In neuroscience, long-term potentiation is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons; the opposite of LTP is long-term depression, which produces a long-lasting decrease in synaptic strength. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength; as memories are thought to be encoded by modification of synaptic strength, LTP is considered one of the major cellular mechanisms that underlies learning and memory. LTP was discovered in the rabbit hippocampus by Terje Lømo in 1966 and has remained a popular subject of research since. Many modern LTP studies seek to better understand its basic biology, while others aim to draw a causal link between LTP and behavioral learning. Still others try to develop methods, pharmacologic or otherwise, of enhancing LTP to improve learning and memory.
LTP is a subject of clinical research, for example, in the areas of Alzheimer's disease and addiction medicine. At the end of the 19th century, scientists recognized that the number of neurons in the adult brain did not increase with age, giving neurobiologists good reason to believe that memories were not the result of new neuron production. With this realization came the need to explain how memories could form in the absence of new neurons; the Spanish neuroanatomist Santiago Ramón y Cajal was among the first to suggest a mechanism of learning that did not require the formation of new neurons. In his 1894 Croonian Lecture, he proposed that memories might instead be formed by strengthening the connections between existing neurons to improve the effectiveness of their communication. Hebbian theory, introduced by Donald Hebb in 1949, echoed Ramón y Cajal's ideas, further proposing that cells may grow new connections or undergo metabolic changes that enhance their ability to communicate: Let us assume that the persistence or repetition of a reverberatory activity tends to induce lasting cellular changes that add to its stability....
When an axon of cell A is near enough to excite a cell B and or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B, is increased. Though these theories of memory formation are now well established, they were farsighted for their time: late 19th and early 20th century neuroscientists and psychologists were not equipped with the neurophysiological techniques necessary for elucidating the biological underpinnings of learning in animals; these skills would not come until the half of the 20th century, at about the same time as the discovery of long-term potentiation. LTP was first observed by Terje Lømo in 1966 in the Oslo, laboratory of Per Andersen. There, Lømo conducted a series of neurophysiological experiments on anesthetized rabbits to explore the role of the hippocampus in short-term memory. Lømo's experiments focused on connections, or synapses, from the perforant pathway to the dentate gyrus.
These experiments were carried out by stimulating presynaptic fibers of the perforant pathway and recording responses from a collection of postsynaptic cells of the dentate gyrus. As expected, a single pulse of electrical stimulation to fibers of the perforant pathway caused excitatory postsynaptic potentials in cells of the dentate gyrus. What Lømo unexpectedly observed was that the postsynaptic cells' response to these single-pulse stimuli could be enhanced for a long period of time if he first delivered a high-frequency train of stimuli to the presynaptic fibers; when such a train of stimuli was applied, subsequent single-pulse stimuli elicited stronger, prolonged EPSPs in the postsynaptic cell population. This phenomenon, whereby a high-frequency stimulus could produce a long-lived enhancement in the postsynaptic cells' response to subsequent single-pulse stimuli, was called "long-lasting potentiation". Timothy Bliss, who joined the Andersen laboratory in 1968, collaborated with Lømo and in 1973 the two published the first characterization of long-lasting potentiation in the rabbit hippocampus.
Bliss and Tony Gardner-Medwin published a similar report of long-lasting potentiation in the awake animal which appeared in the same issue as the Bliss and Lømo report. In 1975, Douglas and Goddard proposed "long-term potentiation" as a new name for the phenomenon of long-lasting potentiation. Andersen suggested that the authors chose "long-term potentiation" because of its pronounced acronym, "LTP"; the physical and biological mechanism of LTP is still not understood, but some successful models have been developed. Studies of dendritic spines, protruding structures on dendrites that physically grow and retract over the course of minutes or hours, have suggested a relationship between the electrical resistance of the spine and the effective synapse strength, due to their relationship with intracellular calcium transients. Mathematical models such as BCM Theory, which depends on intracellular calcium in relation to NMDA receptor voltage gates, have been developed since the 1980s and modify the traditional a priori Hebbian learning model with both biological and experimental justification.
