Search This Blog

Friday, January 31, 2020

Wirehead (science fiction)

From Wikipedia, the free encyclopedia
 
The wires of an implanted deep brain stimulation (DBS) device are visible as white lines in an X-ray of the skull. Large white areas around maxilla and mandible are metal dentures and are unrelated to the DBS device
 
Artist's conception of two DBS wires/electrodes in the human brain.
 
Enlarged artist's conception of two DBS wires/electrodes with multiple contact points in each wire.

Wirehead is a term used in science fiction works to denote different kinds of interaction between people and technology. The typical wirehead idea is that of a wire going into a human's brain and safe amounts of electricity applied to the wire-conductor to directly interact with the brain, or the specific "pleasure centers" of the brain.

Written fiction


Known Space stories

In Larry Niven's Known Space stories, a wirehead is someone who has been fitted with an electronic brain implant (called a "droud" in the stories) to stimulate the pleasure centres of their brain. In the Known Space universe, wireheading is the most addictive habit known (Louis Wu is the only given example of a recovered addict), and wireheads usually die from neglecting themselves in favour of the ceaseless pleasure. Wireheading is so powerful and easy that it becomes an evolutionary pressure, selecting against that portion of Known Space humanity without self-control. Also in this science fiction there is a device called a "tasp" (similar to transcranial magnetic stimulation) that does not need a surgical implant; the pleasure center of a person's brain is found and remotely stimulated (considered a violation without seeking the person's consent beforehand), an important device in the Ringworld novels

A wirehead's death is central to Niven's Gil 'the Arm' Hamilton story, "Death by Ecstasy", published by Galaxy Magazine in 1969, and a main character in the book Ringworld Engineers is a former wirehead trying to quit. 

Niven's stories explain wireheads by mentioning a study in which experimental rats had electrodes implanted at strategic locations in their brains, so that an applied current would induce a pleasant feeling. If the current could be obtained any time the rats pushed the lever, they would use it over and over, ignoring food and physical necessities until they died. Such experiments were actually conducted by James Olds and Peter Milner in the 1950s, first discovering the locations of such areas, and later showing extremes to which rats would go to obtain the stimulus again.

Mindkiller

Mindkiller, a 1982 sci-fi novel by Spider Robinson set in the late 1980s, explores the social implications of technologies to manipulate the brain, beginning with wireheading, the use of electric current to stimulate the pleasure center of the brain in order to achieve a narcotic high.

Shaper/Mechanist stories

In the Shaper/Mechanist stories of Bruce Sterling, "wirehead" is the Mechanist term for a human who has given up corporeal existence and become an infomorph

The Terminal Man

In The Terminal Man (1972) by Michael Crichton, forty electrodes are implanted into the brain of the character Harold Franklin "Harry" Benson to control seizures. However, his pleasure center is also stimulated, and his body begins producing more seizures to receive the pleasurable sensation.

Film and Television


Brainstorm

In the 1983 film Brainstorm a wireless brain connection machine is made. A character named Hal Abramson abuses the device with a signal of never ending sexual pleasure. 

The Outer Limits 1995 TV series


In The Outer Limits episode named "Awakening", season three, episode 10, a neurologically impaired woman receives a brain implant to help her become more like a typical human.

The Centurions (animated series)

In episode 41, "Zone Dancer" of the 1986The Centurions animated series, the lead character Crystal Kane is accused of "Zone Dancing" (the series' term for computer hacking) and seen using a "droud" to interface her brain with computer networks in what is probably the first animated representation of cyberspace and virtual reality. The story, written by Michael Reaves, weaves a future noir tale of cyberpunk espionage, cloning and private-eye procedural, all set in the universe of the animated series and makes copious references to William Gibson's Neuromancer. There is even a Zone Dancer named Gibson and, in what may be an homage to Larry Niven's Louis Wu, a cyberneticst named Dr. Wu.

 

House

The title character of the television show House is a physician who suffers from chronic pain. In the episode "Half-Wit", House seeks a medical procedure to stimulate the "pleasure center" of his brain.

Non-fictional examples

In 1924, Dr Hans Berger succeeded in recording the first human electroencephalogram (EEG).

Dr William Grey Walter wrote a paper in 1938 on the EEG ELECTRO-ENCEPHALOGRAPHY, the measurement of electrical activity in the brain using wires of different types.

Dr Wilder Penfield and Dr Herbert Jasper stimulated the brain to find the places where the patients seizures were coming from.

Dr Reginald Bickford in 1944 is reported to have recorded the EEG of psychiatric patients who had had lobotomies.

After the 1949 Nobel prize was awarded to António Egas Moniz for the procedure of lobotomy, a more precise method of destroying brain structures was pursued. In the year 1955 the placing of wires into the mentally ill patient was performed by Dr C.W. Sem Jacobsen. Dr S. Sherwood also performed wire implantation. In the year 1961 five patients had wires implanted to treat their mental illness and a precision leucotomy was performed for favorable results.

In the 1950s there are several doctors who continued to place wires into the human brain. They worked on epileptic and psychiatric patients brains.

Silver and copper electrodes were found to be toxic to brain tissue. Electrodes are encapsulated by fibrous growths as a inflammatory bodily response to a foreign object.

Dr. J. Lawrence Pool wrote "Effects of Electrical Stimulation of the Human Cerebellar Cortex" and described stimulation of a patients brain. April 1943.

Dr. B S Nashold is used as a reference in many medical writings.

Dr. Robert Galbraith Heath placed electrodes in his subjects' brains in the 1950s to try to treat their mental illness. Dr. Heath wrote several papers on his work of stimulating the various regions of the brain.

