism and Eastern Orthodoxy, while human beings are not ontologically identical with the Creator, they are nonetheless capable with uniting with his Divine Nature via theosis, and especially, through the devout reception of the Holy Eucharist. This is a supernatural union, over and above that natural union, of which St. John of the Cross says, "it must be known that God dwells and is present substantially in every soul, even in that of the greatest sinner in the world, and this union is natural." Julian of Norwich, while maintaining the orthodox duality of Creator and creature, nonetheless speaks of God as "the true Father and true Mother" of all natures; thus, he indwells them substantially and thus preserves them from annihilation, as without this sustaining indwelling everything would cease to exist.

Christian Monism

Some Christian theologians are avowed monists, such as Paul Tillich. Since God is he "in whom we live and move and have our being" (Book of Acts 17.28), it follows that everything that has being partakes in God.

Mormonism

Latter Day Saint theology also expresses a form of dual-aspect monism via materialism and eternalism, claiming that creation was ex materia (as opposed to ex nihilo in conventional Christianity), as expressed by Parley Pratt and echoed in view by the movement's founder Joseph Smith, making no distinction between the spiritual and the material, these being not just similarly eternal, but ultimately two manifestations of the same reality or substance.

"God, the father is material. Jesus Christ is material. Angels are material. Spirits are material. Men are material. The universe is material ... Nothing exists which is not material."

— Parley Pratt

Parley Pratt implies a vitalism paired with evolutionary adaptation noting, “these eternal, self-existing elements possess in themselves certain inherent properties or attributes, in a greater or less degree; or, in other words, they possess intelligence, adapted to their several spheres.” 

Parley Pratt’s view is also similar to Gottfried Leibniz’s monadology, which holds that “reality consists of mind atoms that are living centers of force.” 

Brigham Young anticipates a proto-mentality of elementary particles with his vitalist view, “there is life in all matter, throughout the vast extent of all the eternities; it is in the rock, the sand, the dust, in water, air, the gases, and in short, in every description and organization of matter; whether it be solid, liquid, or gaseous, particle operating with particle.” 

The LDS conception of matter is “essentially dynamic rather than static, if indeed it is not a kind of living energy, and that it is subject at least to the rule of intelligence.” 

John A. Widstoe held a similar, more vitalist view, that “Life is nothing more than matter in motion; that, therefore, all matter possess a kind of life… Matter… [is] intelligence… hence everything in the universe is alive.” However, Widstoe resisted outright affirming a belief in panpsychism. 

Islam

See also: Tawhid

Quran

Vincent Cornell argues that the Quran provides a monist image of God by describing reality as a unified whole, with God being a single concept that would describe or ascribe all existing things.

But most argue that Abrahamic religious scriptures, especially the Quran, see creation and God as two separate existences. It explains that everything has been created by God and is under his control, but at the same time distinguishes creation as being dependent on the existence of God.

Sufism

See also: Sufism

Some Sufi mystics advocate monism. One of the most notable being the 13th-century Persian poet Rumi (1207–73) in his didactic poem Masnavi espoused monism. Rumi says in the Masnavi,

In the shop for Unity (wahdat); anything that you see there except the One is an idol.

Other Sufi mystics however, such as Ahmad Sirhindi, upheld dualistic Monotheism (the separation of God and the Universe).

The most influential of the Islamic monists was the Sufi philosopher Ibn Arabi (1165–1240). He developed the concept of 'unity of being' (Arabic: waḥdat al-wujūd), which some argue is a monistic philosophy. Born in al-Andalus, he made an enormous impact on the Muslim world, where he was crowned "the great Master". In the centuries following his death, his ideas became increasingly controversial. Ahmad Sirhindi criticised monistic understanding of 'unity of being', advocating the dualistic-compatible 'unity of witness' (Arabic: wahdat ash-shuhud), maintaining separation of creator and creation. Later, Shah Waliullah Dehlawi reconciled the two ideas maintaining that their differences are semantic differences, arguing that the universal existence (which is different in creation to creator) and the divine essence are different and that the universal existence emanates (in a non-platonic sense) from the divine essence and that the relationship between them is similar to the relationship between the number four and a number being even.

Shi'ism

See also: Shi'ism

The doctrine of waḥdat al-wujūd also enjoys considerable following in the rationalist philosophy of Twelver Shi'ism, with the most famous modern-day adherent being Ruhollah Khomeini.

Baháʼí Faith

Main article: Baháʼí Faith and the unity of religion

Although the teachings of the Baháʼí Faith have a strong emphasis on social and ethical issues, there exist a number of foundational texts that have been described as mystical. Some of these include statements of a monist nature (e.g., The Seven Valleys and the Hidden Words). The differences between dualist and monist views are reconciled by the teaching that these opposing viewpoints are caused by differences in the observers themselves, not in that which is observed. This is not a 'higher truth/lower truth' position. God is unknowable. For man it is impossible to acquire any direct knowledge of God or the Absolute, because any knowledge that one has, is relative.

Non-dualism

Main article: Nondualism

According to nondualism, many forms of religion are based on an experiential or intuitive understanding of "the Real". Nondualism, a modern reinterpretation of these religions, prefers the term "nondualism", instead of monism, because this understanding is "nonconceptual", "not graspable in an idea".

To these nondual traditions belong Hinduism (including Vedanta, some forms of Yoga, and certain schools of Shaivism), Taoism, Pantheism, Rastafari, and similar systems of thought.

History of serfdom

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/History_of_serfdom 

Like slavery, serfdom has a long history that dates to ancient times.

Origins

Social institutions similar to serfdom occurred in the ancient world. The status of the helots in the ancient Greek city-state of Sparta resembled that of medieval serfs. By the 3rd century AD, the Roman Empire faced a labour shortage. Large Roman landowners increasingly relied on Roman freemen, acting as tenant farmers, (instead of on slaves) to provide labour. The status of these tenant farmers, eventually known as coloni, steadily eroded. Because the tax system implemented by Diocletian (reigned 284-305) assessed taxes based both on land and on the inhabitants of that land, it became administratively inconvenient for peasants to leave the land where the census counted them. In 332 AD Emperor Constantine issued legislation that greatly restricted the rights of the coloni and tied them to the land. Some see these laws as the beginning of medieval serfdom in Europe.

However, medieval serfdom really began with the breakup of the Carolingian Empire around the 10th century. The demise of this empire, which had ruled much of western Europe for more than 200 years, ushered in a long period during which no strong central government existed in most of Europe. During this period, powerful feudal lords encouraged the establishment of serfdom as a source of agricultural labor. Serfdom, indeed, was an institution that reflected a fairly common practice whereby great landlords ensured that others worked to feed them and were held down, legally and economically, while doing so.