Still others have proposed re-arranging or synchronizing the relationship between receptor regulation, LTP, synaptic strength. Since its original discovery in the rabbit hippocampus, LTP has been observed in a variety of other neural structures, including the cerebral cortex, cerebellum and many others. Robert Malenka, a prominent LTP researcher, has suggested that LTP may occur at all excitatory synapses in the ma
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is an ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system. It has been traditionally classified as a non-NMDA-type receptor, along with the kainate receptor, its name is derived from its ability to be activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a occurring agonist quisqualate and was only given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen. AMPARs are found in many parts of the brain and are the most found receptor in the nervous system; the AMPA receptor GluA2 tetramer was the first glutamate receptor ion channel. AMPARs are composed of four types of subunits, designated as GluA1, GluA2, GluA3, GluA4, alternatively called GluRA-D2, which combine to form tetramers. Most AMPARs are heterotetrameric, consisting of symmetric'dimer of dimers' of GluA2 and either GluA1, GluA3 or GluA4.
Dimerization starts in the endoplasmic reticulum with the interaction of N-terminal LIVBP domains "zips up" through the ligand-binding domain into the transmembrane ion pore. The conformation of the subunit protein in the plasma membrane caused controversy for some time. While the amino acid sequence of the subunit indicated that there seemed to be four transmembrane domains, proteins interacting with the subunit indicated that the N-terminus seemed to be extracellular, while the C-terminus seemed to be intracellular. However, if each of the four transmembrane domains went all the way through the plasma membrane the two termini would have to be on the same side of the membrane, it was discovered that the second "transmembrane" domain does not in fact cross the membrane at all, but kinks back on itself within the membrane and returns to the intracellular side. When the four subunits of the tetramer come together, this second membranous domain forms the ion-permeable pore of the receptor. AMPAR subunits differ most in their C-terminal sequence, which determines their interactions with scaffolding proteins.
All AMPARs contain which PDZ domain they bind to differs. For example, GluA1 binds to SAP97 through SAP97's class I PDZ domain, while GluA2 binds to PICK1 and GRIP/ABP. Of note, AMPARs cannot directly bind to the common synaptic protein PSD-95 owing to incompatible PDZ domains, although they do interact with PSD-95 via stargazin. Phosphorylation of AMPARs can regulate channel localization and open probability. GluA1 has four known phosphorylation sites at serine 818, S831, threonine 840, S845. S818 is phosphorylated by protein kinase C, is necessary for long-term potentiation. S831 is phosphorylated by CaMKII and PKC during LTP, which helps deliver GluA1-containing AMPAR to the synapse, increases their single channel conductance; the T840 site was more discovered, has been implicated in LTD. S845 is phosphorylated by PKA which regulates its open probability; each AMPAR has one for each subunit. The binding site is believed to be formed by the N-terminal tail and the extracellular loop between transmembrane domains three and four.
When an agonist binds, these two loops move towards each other. The channel opens when two sites are occupied, increases its current as more binding sites are occupied. Once open, the channel may undergo rapid desensitization; the mechanism of desensitization is believed to be due to a small change in angle of one of the parts of the binding site, closing the pore. AMPARs open and close and are thus responsible for most of the fast excitatory synaptic transmission in the central nervous system; the AMPAR's permeability to calcium and other cations, such as sodium and potassium, is governed by the GluA2 subunit. If an AMPAR lacks a GluA2 subunit it will be permeable to sodium and calcium; the presence of a GluA2 subunit will always render the channel impermeable to calcium. This is determined by post-transcriptional modification — RNA editing — of the Q-to-R editing site of the GluA2 mRNA. Here, A→I editing alters the uncharged amino acid glutamine to the positively charged arginine in the receptor's ion channel.
The positively charged amino acid at the critical point makes it energetically unfavourable for calcium to enter the cell through the pore. All of the GluA2 subunits in CNS are edited to the GluA2 form; this means that the principal ions gated by AMPARs are sodium and potassium, distinguishing AMPARs from NMDA receptors, which permit calcium influx. Both AMPA and NMDA receptors, have an equilibrium potential near 0 mV; the prevention of calcium entry into the cell on activation of GluA2-containing AMPARs is proposed to guard against excitotoxicity. The subunit composition of the AMPAR is important for the way this receptor is modulated. If an AMPAR lacks GluA2 subunits it is susceptible to being blocked in a voltage-dependent manner by a class of molecules called polyamines. Thus, when the neuron is at a depolarized membrane potential, polyamines will block the AM
The spinal cord is a long, tubular structure made up of nervous tissue, that extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column. It encloses the central canal of the spinal cord; the brain and spinal cord together make up the central nervous system. In humans, the spinal cord begins at the occipital bone where it passes through the foramen magnum, meets and enters the spinal canal at the beginning of the cervical vertebrae; the spinal cord extends down to between the second lumbar vertebrae where it ends. The enclosing bony vertebral column protects the shorter spinal cord, it is around 45 cm in men and around 43 cm long in women. The spinal cord has a varying width, ranging from 13 mm thick in the cervical and lumbar regions to 6.4 mm thick in the thoracic area. The spinal cord functions in the transmission of nerve signals from the motor cortex to the body, from the afferent fibers of the sensory neurons to the sensory cortex, it is a center for coordinating many reflexes and contains reflex arcs that can independently control reflexes.