Dr. Carl Wilhelm Sem-Jacobsen "Depth-electrographic stimulation of the human brain and behavior; from fourteen years of studies and treatment of Parkinson's disease and mental disorders with implanted electrodes,"

José Manuel Rodriguez Delgado also placed electrodes in his patients' brains. He called his inventions a "stimoceiver" and a "chemitrode".
  • 1953 "Induced paroxysmal electrical activity in man recorded simultaneously through subcortical and scalp electrodes"
  • 1955: The patient, a 27-year-old housewife "Stimulation of the amygdaloid nucleus in a schizophrenic patient" by Robert Galbraith Heath
  • 1963: "Electrical self-stimulation of the brain in man" by Robert Galbraith Heath.
  • 1972: A 24-year-old man with temporal lobe epilepsy, identified as patient "B-19". "He was permitted to wear the device for 3 hours at a time: on one occasion he stimulated his septal region 1,200 times, on another occasion 1,500 times, and on a third occasion 900 times. He protested each time the unit was taken from him, pleading to self-stimulate just a few more times..."
  • 1986: A 48-year-old woman with chronic pain. "The patient self-stimulated throughout the day, neglecting personal hygiene and family commitments."
  • 1986: To treat patients suffering from pain due to cancer Dr Young and Dr Brechner made a study of electrical stimulation of the brain.
  • 2012: Cathy Hutchinson who is paralyzed had one hundred electrodes placed on the surface of her brain. With this brain–computer interface she is able to control a variety of devices.
  • 2013: A 49-year-old, right-handed woman had multiple electrodes placed in her brain for epilepsy. She reported an orgasmic ecstasy following the stimulation of the left hippocampus.
  • 2016: The New England Journal of Medicine describes a growing do-it-yourself (DIY) medical engineering culture that includes DIY transcranial direct-current stimulation
  • 2019:"Electronic implants studied for treatment of drug addiction" In China, doctors are treating addiction with brain implants aimed to stimulate the nucleus accumbens.

Brain implant

From Wikipedia, the free encyclopedia
 
A laboratory rat with a brain implant used to record neuronal activity
 
Brain implants, often referred to as neural implants, are technological devices that connect directly to a biological subject's brain – usually placed on the surface of the brain, or attached to the brain's cortex. A common purpose of modern brain implants and the focus of much current research is establishing a biomedical prosthesis circumventing areas in the brain that have become dysfunctional after a stroke or other head injuries. This includes sensory substitution, e.g., in vision. Other brain implants are used in animal experiments simply to record brain activity for scientific reasons. Some brain implants involve creating interfaces between neural systems and computer chips. This work is part of a wider research field called brain-computer interfaces. (Brain-computer interface research also includes technology such as EEG arrays that allow interface between mind and machine but do not require direct implantation of a device.) 

Neural implants such as deep brain stimulation and Vagus nerve stimulation are increasingly becoming routine for patients with Parkinson's disease and clinical depression, respectively.

Purpose

Brain implants electrically stimulate, block or record (or both record and stimulate simultaneously) signals from single neurons or groups of neurons (biological neural networks) in the brain. The blocking technique is called intra-abdominal vagal blocking. This can only be done where the functional associations of these neurons are approximately known. Because of the complexity of neural processing and the lack of access to action potential related signals using neuroimaging techniques, the application of brain implants has been seriously limited until recent advances in neurophysiology and computer processing power. Much research is also being done on the surface chemistry of neural implants in effort to design products which minimize all negative effects that an active implant can have on the brain, and that the body can have on the function of the implant. Researchers are also exploring a range of delivery systems, such as using veins, to deliver these implants without brain surgery; by leaving the skull sealed shut, patients could receive their neural implants without running as great a risk of seizures, strokes, or permanent neural impairments, all of which can be caused by open-brain surgery.

Research and applications

Research in sensory substitution has made significant progress since 1970. Especially in vision, due to the knowledge of the working of the visual system, eye implants (often involving some brain implants or monitoring) have been applied with demonstrated success. For hearing, cochlear implants are used to stimulate the auditory nerve directly. The vestibulocochlear nerve is part of the peripheral nervous system, but the interface is similar to that of true brain implants.

Multiple projects have demonstrated success at recording from the brains of animals for long periods of time. As early as 1976, researchers at the NIH led by Edward Schmidt made action potential recordings of signals from rhesus monkey motor cortexes using immovable "hatpin" electrodes, including recording from single neurons for over 30 days, and consistent recordings for greater than three years from the best electrodes. 

The "hatpin" electrodes were made of pure iridium and insulated with Parylene, materials that are currently used in the Cyberkinetics implementation of the Utah array. These same electrodes, or derivations thereof using the same biocompatible electrode materials, are currently used in visual prosthetics laboratories, laboratories studying the neural basis of learning, and motor prosthetics approaches other than the Cyberkinetics probes.

Schematic of the "Utah" Electrode Array
 
Other laboratory groups produce their own implants to provide unique capabilities not available from the commercial products.

Breakthroughs include studies of the process of functional brain re-wiring throughout the learning of a sensory discrimination, control of physical devices by rat brains, monkeys over robotic arms, remote control of mechanical devices by monkeys and humans, remote control over the movements of roaches, the first reported use of the Utah Array in a human for bidirectional signalling. Currently a number of groups are conducting preliminary motor prosthetic implants in humans. These studies are presently limited to several months by the longevity of the implants. The array now forms the sensor component of the Braingate

Much research is also being done on the surface chemistry of neural implants in effort to design products which minimize all negative effects that an active implant can have on the brain, and that the body can have on the function of the implant. 

Another type of neural implant that is being experimented on is Prosthetic Neuronal Memory Silicon Chips, which imitate the signal processing done by functioning neurons that allows peoples' brains to create long-term memories. 

In 2016, scientists at the University of Illinois at Urbana–Champaign announced development of tiny brain sensors for use postoperative monitoring, which melt away when they are no longer needed.

In 2016, scientists out of the University of Melbourne published proof-of-concept data related to a discovery for Stentrode, a device implanted via the jugular vein, demonstrated the potential for a neural recording device to be engineered onto a stent and implanted into a blood vessel in the brain, without the need for open brain surgery. The technology platform is being developed for patients with paralysis to facilitate control of external devices such as robotic limbs, computers and exoskeletons by translating brain activity. It may ultimately help diagnose and treat a range of brain pathologies, such as epilepsy and Parkinson’s disease.