Heyday

Serfdom as a system provided most of the agricultural labour throughout the Middle Ages. Slavery persisted right through the Middle Ages, but it was rare, diminishing and largely confined to the use of household slaves. Parts of Europe, including much of Scandinavia, never adopted serfdom.

In the later Middle Ages serfdom began to disappear west of the Rhine even as it spread through much of the rest of Europe. This was one important cause for the deep differences between the societies and economies of eastern and western Europe. In Western Europe, the rise of powerful monarchs, towns, and an improving economy weakened the manorial system through the 13th and 14th centuries; serfdom had become rare by 1400.

Serfdom in Western Europe came largely to an end in the 15th and 16th centuries, because of changes in the economy, population, and laws governing lord-tenant relations in Western European nations. The enclosure of manor fields for livestock grazing and for larger arable plots made the economy of serfs' small strips of land in open fields less attractive to landowners. Furthermore, the increasing use of money made tenant farming by serfs less profitable; for much less than it cost to support a serf, a lord could now hire workers who were more skilled and pay them in cash. Paid labour was also more flexible, since workers could be hired only when they were needed.

At the same time, increasing unrest and uprisings by serfs and peasants, like Tyler’s Rebellion in England in 1381, put pressure on the nobility and the clergy to reform the system. As a result, the gradual establishment of new forms of land leases and increased personal liberties accommodated serf and peasant demands to some extent.

Grain pays

 

Grain doesn't pay.

Those two pictures illustrate the notion that agriculture, once extremely profitable to the nobles (szlachta) in the Polish–Lithuanian Commonwealth, became much less profitable from the second half of seventeenth century onwards

Serfdom reached Eastern Europe centuries later than Western Europe—it became dominant around the 15th century. Before that time, Eastern Europe had been much more sparsely populated than Western Europe, and the lords of Eastern Europe created a peasantry-friendly environment to encourage migration east. Serfdom developed in Eastern Europe after the Black Death epidemics of the mid-14th century, which stopped the eastward migration. The resulting high land-to-labour ratio - combined with Eastern Europe's vast, sparsely populated areas - gave the lords an incentive to bind the remaining peasantry to their land. With increased demand for agricultural produce in Western Europe during the later era when Western Europe limited and eventually abolished serfdom, serfdom remained in force throughout Eastern Europe during the 17th century so that nobility-owned estates could produce more agricultural products (especially grain) for the profitable export market.

According to Jerome Blum, the rise of serfdom in Eastern Europe in the 15th century, just as serfdom disappeared in Western Europe, is due to the increasing political influence and economic privileges of the nobles in the government, and reduced competition for labour from cities. The cities declined due to the collapse of the Hanseatic League's and Teutonic Order's trade networks and trade disruptions from war. Eastern European nobles started trading directly with the English and Dutch merchants, bypassing the trading cities.

This pattern applied in Central and Eastern European countries, including Prussia (Prussian Ordinances of 1525), Austria, Hungary (laws of the late 15th and early 16th centuries), the Polish–Lithuanian Commonwealth (szlachta privileges of the early 16th century) and the Russian Empire (laws of the late 16th and first half of the 17th century). This also led to the slower industrial development and urbanisation of those regions. Generally, this process, referred to as "second serfdom" or "export-led serfdom", persisted until the mid-19th century and became very repressive and substantially limited serfs' rights. Before the 1861 abolition of serfdom in Russia, a landowner's estate was often measured by the number of "souls" he owned, a practice made famous by Gogol's 1842 novel Dead Souls.

Many of these countries abolished serfdom during the Napoleonic invasions of the early 19th century. Serfdom remained in force in most of Russia until the Emancipation reform of 1861, enacted on February 19, 1861, though in the Russian-controlled Baltic provinces it had been abolished at the beginning of the 19th century. According to the Russian census of 1857, Russia had 23.1 million private serfs. Russian serfdom was perhaps the most notable Eastern European institution, as it was never influenced by German law and migrations, and serfdom and the manorial system were enforced by the crown (Tsar), not by the nobility.

Decline

For a chronological guide, see Timeline of abolition of slavery and serfdom.

In Western Europe serfdom became progressively less common through the Middle Ages, particularly after the Black Death reduced the rural population and increased the bargaining power of workers. Furthermore, the lords of many manors were willing (for payment) to manumit ("release") their serfs.

Normandy

In Normandy, serfdom had disappeared by 1100. Two possible causes of the disappearance of serfdom in Normandy have been proposed: (1) it might have been implemented to attract peasants to a Normandy depopulated by the Viking invasions or (2) it might be a result of the peasants' revolt of 996 in Normandy.

Great Britain

In England, the end of serfdom began with the Peasants' Revolt in 1381. It had largely died out in England by 1500 as a personal status and was fully ended when Elizabeth I freed the last remaining serfs in 1574. Land held by serf tenure (unless enfranchised) continued to be held by what was thenceforth known as a copyhold tenancy, which was not completely abolished until 1925 (although it was whittled away during the 19th and early 20th centuries). There were Scottish born serfs until the Colliers and Salters (Scotland) Act 1775 prevented the creation of the status, and 1799, when coal miners who had already been kept in serfdom prior to the 1775 Act gained emancipation. However, most Scottish serfs had already been freed.

France

Serfdom was de facto ended in France by Philip IV, Louis X (1315), and Philip V (1318). With the exception of a few isolated cases, serfdom had ceased to exist in France by the 15th century. In Early Modern France, French nobles nevertheless maintained a great number of seigneurial privileges over the free peasants that worked lands under their control. Serfdom was formally abolished in France in 1789.

Other parts of Europe

In other parts of Europe, there had been peasant revolts in Castille, Germany, northern France, Portugal, and Sweden. Although they were often successful, it usually took a long time before legal systems were changed.

Era of the French Revolution

The era of the French Revolution (1790s to 1820s) saw serfdom abolished in most of Western and Central Europe, while its practice remained common in Eastern Europe until the middle of the 19th century (1861 in Russia). In France, serfdom had been in decline for at least three centuries by the start of the Revolution, replaced by various forms of freehold tenancy. The last vestiges of serfdom were officially ended on August 4, 1789 with a decree abolishing the feudal rights of the nobility.

It removed the authority of the manorial courts, eliminated tithes and manorial dues, and freed those who still remained bound to the land. However, the decree was mostly symbolic, as widespread peasant revolts had effectively ended the feudal system beforehand; and ownership of the land still remained in the hands of the landlords, who could continue collecting rents and enforcing tenant contracts.

End of serfdom: a German „Freilassungsbrief“ (Letter for the End of a serfdom) from 1762.