It is the location of groups of spinal interneurons that make up the neural circuits known as central pattern generators. These circuits are responsible for controlling motor instructions for rhythmic movements such as walking; the spinal cord is the main pathway for information connecting the brain and peripheral nervous system. Much shorter than its protecting spinal column, the human spinal cord originates in the brainstem, passes through the foramen magnum, continues through to the conus medullaris near the second lumbar vertebra before terminating in a fibrous extension known as the filum terminale, it is about 45 cm long in men and around 43 cm in women, ovoid-shaped, is enlarged in the cervical and lumbar regions. The cervical enlargement, stretching from the C5 to T1 vertebrae, is where sensory input comes from and motor output goes to the arms and trunk; the lumbar enlargement, located between L1 and S3, handles sensory input and motor output coming from and going to the legs. The spinal cord is continuous with the caudal portion of the medulla, running from the base of the skull to the body of the first lumbar vertebra.
It does not run the full length of the vertebral column in adults. It is made of 31 segments from which branch one pair of sensory nerve roots and one pair of motor nerve roots; the nerve roots merge into bilaterally symmetrical pairs of spinal nerves. The peripheral nervous system is made up of these spinal roots and ganglia; the dorsal roots are afferent fascicles, receiving sensory information from the skin and visceral organs to be relayed to the brain. The roots terminate in dorsal root ganglia, which are composed of the cell bodies of the corresponding neurons. Ventral roots consist of efferent fibers that arise from motor neurons whose cell bodies are found in the ventral gray horns of the spinal cord; the spinal cord are protected by three layers of tissue or membranes called meninges, that surround the canal. The dura mater is the outermost layer, it forms a tough protective coating. Between the dura mater and the surrounding bone of the vertebrae is a space called the epidural space; the epidural space is filled with adipose tissue, it contains a network of blood vessels.
The arachnoid mater, the middle protective layer, is named for its spiderweb-like appearance. The space between the arachnoid and the underlying pia mater is called the subarachnoid space; the subarachnoid space contains cerebrospinal fluid, which can be sampled with a lumbar puncture, or "spinal tap" procedure. The delicate pia mater, the innermost protective layer, is associated with the surface of the spinal cord; the cord is stabilized within the dura mater by the connecting denticulate ligaments, which extend from the enveloping pia mater laterally between the dorsal and ventral roots. The dural sac ends at the vertebral level of the second sacral vertebra. In cross-section, the peripheral region of the cord contains neuronal white matter tracts containing sensory and motor axons. Internal to this peripheral region is the grey matter, which contains the nerve cell bodies arranged in the three grey columns that give the region its butterfly-shape; this central region surrounds the central canal, an extension of the fourth ventricle and contains cerebrospinal fluid.
The spinal cord is elliptical in cross section, being compressed dorsolaterally. Two prominent grooves, or sulci, run along its length; the posterior median sulcus is the groove in the dorsal side, the anterior median fissure is the groove in the ventral side. The human spinal cord is divided into segments. Six to eight motor nerve rootlets branch out of right and left ventro lateral sulci in a orderly manner. Nerve rootlets combine to form nerve roots. Sensory nerve rootlets form off right and left dorsal lateral sulci and form sensory nerve roots; the ventral and dorsal roots combine to form one on each side of the spinal cord. Spinal nerves, with the exception of C1 and C2, form inside the intervertebral foramen; these rootlets form the demarcation between the peripheral nervous systems. The grey column, in the center of the cord, is shaped like a butterfly and consists of cell bodies of interneurons, motor neurons, neuroglia cells and unmyelinated axons; the anterior and posterior grey column present as projections of the grey matter and are known as the horns of the spinal cord.