Military

DARPA has announced its interest in developing "cyborg insects" to transmit data from sensors implanted into the insect during the pupal stage. The insect's motion would be controlled from a Micro-Electro-Mechanical System (MEMS) and could conceivably survey an environment or detect explosives and gas. Similarly, DARPA is developing a neural implant to remotely control the movement of sharks. The shark's unique senses would then be exploited to provide data feedback in relation to enemy ship movement or underwater explosives.

In 2006, researchers at Cornell University invented a new surgical procedure to implant artificial structures into insects during their metamorphic development. The first insect cyborgs, moths with integrated electronics in their thorax, were demonstrated by the same researchers. The initial success of the techniques has resulted in increased research and the creation of a program called Hybrid-Insect-MEMS, HI-MEMS. Its goal, according to DARPA's Microsystems Technology Office, is to develop "tightly coupled machine-insect interfaces by placing micro-mechanical systems inside the insects during the early stages of metamorphosis".

The use of neural implants has recently been attempted, with success, on cockroaches. Surgically applied electrodes were put on the insect, which were remotely controlled by a human. The results, although sometimes different, basically showed that the cockroach could be controlled by the impulses it received through the electrodes. DARPA is now funding this research because of its obvious beneficial applications to the military and other areas.

In 2009 at the Institute of Electrical and Electronics Engineers (IEEE) Micro-electronic mechanical systems (MEMS) conference in Italy, researchers demonstrated the first "wireless" flying-beetle cyborg. Engineers at the University of California at Berkeley pioneered the design of a "remote controlled beetle", funded by the DARPA HI-MEMS Program. This was followed later that year by the demonstration of wireless control of a "lift-assisted" moth-cyborg.

Eventually researchers plan to develop HI-MEMS for dragonflies, bees, rats and pigeons. For the HI-MEMS cybernetic bug to be considered a success, it must fly 100 metres (330 ft) from a starting point, guided via computer into a controlled landing within 5 metres (16 ft) of a specific end point. Once landed, the cybernetic bug must remain in place.

In 2012, DARPA provided seed funding to Dr. Thomas Oxley, a neurointerventionist at Mount Sinai Hospital in New York City, for a technology that became known as Stentrode. Oxley’s group in Australia was the only non-US-based funded by DARPA as part of the Reliable Neural Interface Technology (RE-NET) program. This technology is the first to attempt to provide neural implants through a minimally invasive surgical procedure that does not require cutting into the skull. That is, an electrode array built onto a self-expanding stent, implanted into the brain via cerebral angiography. This pathway can provide safe, easy access and capture a strong signal for a number of indications beyond addressing paralysis, and is currently in clinical trials in patients with severe paralysis seeking to regain the ability to communicate. 

In 2015 it was reported that scientists from the Perception and Recognition Neuro-technologies Laboratory at the Southern Federal University in Rostov-on-Don suggested using rats with microchips planted in their brains to detect explosive devices.

In 2016 it was reported that American engineers are developing a system that would transform locusts into "remote controlled explosive detectors" with electrodes in their brains beaming information about dangerous substances back to their operators.


Rehabilitation

Neurostimulators have been in use since 1997 to ease the symptoms of such diseases as epilepsy, Parkinson's disease, dystonia and recently depression.

Current brain implants are made from a variety of materials such as tungsten, silicon, platinum-iridium, or even stainless steel. Future brain implants may make use of more exotic materials such as nanoscale carbon fibers (nanotubes), and polycarbonate urethane.

Brain implants are also being explored by DARPA as part of the Reliable Neural-Interface Technology (RE-NET) program launched in 2010 to directly address the need for high-performance neural interfaces to control the dexterous functions made possible by DARPA’s advanced prosthetic limbs. The goal is to provide high-bandwidth, intuitive control interface for these limbs, they will not achieve their full potential to improve quality of life for wounded troops.

Historical research

In 1870, Eduard Hitzig and Gustav Fritsch demonstrated that electrical stimulation of the brains of dogs could produce movements. Robert Bartholow showed the same to be true for humans in 1874. By the start of the 20th century, Fedor Krause began to systematically map human brain areas, using patients that had undergone brain surgery.

Prominent research was conducted in the 1950s. Robert G. Heath experimented with aggressive mental patients, aiming to influence his subjects' moods through electrical stimulation.

Yale University physiologist Jose Delgado demonstrated limited control of animal and human subjects' behaviours using electronic stimulation. He invented the stimoceiver or transdermal stimulator, a device implanted in the brain to transmit electrical impulses that modify basic behaviours such as aggression or sensations of pleasure.

Delgado was later to write a popular book on mind control, called Physical Control of the Mind, where he stated: "the feasibility of remote control of activities in several species of animals has been demonstrated [...] The ultimate objective of this research is to provide an understanding of the mechanisms involved in the directional control of animals and to provide practical systems suitable for human application."

In the 1950s, the CIA also funded research into mind control techniques, through programs such as MKULTRA. Perhaps because he received funding for some research through the US Office of Naval Research, it has been suggested (but not proven) that Delgado also received backing through the CIA. He denied this claim in a 2005 article in Scientific American describing it only as a speculation by conspiracy-theorists. He stated that his research was only progressively scientifically motivated to understand how the brain works.

Recent advances in neurotechnologies and neuroimaging, along with an increased understanding of neurocircuitry, are factors contributing to the rapid rise in the use of neurostimulation therapies to treat an increasingly wide range of neurologic and psychiatric disorders. Electrical stimulation technologies are evolving after remaining fairly stagnant for the past 30 years, moving toward potential closed-loop therapeutic control systems with the ability to deliver stimulation with higher spatial resolution to provide continuous customized neuromodulation for optimal clinical outcomes.