Germany

In German history the emancipation of the serfs came between 1770–1830, with the nobility in Schleswig being the first to agree to do so in 1797, followed by the signing of the royal and political leaders of Denmark and Germany in 1804. Prussia abolished serfdom with the "October Edict" of 1807, which upgraded the personal legal status of the peasantry and gave them ownership of half or two-thirds of the lands they were working. The edict applied to all peasants whose holdings were above a certain size, and included both Crown lands and noble estates. The peasants were freed from the obligation of personal services to the lord and annual dues; in return landowners were given ownership of 1/3 to 1/2 of the land. The peasant owned and rented the lands that were deeded to the old owners. The other German states imitated Prussia after 1815.

In sharp contrast to the violence that characterized land reform in the French Revolution, Germany handled it peacefully. In Schleswig the peasants, who had been influenced by the Enlightenment, played an active role; elsewhere they were largely passive. Indeed, for most peasants, customs and traditions continued largely unchanged, including the old habits of deference to the nobles whose legal authority remained quite strong over the villagers. The old paternalistic relationship in East Prussia lasted into the 20th century. What was new was that the peasant could now sell his land, enabling him to move to the city, or buy up the land of his neighbors.

The land reforms in northwestern Germany were driven by progressive governments and local elites. They abolished feudal obligations and divided collectively owned common land into private parcels and thus created a more efficient market-oriented rural economy. It produced increased productivity and population growth. It strengthened the traditional social order because wealthy peasants obtained most of the former common land, while the rural proletariat was left without land; many left for the cities or America. Meanwhile, the division of the common land served as a buffer preserving social peace between nobles and peasants. East of the Elbe River, the Junker class maintained large estates and monopolized political power.

Hapsburg monarchy

In the Hapsburg monarchy, Jozef II issued the Serfdom Patent that abolished serfdom in the German speaking areas in 1781. In the Kingdom of Hungary, Jozef II issued a similar decree in 1785 after the Revolt of Horea in Transylvania. These patents converted the legal standings of all serfs into those of free-holders. All feudal restrictions were abolished in 1848 when all the land property were converted to non-feudal, transferable properties, and feudalism was legally abolished.

The eradication of the feudal system marks the beginning of an era of rapid change in Europe. The change in status following the enclosure movements beginning in the later 18th century, in which various lords abandoned the open field farming of previous centuries and, essentially, took all the best land for themselves in exchange for "freeing" their serfs, may well have made serfdom seem more desirable to many peasant families.

Views of Marx

In his book Das Kapital, in Chapter 26 entitled "The Secret of Primitive Accumulation" and Chapter 27, "Expropriation of the Agricultural Population from the Land", Marx claimed that the feudal relationships of serfdom were violently transformed into private property and free labour: free of possession and free to sell their labour force on the market. Being liberated from serfdom meant being able to sell one's land and work wherever one desired. "The so-called primitive accumulation, therefore, is nothing else than the historical process of divorcing the producer from the means of production. It appears as primitive, because it forms the pre-historic stage of capital and of the mode of production corresponding with it."

In a case history of England, Marx described how the serfs became free peasant proprietors and small farmers, who were, over time, forcibly expropriated and driven off the land, forming a property-less proletariat. He also claimed that more and more legislation was enacted by the state to control and regiment this new class of wage workers. In the meantime, the remaining farmers became capitalist farmers operating more and more on a commercial basis; and gradually, legal monopolies preventing trade and investment by entrepreneurs were broken up.

Taxes levied by the state took the place of labour dues levied by the lord. Although serfdom began its decline in Europe in the Middle Ages, it took many hundreds of years to disappear completely. In addition, the struggles of the working class during the Industrial Revolution can often be compared with the struggles of the serfs during the Middle Ages. In parts of the world today, forced labour is still used.

"Galician slaughter" 1846, by Jan Lewicki (1795–1871); "directed against manorial property (for example, the manorial prisons) and rising against serfdom; Galician, mainly Polish, peasants killed over 1000 noblemen and destroyed 500 manors in 1846."

Russia

Main articles: Serfdom in Russia and Emancipation Reform of 1861

Serfdom became the dominant form of relation between Russian peasants and nobility in the 17th century. Serfdom only existed in central and southern areas of the Russian Empire. It was never established in the North, in the Urals, nor in Siberia. Historian David Moon argues that serfdom was a response to military and economic factors in Russia. It was socially stable and adaptable to changing demographic and economic conditions; revolts were uncommon. Moon says it was not the cause of Russia's backwardness; instead, backwardness blocked alternative methods that were developed in Western Europe. Moon identifies some benefits for serfs, such as assurances of land and some assistance after bad harvests. Moon argues that Russia's defeat in the Crimean War was a catalyst leading to the abolition of serfdom.

Finally, serfdom was abolished by a decree issued by Tsar Alexander II in 1861. Scholars have proposed multiple overlapping reasons to account for the abolition, including fear of a large-scale revolt by the serfs, the financial needs of the government, evolving cultural sensibilities, the military need for soldiers, and, among Marxists, the unprofitability of serfdom.

Reelin

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Reelin

RELN

Reelin, encoded by the RELN gene, is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this important role in early development, reelin continues to work in the adult brain. It modulates synaptic plasticity by enhancing the induction and maintenance of long-term potentiation. It also stimulates dendrite and dendritic spine development and regulates the continuing migration of neuroblasts generated in adult neurogenesis sites like the subventricular and subgranular zones. It is found not only in the brain but also in the liver, thyroid gland, adrenal gland, Fallopian tube, breast and in comparatively lower levels across a range of anatomical regions.

Reelin has been suggested to be implicated in pathogenesis of several brain diseases. The expression of the protein has been found to be significantly lower in schizophrenia and psychotic bipolar disorder, but the cause of this observation remains uncertain, as studies show that psychotropic medication itself affects reelin expression. Moreover, epigenetic hypotheses aimed at explaining the changed levels of reelin expression are controversial. Total lack of reelin causes a form of lissencephaly. Reelin may also play a role in Alzheimer's disease, temporal lobe epilepsy and autism.

Reelin's name comes from the abnormal reeling gait of reeler mice, which were later found to have a deficiency of this brain protein and were homozygous for mutation of the RELN gene. The primary phenotype associated with loss of reelin function is a failure of neuronal positioning throughout the developing central nervous system (CNS). The mice heterozygous for the reelin gene, while having little neuroanatomical defects, display the endophenotypic traits linked to psychotic disorders.

Discovery

Normal and Reeler mice brain slices.