Together, the gr
Neuroplasticity known as brain plasticity, neuroelasticity, or neural plasticity, is the ability of the brain to change throughout an individual's life, e.g. brain activity associated with a given function can be transferred to a different location, the proportion of grey matter can change, synapses may strengthen or weaken over time. Research in the latter half of the 20th century showed that many aspects of the brain can be altered through adulthood. However, the developing brain exhibits a higher degree of plasticity than the adult brain. Neuroplasticity can be observed at multiple scales, from microscopic changes in individual neurons to larger-scale changes such as cortical remapping in response to injury. Behavior, environmental stimuli and emotions may cause neuroplastic change through activity-dependent plasticity, which has significant implications for healthy development, learning and recovery from brain damage. At the single cell level, synaptic plasticity refers to changes in the connections between neurons, whereas non-synaptic plasticity refers to changes in their intrinsic excitability.
JT Wall and J Xu have traced the mechanisms underlying neuroplasticity. Re-organization occurs at every level in the processing hierarchy; the adult brain is not "hard-wired" with fixed neuronal circuits. There are many instances of cortical and subcortical rewiring of neuronal circuits in response to training as well as in response to injury. There is solid evidence that neurogenesis occurs in the adult, mammalian brain—and such changes can persist well into old age; the evidence for neurogenesis is restricted to the hippocampus and olfactory bulb, but current research has revealed that other parts of the brain, including the cerebellum, may be involved as well. However, the degree of rewiring induced by the integration of new neurons in the established circuits is not known, such rewiring may well be functionally redundant. There is now ample evidence for the active, experience-dependent re-organization of the synaptic networks of the brain involving multiple inter-related structures including the cerebral cortex.
The specific details of how this process occurs at the molecular and ultrastructural levels are topics of active neuroscience research. The way experience can influence the synaptic organization of the brain is the basis for a number of theories of brain function including the general theory of mind and Neural Darwinism; the concept of neuroplasticity is central to theories of memory and learning that are associated with experience-driven alteration of synaptic structure and function in studies of classical conditioning in invertebrate animal models such as Aplysia. A surprising consequence of neuroplasticity is that the brain activity associated with a given function can be transferred to a different location. Neuroplasticity is the fundamental issue that supports the scientific basis for treatment of acquired brain injury with goal-directed experiential therapeutic programs in the context of rehabilitation approaches to the functional consequences of the injury. Neuroplasticity is gaining popularity as a theory that, at least in part, explains improvements in functional outcomes with physical therapy post-stroke.
Rehabilitation techniques that are supported by evidence which suggest cortical reorganization as the mechanism of change include constraint-induced movement therapy, functional electrical stimulation, treadmill training with body-weight support, virtual reality therapy. Robot assisted therapy is an emerging technique, hypothesized to work by way of neuroplasticity, though there is insufficient evidence to determine the exact mechanisms of change when using this method. One group has developed a treatment that includes increased levels of progesterone injections in brain-injured patients. "Administration of progesterone after traumatic brain injury and stroke reduces edema and neuronal cell death, enhances spatial reference memory and sensory motor recovery." In a clinical trial, a group of injured patients had a 60% reduction in mortality after three days of progesterone injections. However, a study published in the New England Journal of Medicine in 2014 detailing the results of a multi-center NIH-funded phase III clinical trial of 882 patients found that treatment of acute traumatic brain injury with the hormone progesterone provides no significant benefit to patients when compared with placebo.