Concerns and ethical considerations

Ethical questions raised include who are good candidates to receive neural implants and what are good and bad uses of neural implants. Whilst deep brain stimulation is increasingly becoming routine for patients with Parkinson's disease, there may be some behavioural side effects. Reports in the literature describe the possibility of apathy, hallucinations, compulsive gambling, hypersexuality, cognitive dysfunction, and depression. However, these may be temporary and related to correct placement and calibration of the stimulator and so are potentially reversible.

Some transhumanists, such as Raymond Kurzweil and Kevin Warwick, see brain implants as part of a next step for humans in progress and evolution, whereas others, especially bioconservatives, view them as unnatural, with humankind losing essential human qualities. It raises controversy similar to other forms of human enhancement. For instance, it is argued that implants would technically change people into cybernetic organisms (cyborgs). It's also expected that all research will comply to the Declaration of Helsinki. Yet further, the usual legal duties apply such as information to the person wearing implants and that the implants are voluntary, with (very) few exceptions.

Other concerns involve vulnerabilities of neural implants to cybercrime or intrusive surveillance as neural implants could be hacked, misused or misdesigned.

Sadja states that "one's private thoughts are important to protect" and doesn't consider it a good idea to just charge the government or any company with protecting them. Walter Glannon, a neuroethicist of the University of Calgary notes that "there is a risk of the microchips being hacked by third parties" and that "this could interfere with the user's intention to perform actions, violate privacy by extracting information from the chip".

Synaptogenesis

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

Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenesis. Synaptogenesis is particularly important during an individual's critical period, during which there is a certain degree of synaptic pruning due to competition for neural growth factors by neurons and synapses. Processes that are not used, or inhibited during their critical period will fail to develop normally later on in life.

Formation of the neuromuscular junction


Function

The neuromuscular junction (NMJ) is the most well-characterized synapse in that it provides a simple and accessible structure that allows for easy manipulation and observation. The synapse itself is composed of three cells: the motor neuron, the myofiber, and the Schwann cell. In a normally functioning synapse, a signal will cause the motor neuron to depolarize, by releasing the neurotransmitter acetylcholine (ACh). Acetylcholine travels across the synaptic cleft where it reaches acetylcholine receptors (AChR) on the plasma membrane of the myofiber, the sarcolemma. As the AChRs open ion channels, the membrane depolarizes, causing muscle contraction. The entire synapse is covered in a myelin sheath provided by the Schwann cell to insulate and encapsulate the junction. Another important part of the neuromuscular system and central nervous system are the astrocytes. While originally they were thought to have only functioned as support for the neurons, they play an important role in functional plasticity of synapses.

Origin and movement of cells

During development, each of the three germ layer cell types arises from different regions of the growing embryo. The individual myoblasts originate in the mesoderm and fuse to form a multi-nucleated myotube. During or shortly after myotube formation, motoneurons from the neural tube form preliminary contacts with the myotube. The Schwann cells arise from the neural crest and are led by the axons to their destination. Upon reaching it, they form a loose, unmyelinated covering over the innervating axons. The movement of the axons (and subsequently the Schwann cells) is guided by the growth cone, a filamentous projection of the axon that actively searches for neurotrophins released by the myotube.

The specific patterning of synapse development at the neuromuscular junction shows that the majority of muscles are innervated at their midpoints. Although it may seem that the axons specifically target the midpoint of the myotube, several factors reveal that this is not a valid claim. It appears that after the initial axonal contact, the newly formed myotube proceeds to grow symmetrically from that point of innervation. Coupled with the fact that AChR density is the result of axonal contact instead of the cause, the structural patterns of muscle fibers can be attributed to both myotatic growth as well as axonal innervation.

The preliminary contact formed between the motoneuron and the myotube generates synaptic transmission almost immediately, but the signal produced is very weak. There is evidence that Schwann cells may facilitate these preliminary signals by increasing the amount of spontaneous neurotransmitter release through small molecule signals. After about a week, a fully functional synapse is formed following several types of differentiation in both the post-synaptic muscle cell and the pre-synaptic motoneuron. This pioneer axon is of crucial importance because the new axons that follow have a high propensity for forming contacts with well-established synapses.

Post-synaptic differentiation

The most noticeable difference in the myotube following contact with the motoneuron is the increased concentration of AChR in the plasma membrane of the myotube in the synapse. This increased amount of AChR allows for more effective transmission of synaptic signals, which in turn leads to a more-developed synapse. The density of AChR is > 10,000/μm2 and approximately 10/μm2 around the edge. This high concentration of AChR in the synapse is achieved through clustering of AChR, up-regulation of the AChR gene transcription in the post-synaptic nuclei, and down-regulation of the AChR gene in the non-synaptic nuclei. The signals that initiate post-synaptic differentiation may be neurotransmitters released directly from the axon to the myotube, or they may arise from changes activated in the extracellular matrix of the synaptic cleft.

Clustering

AChR experiences multimerization within the post-synaptic membrane largely due to the signaling molecule Agrin. The axon of the motoneuron releases agrin, a proteoglycan that initiates a cascade that eventually leads to AChR association. Agrin binds to a muscle-specific kinase (MuSK) receptor in the post-synaptic membrane, and this in turn leads to downstream activation of the cytoplasmic protein Rapsyn. Rapsyn contains domains that allow for AChR association and multimerization, and it is directly responsible for AChR clustering in the post-synaptic membrane: rapsyn-deficient mutant mice fail to form AChR clusters.

Synapse-specific transcription

The increased concentration of AChR is not simply due to a rearrangement of pre-existing synaptic components. The axon also provides signals that regulate gene expression within the myonuclei directly beneath the synapse. This signaling provides for localized up-regulation of transcription of AChR genes and consequent increase in local AChR concentration. The two signaling molecules released by the axon are calcitonin gene-related peptide (CGRP) and neuregulin, which trigger a series of kinases that eventually lead to transcriptional activation of the AChR genes.