Mutant mice have provided insight into the underlying molecular mechanisms of the development of the central nervous system. Useful spontaneous mutations were first identified by scientists who were interested in motor behavior, and it proved relatively easy to screen littermates for mice that showed difficulties moving around the cage. A number of such mice were found and given descriptive names such as reeler, weaver, lurcher, nervous, and staggerer.

The "reeler" mouse was described for the first time in 1951 by D.S.Falconer in Edinburgh University as a spontaneous variant arising in a colony of at least mildly inbred snowy-white bellied mice stock in 1948. Histopathological studies in the 1960s revealed that the cerebellum of reeler mice is dramatically decreased in size while the normal laminar organization found in several brain regions is disrupted. The 1970s brought about the discovery of cellular layer inversion in the mouse neocortex, which attracted more attention to the reeler mutation.

In 1994, a new allele of reeler was obtained by means of insertional mutagenesis. This provided the first molecular marker of the locus, permitting the RELN gene to be mapped to chromosome 7q22 and subsequently cloned and identified. Japanese scientists at Kochi Medical School successfully raised antibodies against normal brain extracts in reeler mice, later these antibodies were found to be specific monoclonal antibodies for reelin, and were termed CR-50 (Cajal-Retzius marker 50). They noted that CR-50 reacted specifically with Cajal-Retzius neurons, whose functional role was unknown until then.

The Reelin receptors, apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR), were discovered by Trommsdorff, Herz and colleagues, who initially found that the cytosolic adaptor protein Dab1 interacts with the cytoplasmic domain of LDL receptor family members. They then went on to show that the double knockout mice for ApoER2 and VLDLR, which both interact with Dab1, had cortical layering defects similar to those in reeler.

The downstream pathway of reelin was further clarified with the help of other mutant mice, including yotari and scrambler. These mutants have phenotypes similar to that of reeler mice, but without mutation in reelin. It was then demonstrated that the mouse disabled homologue 1 (Dab1) gene is responsible for the phenotypes of these mutant mice, as Dab1 protein was absent (yotari) or only barely detectable (scrambler) in these mutants. Targeted disruption of Dab1 also caused a phenotype similar to that of reeler. Pinpointing the DAB1 as a pivotal regulator of the reelin signaling cascade started the tedious process of deciphering its complex interactions.

There followed a series of speculative reports linking reelin's genetic variation and interactions to schizophrenia, Alzheimer's disease, autism and other highly complex dysfunctions. These and other discoveries, coupled with the perspective of unraveling the evolutionary changes that allowed for the creation of human brain, highly intensified the research. As of 2008, some 13 years after the gene coding the protein was discovered, hundreds of scientific articles address the multiple aspects of its structure and functioning.

Tissue distribution and secretion

Studies show that reelin is absent from synaptic vesicles and is secreted via constitutive secretory pathway, being stored in Golgi secretory vesicles. Reelin's release rate is not regulated by depolarization, but strictly depends on its synthesis rate. This relationship is similar to that reported for the secretion of other extracellular matrix proteins.

During the brain development, reelin is secreted in the cortex and hippocampus by the so-called Cajal-Retzius cells, Cajal cells, and Retzius cells. Reelin-expressing cells in the prenatal and early postnatal brain are predominantly found in the marginal zone (MZ) of the cortex and in the temporary subpial granular layer (SGL), which is manifested to the highest extent in human, and in the hippocampal stratum lacunosum-moleculare and the upper marginal layer of the dentate gyrus.

In the developing cerebellum, reelin is expressed first in the external granule cell layer (EGL), before the granule cell migration to the internal granule cell layer (IGL) takes place.

Having peaked just after the birth, the synthesis of reelin subsequently goes down sharply, becoming more diffuse compared with the distinctly laminar expression in the developing brain. In the adult brain, reelin is expressed by GABA-ergic interneurons of the cortex and glutamatergic cerebellar neurons, the glutamatergic stellate cells and fan cells in the superficial entorhinal cortex that are supposed to carry a role in encoding new episodic memories,  and by the few extant Cajal-Retzius cells. Among GABAergic interneurons, reelin seems to be detected predominantly in those expressing calretinin and calbindin, like bitufted, horizontal, and Martinotti cells, but not parvalbumin-expressing cells, like chandelier or basket neurons. In the white matter, a minute proportion of interstitial neurons has also been found to stain positive for reelin expression.

Schema of the reelin protein

Outside the brain, reelin is found in adult mammalian blood, liver, pituitary pars intermedia, and adrenal chromaffin cells. In the liver, reelin is localized in hepatic stellate cells. The expression of reelin increases when the liver is damaged, and returns to normal following its repair. In the eyes, reelin is secreted by retinal ganglion cells and is also found in the endothelial layer of the cornea. Just as in the liver, its expression increases after an injury has taken place.

The protein is also produced by the odontoblasts, which are cells at the margins of the dental pulp. Reelin is found here both during odontogenesis and in the mature tooth. Some authors suggest that odontoblasts play an additional role as sensory cells able to transduce pain signals to the nerve endings. According to the hypothesis, reelin participates in the process by enhancing the contact between odontoblasts and the nerve terminals.

Structure

The structure of two murine reelin repeats as revealed by X-ray crystallography and electron tomography.

Reelin is composed of 3461 amino acids with a relative molecular mass of 388 kDa. It also has serine protease activity. Murine RELN gene consists of 65 exons spanning approximately 450 kb. One exon, coding for only two amino acids near the protein's C-terminus, undergoes alternative splicing, but the exact functional impact of this is unknown. Two transcription initiation sites and two polyadenylation sites are identified in the gene structure.

The reelin protein starts with a signaling peptide 27 amino acids in length, followed by a region bearing similarity to F-spondin (the reeler domain), marked as "SP" on the scheme, and by a region unique to reelin, marked as "H". Next comes 8 repeats of 300–350 amino acids. These are called reelin repeats and have an epidermal growth factor motif at their center, dividing each repeat into two subrepeats, A (the BNR/Asp-box repeat) and B (the EGF-like domain). Despite this interruption, the two subdomains make direct contact, resulting in a compact overall structure.

The final reelin domain contains a highly basic and short C-terminal region (CTR, marked "+") with a length of 32 amino acids. This region is highly conserved, being 100% identical in all investigated mammals. It was thought that CTR is necessary for reelin secretion, because the Orleans reeler mutation, which lacks a part of 8th repeat and the whole CTR, is unable to secrete the misshaped protein, leading to its concentration in cytoplasm. However, other studies have shown that the CTR is not essential for secretion itself, but mutants lacking the CTR were much less efficient in activating downstream signaling events.