For decades, researchers assumed that humans had to acquire binocular vision, in particular stereopsis, in early childhood or they would never gain it. In recent years, successful improvements in persons with amblyopia, convergence insufficiency or other stereo vision anomalies have become prime examples of neuroplasticity. Several companies have offered so-called cognitive training software programs for various purposes that claim to work via neuroplasticity. A systematic meta-analytic review found that "There is no evidence from the analysis carried out that Fast ForWord is effective as a treatment for children's oral language or reading difficulties". A 2016 review found little evidence supporting any of the claims of Fast ForWord and other commercial products, as their task-specific effects fail to generalise to other tasks. Neuroplasticity is involved in the development of sensory function. Th
Aplysia is a genus of medium-sized to large sea slugs sea hares, which are one clade of large sea slugs, marine gastropod mollusks. These benthic herbivorous creatures can become rather large compared with most other mollusks, they graze in tidal and subtidal zones of tropical waters in the Indo-Pacific Ocean. Aplysia species, when threatened release clouds of ink, it is believed in order to blind the attacker. Following the lead of Eric R. Kandel, the genus has been studied as a model organism by neurobiologists, because its gill and siphon withdrawal reflex, as studied in Aplysia californica, is mediated by electrical synapses, which allow several neurons to fire synchronously; this quick neural response is necessary for a speedy reaction to danger by the animal. Aplysia has only about 20,000 neurons, making it a favorite subject for investigation by neuroscientists. The'tongue' on the underside is controlled by only two neurons, which allowed complete mapping of the innervation network to be carried out.
In neurons that mediate several forms of long-term memory in Aplysia, the DNA repair enzyme poly ADP ribose polymerase 1 is activated. In all eukaryotic cells tested, the addition of polyADP-ribosyl groups to proteins occurs as a response to DNA damage, thus the finding of activation of PARP-1 during learning and its requirement for long-term memory was surprising. Cohen-Aromon et al. suggested that fast and transient decondensation of chromatin structure by polyADP-ribosylation enables the transcription needed to form long-term memory without strand-breaks in DNA. Subsequent to these findings in Aplysia, further research was done with mice and it was found that polyADP-ribosylation is required for long-term memory formation in mammals. In 2018, scientists from the University of California, Los Angeles, have shown that the behavioral modifications characteristic of a form of nonassociative long-term memory in Aplysia can be transferred by RNA. Operant conditioning is considered a form of associative learning.
Because operant conditioning involves intricate interaction between an action and a stimulus it is associated with the acquisition of compulsive behavior. The Aplysia species serve as an ideal model system for the physical studying of food-reward learning, due to “the neuronal components of parts of its ganglionic nervous system that are responsible for the generation of feeding movements.” As a result, Aplysia has been used in associative learning studies to derive certain aspects of feeding and operant conditioning in the context of compulsive behavior. In Aplysia, the primary reflex studied by scientists while studying operant conditioning is the gill and siphon withdrawal reflex; the gill and siphon withdrawal reflex allows the Aplysia to pull back its siphon and gill for protection. The links between the synapses during the gill and siphon withdrawal reflex are directly correlated with many behavioral traits in the Aplysia such as its habits and conditioning. Scientists have studied the conditioning of the Aplysia to identify correlations with conditioning in mammals regarding behavioral responses such as addiction.
Through experiments on the conditioning of the Aplysia, links have been discovered with the synaptic plasticity for reward functions involved in the trait of addiction within mammals. Synaptic plasticity is the idea that the synapses will become stronger or weaker depending on how much those specific synapses are used. Conditioning of these synapses can lead them to become stronger or weaker by causing the neurons to fire or not fire when influenced by a stimulus; the conditioning of behavioral traits is based on the idea of a reward function. A reward function is; the neurons will adapt to that stimulus, fire those neurons more even if the stimulus has a negative effect on the subject. In mammals, the reward function is controlled by ventral tegmental area dopamine neurons. During conditioning, the VTA dopamine neurons have an increased effect on the stimuli being conditioned, a decreased effect on the stimuli not being conditioned; this induces the synapses to form an expectation for reward for the stimuli being conditioned.
The properties of the synapses displayed in the tests on conditioning involving the Aplysia are proposed to be directly comparable to behavioral responses such as addiction in mammals. The California sea hare, Aplysia californica, is a simultaneous hermaphrodite. A. californica has the ability to store and digest allosperm and mates with multiple partners. Studies of multiple matings in A. californica have provided insights on how conflicts between the sexes are resolved. A potent sex pheromone, the water-borne protein attractin, is employed in promoting and maintaining mating in Aplysia. Attractin interacts with three other Aplysia protein pheromones in a binary fashion to stimulate mate attraction. Aplysia species were once thought to use ink to escape from predators, much like the octopus. Instead, recent research has made it clear that these sea slugs are able to produce and secrete multiple compounds within their ink, including the chemodeterrant Aplysioviolin and toxic substances such as ammonia for self-defense.
The ability of the Aplysia species to hold toxins within their bodies without poisoning itself is a result of the unique way