Extrasynaptic repression

Repression of the AChR gene in the non-synaptic nuclei is an activity-dependent process involving the electrical signal generated by the newly formed synapse. Reduced concentration of AChR in the extrasynaptic membrane in addition to increased concentration in the post-synaptic membrane helps ensure the fidelity of signals sent by the axon by localizing AChR to the synapse. Because the synapse begins receiving inputs almost immediately after the motoneuron comes into contact with the myotube, the axon quickly generates an action potential and releases ACh. The depolarization caused by AChR induces muscle contraction and simultaneously initiates repression of AChR gene transcription across the entire muscle membrane. Note that this affects gene transcription at a distance: the receptors that are embedded within the post-synaptic membrane are not susceptible to repression.

Pre-synaptic differentiation

Although the mechanisms regulating pre-synaptic differentiation are unknown, the changes exhibited at the developing axon terminal are well characterized. The pre-synaptic axon shows an increase in synaptic volume and area, an increase of synaptic vesicles, clustering of vesicles at the active zone, and polarization of the pre-synaptic membrane. These changes are thought to be mediated by neurotrophin and cell adhesion molecule release from muscle cells, thereby emphasizing the importance of communication between the motoneuron and the myotube during synaptogenesis. Like post-synaptic differentiation, pre-synaptic differentiation is thought to be due to a combination of changes in gene expression and a redistribution of pre-existing synaptic components. Evidence for this can be seen in the up-regulation of genes expressing vesicle proteins shortly after synapse formation as well as their localization at the synaptic terminal.

Synaptic maturation

Immature synapses are multiply innervated at birth, due the high propensity for new axons to innervate at a pre-existing synapse. As the synapse matures, the synapses segregate and eventually all axonal inputs except for one retract in a process called synapse elimination. Furthermore, the post-synaptic end plate grows deeper and creates folds through invagination to increase the surface area available for neurotransmitter reception. At birth, Schwann cells form loose, unmyelinated covers over groups of synapses, but as the synapse matures, Schwann cells become dedicated to a single synapse and form a myelinated cap over the entire neuromuscular junction.

Synapse elimination

The process of synaptic pruning known as synapse elimination is a presumably activity-dependent process that involves competition between axons. Hypothetically, a synapse strong enough to produce an action potential will trigger the myonuclei directly across from the axon to release synaptotrophins that will strengthen and maintain well-established synapses. This synaptic strengthening is not conferred upon the weaker synapses, thereby starving them out. It has also been suggested that in addition to the synaptotrophins released to the synapse exhibiting strong activity, the depolarization of the post-synaptic membrane causes release of synaptotoxins that ward off weaker axons.

Synapse formation specificity

A remarkable aspect of synaptogenesis is the fact that motoneurons are able to distinguish between fast and slow-twitch muscle fibers; fast-twitch muscle fibers are innervated by "fast" motoneurons, and slow-twitch muscle fibers are innervated by "slow" motoneurons. There are two hypothesized paths by which the axons of motoneurons achieve this specificity, one in which the axons actively recognize the muscles that they innervate and make selective decisions based on inputs, and another that calls for more indeterminate innervation of muscle fibers. In the selective paths, the axons recognize the fiber type, either by factors or signals released specifically by the fast or slow-twitch muscle fibers. In addition, selectivity can be traced to the lateral position that the axons are predeterminately arranged in order to link them to the muscle fiber that they will eventually innervate. The hypothesized non-selective pathways indicate that the axons are guided to their destinations by the matrix through which they travel. Essentially, a path is laid out for the axon and the axon itself is not involved in the decision-making process. Finally, the axons may non-specifically innervate muscle fibers and cause the muscles to acquire the characteristics of the axon that innervates them. In this path, a "fast" motoneuron can convert any muscle fiber into a fast-twitch muscle fiber. There is evidence for both selective and non-selective paths in synapse formation specificity, leading to the conclusion that the process is a combination of several factors.

Central nervous system synapse formation

Although the study of synaptogenesis within the central nervous system (CNS) is much more recent than that of the NMJ, there is promise of relating the information learned at the NMJ to synapses within the CNS. Many similar structures and basic functions exist between the two types of neuronal connections. At the most basic level, the CNS synapse and the NMJ both have a nerve terminal that is separated from the postsynaptic membrane by a cleft containing specialized extracellular material. Both structures exhibit localized vesicles at the active sites, clustered receptors at the post-synaptic membrane, and glial cells that encapsulate the entire synaptic cleft. In terms of synaptogenesis, both synapses exhibit differentiation of the pre- and post-synaptic membranes following initial contact between the two cells. This includes the clustering of receptors, localized up-regulation of protein synthesis at the active sites, and neuronal pruning through synapse elimination.

Despite these similarities in structure, there is a fundamental difference between the two connections. The CNS synapse is strictly neuronal and does not involve muscle fibers: for this reason the CNS uses different neurotransmitter molecules and receptors. More importantly, neurons within the CNS often receive multiple inputs that must be processed and integrated for successful transfer of information. Muscle fibers are innervated by a single input and operate in an all or none fashion. Coupled with the plasticity that is characteristic of the CNS neuronal connections, it is easy to see how increasingly complex CNS circuits can become.

Factors regulating synaptogenesis in the CNS


Signaling

The main method of synaptic signaling in the NMJ is through use of the neurotransmitter acetylcholine and its receptor. The CNS homolog is glutamate and its receptors, and one of special significance is the N-methyl-D-aspartate (NMDA) receptor. It has been shown that activation of NMDA receptors initiates synaptogenesis through activation of downstream products. The heightened level of NMDA receptor activity during development allows for increased influx of calcium, which acts as a secondary signal. Eventually, immediate early genes (IEG) are activated by transcription factors and the proteins required for neuronal differentiation are translated. The NMDA receptor function is associated with the estrogen receptor in hippocampal neurons. Experiments conducted with estradiol show that exposure to the estrogen significantly increases synaptic density and protein concentration.