Reelin is cleaved in vivo at two sites located after domains 2 and 6 – approximately between repeats 2 and 3 and between repeats 6 and 7, resulting in the production of three fragments. This splitting does not decrease the protein's activity, as constructs made of the predicted central fragments (repeats 3–6) bind to lipoprotein receptors, trigger Dab1 phosphorylation and mimic functions of reelin during cortical plate development. Moreover, the processing of reelin by embryonic neurons may be necessary for proper corticogenesis.

Function

As they travel through the rostral migratory stream, neuroblasts are held together, probably in part by thrombospondin-1's binding to the reelin receptors ApoER2 and VLDLR. As they arrive to the destination, the groups are dispersed by reelin and cells strike out on their individual paths. A fragment of an illustration from Lennington et al., 2003.

The primary functions of Reelin are the regulation of corticogenesis and neuronal cell positioning in the prenatal period, but the protein also continues to play a role in adults. Reelin is found in numerous tissues and organs, and one could roughly subdivide its functional roles by the time of expression and by localisation of its action.

During development

A number of non-nervous tissues and organs express reelin during development, with the expression sharply going down after organs have been formed. The role of the protein here is largely unexplored, because the knockout mice show no major pathology in these organs. Reelin's role in the growing central nervous system has been extensively characterized. It promotes the differentiation of progenitor cells into radial glia and affects the orientation of its fibers, which serve as the guides for the migrating neuroblasts. The position of reelin-secreting cell layer is important, because the fibers orient themselves in the direction of its higher concentration. For example, reelin regulates the development of layer-specific connections in hippocampus and entorhinal cortex.^[

Reelin controls the direction of radial glia growth. A fragment of an illustration from Nomura T. et al., 2008. Reelin-expressing cells (red) on C stimulate the growth of green glial fibers, while on B, where the red cells do not express reelin, radial glia is more disarrayed.

Mammalian corticogenesis is another process where reelin plays a major role. In this process the temporary layer called preplate is split into the marginal zone on the top and subplate below, and the space between them is populated by neuronal layers in the inside-out pattern. Such an arrangement, where the newly created neurons pass through the settled layers and position themselves one step above, is a distinguishing feature of mammalian brain, in contrast to the evolutionary older reptile cortex, in which layers are positioned in an "outside-in" fashion. When reelin is absent, like in the mutant reeler mouse, the order of cortical layering becomes roughly inverted, with younger neurons finding themselves to be unable to pass the settled layers. Subplate neurons fail to stop and invade the upper most layer, creating the so-called superplate in which they mix with Cajal-Retzius cells and some cells normally destined for the second layer.

Increased reelin expression changes the morphology of migrating neurons: unlike the round neurons with short branches (C) they assume bipolar shape (D) and attach themselves (E) to the radial glia fibers that are extending in the direction of reelin-expressing cells. Nomura T. et al., 2008.

There is no agreement concerning the role of reelin in the proper positioning of cortical layers. The original hypothesis, that the protein is a stop signal for the migrating cells, is supported by its ability to induce the dissociation, its role in asserting the compact granule cell layer in the hippocampus, and by the fact that migrating neuroblasts evade the reelin-rich areas. But an experiment in which murine corticogenesis went normally despite the malpositioned reelin secreting layer, and lack of evidence that reelin affects the growth cones and leading edges of neurons, caused some additional hypotheses to be proposed. According to one of them, reelin makes the cells more susceptible to some yet undescribed positional signaling cascade.

Reelin may also ensure correct neuronal positioning in the spinal cord: according to one study, location and level of its expression affects the movement of sympathetic preganglionic neurons.

The protein is thought to act on migrating neuronal precursors and thus controls correct cell positioning in the cortex and other brain structures. The proposed role is one of a dissociation signal for neuronal groups, allowing them to separate and go from tangential chain-migration to radial individual migration. Dissociation detaches migrating neurons from the glial cells that are acting as their guides, converting them into individual cells that can strike out alone to find their final position.

Top: Representative image of somatic reelin immunoreactivities found in 12-day-in-vitro hippocampal neurons. Bottom: reelin immunofluorescence (red) overlaid with MAP2 counterstain (green). A fragment of an illustration from Campo et al., 2009.

Reelin takes part in the developmental change of NMDA receptor configuration, increasing mobility of NR2B-containing receptors and thus decreasing the time they spend at the synapse. It has been hypothesized that this may be a part of the mechanism behind the "NR2B-NR2A switch" that is observed in the brain during its postnatal development. Ongoing reelin secretion by GABAergic hippocampal neurons is necessary to keep NR2B-containing NMDA receptors at a low level.

In adults

In the adult nervous system, reelin plays an eminent role at the two most active neurogenesis sites, the subventricular zone and the dentate gyrus. In some species, the neuroblasts from the subventricular zone migrate in chains in the rostral migratory stream (RMS) to reach the olfactory bulb, where reelin dissociates them into individual cells that are able to migrate further individually. They change their mode of migration from tangential to radial, and begin using the radial glia fibers as their guides. There are studies showing that along the RMS itself the two receptors, ApoER2 and VLDLR, and their intracellular adapter DAB1 function independently of Reelin, most likely by the influence of a newly proposed ligand, thrombospondin-1. In the adult dentate gyrus, reelin provides guidance cues for new neurons that are constantly arriving to the granule cell layer from subgranular zone, keeping the layer compact.

Reelin also plays an important role in the adult brain by modulating cortical pyramidal neuron dendritic spine expression density, the branching of dendrites, and the expression of long-term potentiation as its secretion is continued diffusely by the GABAergic cortical interneurons those origin is traced to the medial ganglionic eminence.

In the adult organism the non-neural expression is much less widespread, but goes up sharply when some organs are injured. The exact function of reelin upregulation following an injury is still being researched.

Evolutionary significance

Cajal-Retzius cells, as drawn by Cajal in 1891. The development of a distinct layer of these reelin-secreting cells played a major role in brain evolution.

 

Neuronal development: mammals (left) and avians (right) have different patterns of reelin expression (pink). Nomura T. et al., 2008.

Reelin-DAB1 interactions could have played a key role in the structural evolution of the cortex that evolved from a single layer in the common predecessor of the amniotes into multiple-layered cortex of contemporary mammals. Research shows that reelin expression goes up as the cortex becomes more complex, reaching the maximum in the human brain in which the reelin-secreting Cajal-Retzius cells have significantly more complex axonal arbour. Reelin is present in the telencephalon of all the vertebrates studied so far, but the pattern of expression differs widely. For example, zebrafish have no Cajal-Retzius cells at all; instead, the protein is being secreted by other neurons. These cells do not form a dedicated layer in amphibians, and radial migration in their brains is very weak.

As the cortex becomes more complex and convoluted, migration along the radial glia fibers becomes more important for the proper lamination. The emergence of a distinct reelin-secreting layer is thought to play an important role in this evolution. There are conflicting data concerning the importance of this layer, and these are explained in the literature either by the existence of an additional signaling positional mechanism that interacts with the reelin cascade, or by the assumption that mice that are used in such experiments have redundant secretion of reelin compared with more localized synthesis in the human brain.

Cajal-Retzius cells, most of which disappear around the time of birth, coexpress reelin with the HAR1 gene that is thought to have undergone the most significant evolutionary change in humans compared with chimpanzee, being the most "evolutionary accelerated" of the genes from the human accelerated regions. There is also evidence of that variants in the DAB1 gene have been included in a recent selective sweep in Chinese populations.

Mechanism of action

The main reelin signaling cascade (ApoER2 and VLDLR) and its interaction with LIS1. Zhang et al., 2008
SFK: Src family kinases.
JIP: JNK-interacting protein 1

Receptors

Reelin's control of cell-cell interactions is thought to be mediated by binding of reelin to the two members of low density lipoprotein receptor gene family: VLDLR and the ApoER2. The two main reelin receptors seem to have slightly different roles: VLDLR conducts the stop signal, while ApoER2 is essential for the migration of late-born neocortical neurons. It also has been shown that the N-terminal region of reelin, a site distinct from the region of reelin shown to associate with VLDLR/ApoER2 binds to the alpha-3-beta-1 integrin receptor. The proposal that the protocadherin CNR1 behaves as a Reelin receptor has been disproven.

As members of lipoprotein receptor superfamily, both VLDLR and ApoER2 have in their structure an internalization domain called NPxY motif. After binding to the receptors reelin is internalized by endocytosis, and the N-terminal fragment of the protein is re-secreted. This fragment may serve postnatally to prevent apical dendrites of cortical layer II/III pyramidal neurons from overgrowth, acting via a pathway independent of canonical reelin receptors.

Reelin receptors are present on both neurons and glial cells. Furthermore, radial glia express the same amount of ApoER2 but being ten times less rich in VLDLR. beta-1 integrin receptors on glial cells play more important role in neuronal layering than the same receptors on the migrating neuroblasts.

Reelin-dependent strengthening of long-term potentiation is caused by ApoER2 interaction with NMDA receptor. This interaction happens when ApoER2 has a region coded by exon 19. ApoER2 gene is alternatively spliced, with the exon 19-containing variant more actively produced during periods of activity. According to one study, the hippocampal reelin expression rapidly goes up when there is need to store a memory, as demethylases open up the RELN gene. The activation of dendrite growth by reelin is apparently conducted through Src family kinases and is dependent upon the expression of Crk family proteins, consistent with the interaction of Crk and CrkL with tyrosine-phosphorylated Dab1. Moreover, a Cre-loxP recombination mouse model that lacks Crk and CrkL in most neurons was reported to have the reeler phenotype, indicating that Crk/CrkL lie between DAB1 and Akt in the reelin signaling chain.

Signaling cascades

Reelin activates the signaling cascade of Notch-1, inducing the expression of FABP7 and prompting progenitor cells to assume radial glial phenotype. In addition, corticogenesis in vivo is highly dependent upon reelin being processed by embryonic neurons, which are thought to secrete some as yet unidentified metalloproteinases that free the central signal-competent part of the protein. Some other unknown proteolytic mechanisms may also play a role. It is supposed that full-sized reelin sticks to the extracellular matrix fibers on the higher levels, and the central fragments, as they are being freed up by the breaking up of reelin, are able to permeate into the lower levels. It is possible that as neuroblasts reach the higher levels they stop their migration either because of the heightened combined expression of all forms of reelin, or due to the peculiar mode of action of the full-sized reelin molecules and its homodimers.

The intracellular adaptor DAB1 binds to the VLDLR and ApoER2 through an NPxY motif and is involved in transmission of Reelin signals through these lipoprotein receptors. It becomes phosphorylated by Src and Fyn kinases and apparently stimulates the actin cytoskeleton to change its shape, affecting the proportion of integrin receptors on the cell surface, which leads to the change in adhesion. Phosphorylation of DAB1 leads to its ubiquitination and subsequent degradation, and this explains the heightened levels of DAB1 in the absence of reelin. Such negative feedback is thought to be important for proper cortical lamination. Activated by two antibodies, VLDLR and ApoER2 cause DAB1 phosphorylation but seemingly without the subsequent degradation and without rescuing the reeler phenotype, and this may indicate that a part of the signal is conducted independently of DAB1.

Reelin stimulates the progenitor cells to differentiate into radial glia, inducing the expression of radial glial marker BLBP by affecting the NOTCH1 cascade. A fragment of an illustration from Keilani et al., 2008.

A protein having an important role in lissencephaly and accordingly called LIS1 (PAFAH1B1), was shown to interact with the intracellular segment of VLDLR, thus reacting to the activation of reelin pathway.

Complexes

Reelin molecules have been shown to form a large protein complex, a disulfide-linked homodimer. If the homodimer fails to form, efficient tyrosine phosphorylation of DAB1 in vitro fails. Moreover, the two main receptors of reelin are able to form clusters that most probably play a major role in the signaling, causing the intracellular adaptor DAB1 to dimerize or oligomerize in its turn. Such clustering has been shown in the study to activate the signaling chain even in the absence of Reelin itself. In addition, reelin itself can cut the peptide bonds holding other proteins together, being a serine protease, and this may affect the cellular adhesion and migration processes. Reelin signaling leads to phosphorylation of actin-interacting protein cofilin 1 at ser3; this may stabilize the actin cytoskeleton and anchor the leading processes of migrating neuroblasts, preventing their further growth.

Interaction with Cdk5

Cyclin-dependent kinase 5 (Cdk5), a major regulator of neuronal migration and positioning, is known to phosphorylate DAB1 and other cytosolic targets of reelin signaling, such as Tau, which could be activated also via reelin-induced deactivation of GSK3B, and NUDEL, associated with Lis1, one of the DAB1 targets. LTP induction by reelin in hippocampal slices fails in p35 knockouts. P35 is a key Cdk5 activator, and double p35/Dab1, p35/RELN, p35/ApoER2, p35/VLDLR knockouts display increased neuronal migration deficits, indicating a synergistic action of reelin → ApoER2/VLDLR → DAB1 and p35/p39 → Cdk5 pathways in the normal corticogenesis.