Synaptic signaling during synaptogenesis is not only activity-dependent, but is also dependent on the environment in which the neurons are located. For instance, brain-derived neurotrophic factor (BDNF) is produced by the brain and regulates several functions within the developing synapse, including enhancement of transmitter release, increased concentration of vesicles, and cholesterol biosynthesis. Cholesterol is essential to synaptogenesis because the lipid rafts that it forms provide a scaffold upon which numerous signaling interactions can occur. BDNF-null mutants show significant defects in neuronal growth and synapse formation. Aside from neurotrophins, cell-adhesion molecules are also essential to synaptogenesis. Often the binding of pre-synaptic cell-adhesion molecules with their post-synaptic partners triggers specializations that facilitate synaptogenesis. Indeed, a defect in genes encoding neuroligin, a cell-adhesion molecule found in the post-synaptic membrane, has been linked to cases of autism and mental retardation. Finally, many of these signaling processes can be regulated by matrix metalloproteinases (MMPs) as the targets of many MMPs are these specific cell-adhesion molecules.

Morphology

The special structure found in the CNS that allows for multiple inputs is the dendritic spine, the highly dynamic site of excitatory synapses. This morphological dynamism is due to the specific regulation of the actin cytoskeleton, which in turn allows for regulation of synapse formation. Dendritic spines exhibit three main morphologies: filopodia, thin spines, and mushroom spines. The filopodia play a role in synaptogenesis through initiation of contact with axons of other neurons. Filopodia of new neurons tend to associate with multiply synapsed axons, while the filopodia of mature neurons tend to sites devoid of other partners. The dynamism of spines allows for the conversion of filopodia into the mushroom spines that are the primary sites of glutamate receptors and synaptic transmission.

Environmental enrichment

Rats raised with environmental enrichment have 25% more synapses than controls. This effect occurs whether a more stimulating environment is experienced immediately following birth, after weaning, or during maturity. Stimulation effects not only synaptogenesis upon pyramidal neurons but also stellate ones.

Contributions of the Wnt protein family

The (Wnt) family, includes several embryonic morphogens that contribute to early pattern formation in the developing embryo. Recently data have emerged showing that the Wnt protein family has roles in the later development of synapse formation and plasticity. Wnt contribution to synaptogenesis has been verified in both the central nervous system and the neuromuscular junction.

Central nervous system

Wnt family members contribute to synapse formation in the cerebellum by inducing presynaptic and postsynaptic terminal formation. This brain region contains three main neuronal cell types- Purkinje cells, granule cells and mossy fiber cells. Wnt-3 expression contributes to Purkinje cell neurite outgrowth and synapse formation. Granule cells express Wnt-7a to promote axon spreading and branching in their synaptic partner, mossy fiber cells. Retrograde secretion of Wnt-7a to mossy fiber cells causes growth cone enlargement by spreading microtubules. Furthermore, Wnt-7a retrograde signaling recruits synaptic vesicles and presynaptic proteins to the synaptic active zone. Wnt-5a performs a similar function on postsynaptic granule cells; this Wnt stimulates receptor assembly and clustering of the scaffolding protein PSD-95.

In the hippocampus Wnts in conjunction with cell electrical activity promote synapse formation. Wnt7b is expressed in maturing dendrites, and the expression of the Wnt receptor Frizzled (Fz), increases highly with synapse formation in the hippocampus. NMDA glutamate receptor activation increases Wnt2 expression. Long term potentiation (LTP) due to NMDA activation and subsequent Wnt expression leads to Fz-5 localization at the postsynaptic active zone. Furthermore, Wnt7a and Wnt2 signaling after NMDA receptor mediated LTP leads to increased dendritic arborization and regulates activity induced synaptic plasticity. Blocking Wnt expression in the hippocampus mitigates these activity dependent effects by reducing dendritic arborization and subsequently, synaptic complexity.

Neuromuscular junction

Similar mechanisms of action by Wnts in the central nervous system are observed in the neuromuscular junction (NMJ) as well. In the Drosophila NMJ mutations in the Wnt5 receptor Derailed (drl) reduce the number of and density of synaptic active zones. The major neurotransmitter in this system is glutamate. Wnt is needed to localize glutamatergic receptors on postsynaptic muscle cells. As a result, Wnt mutations diminish evoked currents on the postsynaptic muscle.

In the vertebrate NMJ, motor neuron expression of Wnt-11r contributes to acetylcholine receptor (AChR) clustering in the postsynaptic density of muscle cells. Wnt-3 is expressed by muscle fibers and is secreted retrogradely onto motor neurons. In motor neurons, Wnt-3 works with Agrin to promote growth cone enlargement, axon branching and synaptic vesicle clustering.

Dendritic spine

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Dendritic_spine
 
Dendritic spine
Dendritic spines.jpg
Spiny dendrite of a striatal medium spiny neuron.
Spline types 3D.png
Common types of dendritic spines.
Details
Identifiers
Latingemmula dendritica
MeSHD049229
THH2.00.06.1.00036

A dendritic spine (or spine) is a small membranous protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body. Most spines have a bulbous head (the spine head), and a thin neck that connects the head of the spine to the shaft of the dendrite. The dendrites of a single neuron can contain hundreds to thousands of spines. In addition to spines providing an anatomical substrate for memory storage and synaptic transmission, they may also serve to increase the number of possible contacts between neurons.

Structure

Dendritic spines are small with spine head volumes ranging 0.01 μm3 to 0.8 μm3. Spines with strong synaptic contacts typically have a large spine head, which connects to the dendrite via a membranous neck. The most notable classes of spine shape are "thin", "stubby", "mushroom", and "branched". Electron microscopy studies have shown that there is a continuum of shapes between these categories. The variable spine shape and volume is thought to be correlated with the strength and maturity of each spine-synapse. 

Distribution

Dendritic spines usually receive excitatory input from axons, although sometimes both inhibitory and excitatory connections are made onto the same spine head. Excitatory axon proximity to dendritic spines is not sufficient to predict the presence of a synapse, as demonstrated by the Lichtman lab in 2015.

Spines are found on the dendrites of most principal neurons in the brain, including the pyramidal neurons of the neocortex, the medium spiny neurons of the striatum, and the Purkinje cells of the cerebellum. Dendritic spines occur at a density of up to 5 spines/1 μm stretch of dendrite. Hippocampal and cortical pyramidal neurons may receive tens of thousands of mostly excitatory inputs from other neurons onto their equally numerous spines, whereas the number of spines on Purkinje neuron dendrites is an order of magnitude larger. 

Cytoskeleton and organelles

The cytoskeleton of dendritic spines is particularly important in their synaptic plasticity; without a dynamic cytoskeleton, spines would be unable to rapidly change their volumes or shapes in responses to stimuli. These changes in shape might affect the electrical properties of the spine. The cytoskeleton of dendritic spines is primarily made of filamentous actin (F-actin). tubulin Monomers and microtubule-associated proteins (MAPs) are present, and organized microtubules are present. Because spines have a cytoskeleton of primarily actin, this allows them to be highly dynamic in shape and size. The actin cytoskeleton directly determines the morphology of the spine, and actin regulators, small GTPases such as Rac, RhoA, and CDC42, rapidly modify this cytoskeleton. Overactive Rac1 results in consistently smaller dendritic spines.

In addition to their electrophysiological activity and their receptor-mediated activity, spines appear to be vesicularly active and may even translate proteins. Stacked discs of the smooth endoplasmic reticulum (SERs) have been identified in dendritic spines. Formation of this "spine apparatus" depends on the protein synaptopodin and is believed to play an important role in calcium handling. "Smooth" vesicles have also been identified in spines, supporting the vesicular activity in dendritic spines. The presence of polyribosomes in spines also suggests protein translational activity in the spine itself, not just in the dendrite. 

Physiology


Receptor activity

Dendritic spines express glutamate receptors (e.g. AMPA receptor and NMDA receptor) on their surface. The TrkB receptor for BDNF is also expressed on the spine surface, and is believed to play a role in spine survival. The tip of the spine contains an electron-dense region referred to as the "postsynaptic density" (PSD). The PSD directly apposes the active zone of its synapsing axon and comprises ~10% of the spine's membrane surface area; neurotransmitters released from the active zone bind receptors in the postsynaptic density of the spine. Half of the synapsing axons and dendritic spines are physically tethered by calcium-dependent cadherin, which forms cell-to-cell adherent junctions between two neurons. 

Glutamate receptors (GluRs) are localized to the postsynaptic density, and are anchored by cytoskeletal elements to the membrane. They are positioned directly above their signalling machinery, which is typically tethered to the underside of the plasma membrane, allowing signals transmitted by the GluRs into the cytosol to be further propagated by their nearby signalling elements to activate signal transduction cascades. The localization of signalling elements to their GluRs is particularly important in ensuring signal cascade activation, as GluRs would be unable to affect particular downstream effects without nearby signallers.

Signalling from GluRs is mediated by the presence of an abundance of proteins, especially kinases, that are localized to the postsynaptic density. These include calcium-dependent calmodulin, CaMKII (calmodulin-dependent protein kinase II), PKC (Protein Kinase C), PKA (Protein Kinase A), Protein Phosphatase-1 (PP-1), and Fyn tyrosine kinase. Certain signallers, such as CaMKII, are upregulated in response to activity.

Spines are particularly advantageous to neurons by compartmentalizing biochemical signals. This can help to encode changes in the state of an individual synapse without necessarily affecting the state of other synapses of the same neuron. The length and width of the spine neck has a large effect on the degree of compartmentalization, with thin spines being the most biochemically isolated spines. 

Plasticity

Dendritic spines are very "plastic", that is, spines change significantly in shape, volume, and number in small time courses. Because spines have a primarily actin cytoskeleton, they are dynamic, and the majority of spines change their shape within seconds to minutes because of the dynamicity of actin remodeling. Furthermore, spine number is very variable and spines come and go; in a matter of hours, 10-20% of spines can spontaneously appear or disappear on the pyramidal cells of the cerebral cortex, although the larger "mushroom"-shaped spines are the most stable.

Spine maintenance and plasticity is activity-dependent and activity-independent. BDNF partially determines spine levels, and low levels of AMPA receptor activity is necessary to maintain spine survival, and synaptic activity involving NMDA receptors encourages spine growth. Furthermore, two-photon laser scanning microscopy and confocal microscopy have shown that spine volume changes depending on the types of stimuli that are presented to a synapse. 

Importance to learning and memory


Evidence of importance

A depiction of spine formation and elimination.
Experience-dependent spine formation and elimination

Spine plasticity is implicated in motivation, learning, and memory. In particular, long-term memory is mediated in part by the growth of new dendritic spines (or the enlargement of pre-existing spines) to reinforce a particular neural pathway. Because dendritic spines are plastic structures whose lifespan is influenced by input activity, spine dynamics may play an important role in the maintenance of memory over a lifetime. 

Age-dependent changes in the rate of spine turnover suggest that spine stability impacts developmental learning. In youth, dendritic spine turnover is relatively high and produces a net loss of spines. This high rate of spine turnover may characterize critical periods of development and reflect learning capacity in adolescence—different cortical areas exhibit differing levels of synaptic turnover during development, possibly reflecting varying critical periods for specific brain regions. In adulthood, however, most spines remain persistent, and the half-life of spines increases. This stabilization occurs due to a developmentally regulated slow-down of spine elimination, a process which may underlie the stabilization of memories in maturity.

Experience-induced changes in dendritic spine stability also point to spine turnover as a mechanism involved in the maintenance of long-term memories, though it is unclear how sensory experience affects neural circuitry. Two general models might describe the impact of experience on structural plasticity. On the one hand, experience and activity may drive the discrete formation of relevant synaptic connections that store meaningful information in order to allow for learning. On the other hand, synaptic connections may be formed in excess, and experience and activity may lead to the pruning of extraneous synaptic connections.