Possible pathological role

Lissencephaly

Disruptions of the RELN gene are considered to be the cause of the rare form of lissencephaly with cerebellar hypoplasia classed as a microlissencephaly called Norman-Roberts syndrome. The mutations disrupt splicing of the RELN mRNA transcript, resulting in low or undetectable amounts of reelin protein. The phenotype in these patients was characterized by hypotonia, ataxia, and developmental delay, with lack of unsupported sitting and profound mental retardation with little or no language development. Seizures and congenital lymphedema are also present. A novel chromosomal translocation causing the syndrome was described in 2007.

Schizophrenia

Reduced expression of reelin and its mRNA levels in the brains of schizophrenia sufferers had been reported in 1998 and 2000, and independently confirmed in postmortem studies of the hippocampus, cerebellum, basal ganglia, and cerebral cortex. The reduction may reach up to 50% in some brain regions and is coupled with reduced expression of GAD-67 enzyme, which catalyses the transition of glutamate to GABA. Blood levels of reelin and its isoforms are also altered in schizophrenia, along with mood disorders, according to one study. Reduced reelin mRNA prefrontal expression in schizophrenia was found to be the most statistically relevant disturbance found in the multicenter study conducted in 14 separate laboratories in 2001 by Stanley Foundation Neuropathology Consortium.

Epigenetic hypermethylation of DNA in schizophrenia patients is proposed as a cause of the reduction, in agreement with the observations dating from the 1960s that administration of methionine to schizophrenic patients results in a profound exacerbation of schizophrenia symptoms in sixty to seventy percent of patients. The proposed mechanism is a part of the "epigenetic hypothesis for schizophrenia pathophysiology" formulated by a group of scientists in 2008 (D. Grayson; A. Guidotti; E. Costa). A postmortem study comparing a DNA methyltransferase (DNMT1) and Reelin mRNA expression in cortical layers I and V of schizophrenic patients and normal controls demonstrated that in the layer V both DNMT1 and Reelin levels were normal, while in the layer I DNMT1 was threefold higher, probably leading to the twofold decrease in the Reelin expression. There is evidence that the change is selective, and DNMT1 is overexpressed in reelin-secreting GABAergic neurons but not in their glutamatergic neighbours. Methylation inhibitors and histone deacetylase inhibitors, such as valproic acid, increase reelin mRNA levels, while L-methionine treatment downregulates the phenotypic expression of reelin.

One study indicated the upregulation of histone deacetylase HDAC1 in the hippocampi of patients. Histone deacetylases suppress gene promoters; hyperacetylation of histones was shown in murine models to demethylate the promoters of both reelin and GAD67. DNMT1 inhibitors in animals have been shown to increase the expression of both reelin and GAD67, and both DNMT inhibitors and HDAC inhibitors shown in one study to activate both genes with comparable dose- and time-dependence. As one study shows, S-adenosyl methionine (SAM) concentration in patients' prefrontal cortex is twice as high as in the cortices of non-affected people. SAM, being a methyl group donor necessary for DNMT activity, could further shift epigenetic control of gene expression.

Chromosome region 7q22 that harbours the RELN gene is associated with schizophrenia, and the gene itself was associated with the disease in a large study that found the polymorphism rs7341475 to increase the risk of the disease in women, but not in men. The women that have the single-nucleotide polymorphism (SNP) are about 1.4 times more likely to get ill, according to the study. Allelic variations of RELN have also been correlated with working memory, memory and executive functioning in nuclear families where one of the members suffers from schizophrenia. The association with working memory was later replicated. In one small study, nonsynonymous polymorphism Val997Leu of the gene was associated with left and right ventricular enlargement in patients.

One study showed that patients have decreased levels of one of reelin receptors, VLDLR, in the peripheral lymphocytes. After six months of antipsychotic therapy the expression went up; according to authors, peripheral VLRLR levels may serve as a reliable peripheral biomarker of schizophrenia.

Considering the role of reelin in promoting dendritogenesis, suggestions were made that the localized dendritic spine deficit observed in schizophrenia could be in part connected with the downregulation of reelin.

Reelin pathway could also be linked to schizophrenia and other psychotic disorders through its interaction with risk genes. One example is the neuronal transcription factor NPAS3, disruption of which is linked to schizophrenia and learning disability. Knockout mice lacking NPAS3 or the similar protein NPAS1 have significantly lower levels of reelin; the precise mechanism behind this is unknown. Another example is the schizophrenia-linked gene MTHFR, with murine knockouts showing decreased levels of reelin in the cerebellum. Along the same line, it is worth noting that the gene coding for the subunit NR2B that is presumably affected by reelin in the process of NR2B->NR2A developmental change of NMDA receptor composition, stands as one of the strongest risk gene candidates. Another shared aspect between NR2B and RELN is that they both can be regulated by the TBR1 transcription factor.

The heterozygous reeler mouse, which is haploinsufficient for the RELN gene, shares several neurochemical and behavioral abnormalities with schizophrenia and bipolar disorder, but the exact relevance of these murine behavioral changes to the pathophysiology of schizophrenia remains debatable.

As previously described, reelin plays a crucial role in modulating early neuroblast migration during brain development. Evidences of altered neural cell positioning in post-mortem schizophrenia patient brains and changes to gene regulatory networks that control cell migration suggests a potential link between altered reelin expression in patient brain tissue to disrupted cell migration during brain development. To model the role of reelin in the context of schizophrenia at a cellular level, olfactory neurosphere-derived cells were generated from the nasal biopsies of schizophrenia patients, and compared to cells from healthy controls. Schizophrenia patient-derived cells have reduced levels of reelin mRNA and protein when compared to healthy control cells, but expresses the key reelin receptors and DAB1 accessory protein. When grown in vitro, schizophrenia patient-derived cells were unable to respond to reelin coated onto tissue culture surfaces; In contrast, cells derived from healthy controls were able to alter their cell migration when exposed to reelin. This work went on to show that the lack of cell migration response in patient-derived cells were caused by the cell's inability to produce enough focal adhesions of the appropriate size when in contact with extracellular reelin. More research into schizophrenia cell-based models are needed to look at the function of reelin, or lack of, in the pathophysiology of schizophrenia.

Bipolar disorder

Decrease in RELN expression with concurrent upregulation of DNMT1 is typical of bipolar disorder with psychosis, but is not characteristic of patients with major depression without psychosis, which could speak of specific association of the change with psychoses. One study suggests that unlike in schizophrenia, such changes are found only in the cortex and do not affect the deeper structures in psychotic bipolar patients, as their basal ganglia were found to have the normal levels of DNMT1 and subsequently both the reelin and GAD67 levels were within the normal range.

In a genetic study conducted in 2009, preliminary evidence requiring further DNA replication suggested that variation of the RELN gene (SNP rs362719) may be associated with susceptibility to bipolar disorder in women.