In lab animals of all ages, environmental enrichment has been related to dendritic branching, spine density, and overall number of synapses. In addition, skill training has been shown to lead to the formation and stabilization of new spines while destabilizing old spines, suggesting that the learning of a new skill involves a rewiring process of neural circuits. Since the extent of spine remodeling correlates with success of learning, this suggests a crucial role of synaptic structural plasticity in memory formation. In addition, changes in spine stability and strengthening occur rapidly and have been observed within hours after training.

Conversely, while enrichment and training are related to increases in spine formation and stability, long-term sensory deprivation leads to an increase in the rate of spine elimination and therefore impacts long-term neural circuitry. Upon restoring sensory experience after deprivation in adolescence, spine elimination is accelerated, suggesting that experience plays an important role in the net loss of spines during development. In addition, other sensory deprivation paradigms—such as whisker trimming—have been shown to increase the stability of new spines.

Research in neurological diseases and injuries shed further light on the nature and importance of spine turnover. After stroke, a marked increase in structural plasticity occurs near the trauma site, and a five- to eightfold increase from control rates in spine turnover has been observed. Dendrites disintegrate and reassemble rapidly during ischemia—as with stroke, survivors showed an increase in dendritic spine turnover. While a net loss of spines is observed in Alzheimer's disease and cases of intellectual disability, cocaine and amphetamine use have been linked to increases in dendritic branching and spine density in the prefrontal cortex and the nucleus accumbens. Because significant changes in spine density occur in various brain diseases, this suggests a balanced state of spine dynamics in normal circumstances, which may be susceptible to disequilibrium under varying pathological conditions.

There is also some evidence for loss of dendritic spines as a consequence of aging. One study using mice has noted a correlation between age-related reductions in spine densities in the hippocampus and age-dependent declines in hippocampal learning and memory.

Importance contested

Despite experimental findings that suggest a role for dendritic spine dynamics in mediating learning and memory, the degree of structural plasticity's importance remains debatable. For instance, studies estimate that only a small portion of spines formed during training actually contribute to lifelong learning. In addition, the formation of new spines may not significantly contribute to the connectivity of the brain, and spine formation may not bear as much of an influence on memory retention as other properties of structural plasticity, such as the increase in size of spine heads.

Modeling

Theoreticians have for decades hypothesized about the potential electrical function of spines, yet our inability to examine their electrical properties has until recently stopped theoretical work from progressing too far. Recent advances in imaging techniques along with increased use of two-photon glutamate uncaging have led to a wealth of new discoveries; we now suspect that there are voltage-dependent sodium, potassium, and calcium channels in the spine heads.

Cable theory provides the theoretical framework behind the most "simple" method for modelling the flow of electrical currents along passive neural fibres. Each spine can be treated as two compartments, one representing the neck, the other representing the spine head. The compartment representing the spine head alone should carry the active properties. 

Baer and Rinzel's continuum model

To facilitate the analysis of interactions between many spines, Baer & Rinzel formulated a new cable theory for which the distribution of spines is treated as a continuum. In this representation, spine head voltage is the local spatial average of membrane potential in adjacent spines. The formulation maintains the feature that there is no direct electrical coupling between neighboring spines; voltage spread along dendrites is the only way for spines to interact.

Spike-diffuse-spike model

The SDS model was intended as a computationally simple version of the full Baer and Rinzel model. It was designed to be analytically tractable and have as few free parameters as possible while retaining those of greatest significance, such as spine neck resistance. The model drops the continuum approximation and instead uses a passive dendrite coupled to excitable spines at discrete points. Membrane dynamics in the spines are modelled using integrate and fire processes. The spike events are modelled in a discrete fashion with the wave form conventionally represented as a rectangular function. 

Modeling spine calcium transients

Calcium transients in spines are a key trigger for synaptic plasticity. NMDA receptors, which have a high permeability for calcium, only conduct ions if the membrane potential is suffiently depolarized. The amount of calcium entering a spine during synaptic activity therefore depends on the depolarization of the spine head. Evidence from calcium imaging experiments (two-photon microscopy) and from compartmental modelling indicates that spines with high resistance necks experience larger calcium transients during synaptic activity.

Development

Dendritic spines can develop directly from dendritic shafts or from dendritic filopodia. During synaptogenesis, dendrites rapidly sprout and retract filopodia, small membrane organelle-lacking membranous protrusions. Recently, I-BAR protein MIM was found to contribute to the initiation process. During the first week of birth, the brain is predominated by filopodia, which eventually develop synapses. However, after this first week, filopodia are replaced by spiny dendrites but also small, stubby spines that protrude from spiny dendrites. In the development of certain filopodia into spines, filopodia recruit presynaptic contact to the dendrite, which encourages the production of spines to handle specialized postsynaptic contact with the presynaptic protrusions. 

Spines, however, require maturation after formation. Immature spines have impaired signaling capabilities, and typically lack "heads" (or have very small heads), only necks, while matured spines maintain both heads and necks.

Clinical significance

Cognitive disorders such as ADHD, autism, intellectual disability, and fragile X syndrome, may be resultant from abnormalities in dendritic spines, especially the number of spines and their maturity. The ratio of matured to immature spines is important in their signaling, as immature spines have impaired synaptic signaling. Fragile X syndrome is characterized by an overabundance of immature spines that have multiple filopodia in cortical dendrites. 

History

Dendritic spines were first described at the end of the 19th century by Santiago Ramón y Cajal on cerebellar neurons. Ramón y Cajal then proposed that dendritic spines could serve as contacting sites between neurons. This was demonstrated more than 50 years later thanks to the emergence of electron microscopy. Until the development of confocal microscopy on living tissues, it was commonly admitted that spines were formed during embryonic development and then would remain stable after birth. In this paradigm, variations of synaptic weight were considered as sufficient to explain memory processes at the cellular level. But since about a decade ago, new techniques of confocal microscopy demonstrated that dendritic spines are indeed motile and dynamic structures that undergo a constant turnover, even after birth.

Cell potency

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