Autism

Main article: Heritability of autism

Autism is a neurodevelopmental disorder that is generally believed to be caused by mutations in several locations, likely triggered by environmental factors. The role of reelin in autism is not decided yet.

Reelin was originally in 2001 implicated in a study finding associations between autism and a polymorphic GGC/CGG repeat preceding the 5' ATG initiator codon of the RELN gene in an Italian population. Longer triplet repeats in the 5' region were associated with an increase in autism susceptibility. However, another study of 125 multiple-incidence families and 68 single-incidence families from the subsequent year found no significant difference between the length of the polymorphic repeats in affected and controls. Although, using a family based association test larger reelin alleles were found to be transmitted more frequently than expected to affected children. An additional study examining 158 subjects with German lineage likewise found no evidence of triplet repeat polymorphisms associated with autism. And a larger study from 2004 consisting of 395 families found no association between autistic subjects and the CGG triplet repeat as well as the allele size when compared to age of first word. In 2010 a large study using data from 4 European cohorts would find some evidence for an association between autism and the rs362780 RELN polymorphism.

Studies of transgenic mice have been suggestive of an association, but not definitive.

Temporal lobe epilepsy: granule cell dispersion

Decreased reelin expression in the hippocampal tissue samples from patients with temporal lobe epilepsy was found to be directly correlated with the extent of granule cell dispersion (GCD), a major feature of the disease that is noted in 45%–73% of patients. The dispersion, according to a small study, is associated with the RELN promoter hypermethylation. According to one study, prolonged seizures in a rat model of mesial temporal lobe epilepsy have led to the loss of reelin-expressing interneurons and subsequent ectopic chain migration and aberrant integration of newborn dentate granule cells. Without reelin, the chain-migrating neuroblasts failed to detach properly. Moreover, in a kainate-induced mouse epilepsy model, exogenous reelin had prevented GCD, according to one study.

Alzheimer's disease

The Reelin receptors ApoER2 and VLDLR belong to the LDL receptor gene family. All members of this family are receptors for Apolipoprotein E (ApoE). Therefore, they are often synonymously referred to as 'ApoE receptors'. ApoE occurs in 3 common isoforms (E2, E3, E4) in the human population. ApoE4 is the primary genetic risk factor for late-onset Alzheimer's disease. This strong genetic association has led to the proposal that ApoE receptors play a central role in the pathogenesis of Alzheimer's disease. According to one study, reelin expression and glycosylation patterns are altered in Alzheimer's disease. In the cortex of the patients, reelin levels were 40% higher compared with controls, but the cerebellar levels of the protein remain normal in the same patients. This finding is in agreement with an earlier study showing the presence of Reelin associated with amyloid plaques in a transgenic AD mouse model. A large genetic study of 2008 showed that RELN gene variation is associated with an increased risk of Alzheimer's disease in women. The number of reelin-producing Cajal-Retzius cells is significantly decreased in the first cortical layer of patients. Reelin has been shown to interact with amyloid precursor protein, and, according to one in-vitro study, is able to counteract the Aβ-induced dampening of NMDA-receptor activity. This is modulated by ApoE isoforms, which selectively alter the recycling of ApoER2 as well as AMPA and NMDA receptors.

Cancer

DNA methylation patterns are often changed in tumours, and the RELN gene could be affected: according to one study, in the pancreatic cancer the expression is suppressed, along with other reelin pathway components In the same study, cutting the reelin pathway in cancer cells that still expressed reelin resulted in increased motility and invasiveness. On the contrary, in prostate cancer the RELN expression is excessive and correlates with Gleason score. Retinoblastoma presents another example of RELN overexpression. This gene has also been seen recurrently mutated in cases of acute lymphoblastic leukaemia.

Other conditions

One genome-wide association study indicates a possible role for RELN gene variation in otosclerosis, an abnormal growth of bone of the middle ear. In a statistical search for the genes that are differentially expressed in the brains of cerebral malaria-resistant versus cerebral malaria-susceptible mice, Delahaye et al. detected a significant upregulation of both RELN and DAB1 and speculated on possible protective effects of such over-expression. In 2020, a study reported a novel variant in RELN gene (S2486G) which was associated with ankylosing spondylitis in a large family. This suggested a potential insight into the pathophysiological involvement of reelin via inflammation and osteogenesis pathways in ankylosing spondylitis, and it could broaden the horizon toward new therapeutic strategies. A 2020 study from UT Southwestern Medical Center suggests circulating Reelin levels might correlate with MS severity and stages, and that lowering Reelin levels might be a novel way to treat MS.

Factors affecting reelin expression

Increased cortical reelin expression in the pups of "High LG" (licking and grooming) rats. A figure from Smit-Righter et al., 2009

The expression of reelin is controlled by a number of factors besides the sheer number of Cajal-Retzius cells. For example, TBR1 transcription factor regulates RELN along with other T-element-containing genes. On a higher level, increased maternal care was found to correlate with reelin expression in rat pups; such correlation was reported in hippocampus and in the cortex. According to one report, prolonged exposure to corticosterone significantly decreased reelin expression in murine hippocampi, a finding possibly pertinent to the hypothetical role of corticosteroids in depression. One small postmortem study has found increased methylation of RELN gene in the neocortex of persons past their puberty compared with those that had yet to enter the period of maturation.

Psychotropic medication

As reelin is being implicated in a number of brain disorders and its expression is usually measured posthumously, assessing the possible medication effects is important.

According to the epigenetic hypothesis, drugs that shift the balance in favour of demethylation have a potential to alleviate the proposed methylation-caused downregulation of RELN and GAD67. In one study, clozapine and sulpiride but not haloperidol and olanzapine were shown to increase the demethylation of both genes in mice pretreated with l-methionine. Valproic acid, a histone deacetylase inhibitor, when taken in combination with antipsychotics, is proposed to have some benefits. But there are studies conflicting the main premise of the epigenetic hypothesis, and a study by Fatemi et al. shows no increase in RELN expression by valproic acid; that indicates the need for further investigation.

Fatemi et al. conducted the study in which RELN mRNA and reelin protein levels were measured in rat prefrontal cortex following a 21-day of intraperitoneal injections of the following drugs:

Reelin expression	Clozapine	Fluoxetine	Haloperidol	Lithium	Olanzapine	Valproic Acid
protein	↓	↔	↓	↓	↑	↔
mRNA	↑	↑	↓	↑	↑	↓

In 2009, Fatemi et al. published the more detailed work on rats using the same medication. Here, cortical expression of several participants (VLDLR, DAB1, GSK3B) of the signaling chain was measured besides reelin itself, and also the expression of GAD65 and GAD67.