Mesolimbic pathway

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

The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the forebrain. The ventral striatum includes the nucleus accumbens and the olfactory tubercle.

The release of dopamine from the mesolimbic pathway into the nucleus accumbens regulates incentive salience (e.g. motivation and desire for rewarding stimuli) and facilitates reinforcement and reward-related motor function learning; it may also play a role in the subjective perception of pleasure. The dysregulation of the mesolimbic pathway and its output neurons in the nucleus accumbens plays a significant role in the development and maintenance of an addiction.

Anatomy

The mesolimbic pathway and its positioning in relation to the other dopaminergic pathways

The mesolimbic pathway is a collection of dopaminergic (i.e., dopamine-releasing) neurons that project from the ventral tegmental area (VTA) to the ventral striatum, which includes the nucleus accumbens (NAcc) and olfactory tubercle. It is one of the component pathways of the medial forebrain bundle, which is a set of neural pathways that mediate brain stimulation reward.

The VTA is located in the midbrain and consists of dopaminergic, GABAergic, and glutamatergic neurons. The dopaminergic neurons in this region receive stimuli from both cholinergic neurons in the pedunculopontine nucleus and the laterodorsal tegmental nucleus as well as glutamatergic neurons in other regions such as the prefrontal cortex. The nucleus accumbens and olfactory tubercle are located in the ventral striatum and are primarily composed of medium spiny neurons. The nucleus accumbens is subdivided into limbic and motor subregions known as the NAcc shell and NAcc core. The medium spiny neurons in the nucleus accumbens receive input from both the dopaminergic neurons of the VTA and the glutamatergic neurons of the hippocampus, amygdala, and medial prefrontal cortex. When they are activated by these inputs, the medium spiny neurons' projections release GABA onto the ventral pallidum.

Function

The mesolimbic pathway regulates incentive salience, motivation, reinforcement learning, and fear, among other cognitive processes.

The mesolimbic pathway is involved in motivational cognition. Depletion of dopamine in this pathway, or lesions at its site of origin, decrease the extent to which an animal is willing to go to obtain a reward (e.g. the number of lever presses for intravenous nicotine delivery in rats or time spent searching for food). Dopaminergic drugs are also able to increase the extent an animal is willing to go to obtain a reward. Moreover, the firing rate of neurons in the mesolimbic pathway increases during anticipation of reward, which may explain craving. Mesolimbic dopamine release was once thought to be the primary mediator of pleasure, but is now believed to have only a minor or secondary role in pleasure perception.

Clinical significance

Mechanisms of addiction

The mesolimbic pathway and a specific set of the pathway's output neurons (e.g. D1-type medium spiny neurons within the nucleus accumbens) play a central role in the neurobiology of addiction. Drug addiction is an illness caused by habitual substance use that induces chemical changes in the brain's circuitry. An addictive drug is defined as a substance that affects the mesolimbic system directly or indirectly by increasing extracellular levels of dopamine.

Common addictive substances such as cocaine, alcohol, and nicotine have been shown to increase extracellular levels of dopamine within the mesolimbic pathway, preferentially within the nucleus accumbens. The mechanisms by which these drugs do so vary depending on the drug prototype. For example, cocaine precludes the re-uptake of synaptic dopamine through blocking the presynaptic dopamine transporter. Another stimulant, amphetamine, reverses the dopamine transporter and induces the release of dopamine from synaptic vesicles. Non-stimulant drugs typically bind with ligand-gated channels or G protein-coupled receptors. Such drugs include alcohol, nicotine, and tetrahydrocannabinol (THC).

Addictive Drugs and their Molecular Interactions

Type	Target	Examples
Alcohol	GABAA Receptor, NMDA Receptor	Beer, wine, and other beverages
Cannabinoids	Cannabinoid Receptor	Marijuana
Nicotine	Nicotinic Acetylcholine Receptor	Tobacco
Opiates	μ Opioid Receptor	Morphine, heroin
Phencyclidine	NMDA Receptor	PCP
Stimulants	Dopamine Transporter	Cocaine, amphetamine, methamphetamine

These dopaminergic activations of the mesolimbic pathway are accompanied by the perception of reward. This stimulus-reward association shows a resistance to extinction and creates an increased motivation to repeat that same behavior that caused it. Additionally, drug intake changes synaptic plasticity in the ventral tegmental area and the nucleus accumbens. Repeated exposure to the drug can lead to lasting changes in the brain that gives rise to addictive behavior.

Relation to other neurological and psychological disorders

The mesolimbic pathway is implicated in schizophrenia, depression, and Parkinson's disease. It is also theorized to be implicated in overuse of digital media, although it could simply be a consequence of a sedentary lifestyle. Each involves distinct structural changes within the mesolimbic pathway.

Nonsynaptic plasticity

From Wikipedia, the free encyclopedia

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

Plasticity in the brain affects the strength of neural connections and pathways.

Nonsynaptic plasticity is a form of neuroplasticity that involves modification of ion channel function in the axon, dendrites, and cell body that results in specific changes in the integration of excitatory postsynaptic potentials and inhibitory postsynaptic potentials. Nonsynaptic plasticity is a modification of the intrinsic excitability of the neuron. It interacts with synaptic plasticity, but it is considered a separate entity from synaptic plasticity. Intrinsic modification of the electrical properties of neurons plays a role in many aspects of plasticity from homeostatic plasticity to learning and memory itself. Nonsynaptic plasticity affects synaptic integration, subthreshold propagation, spike generation, and other fundamental mechanisms of neurons at the cellular level. These individual neuronal alterations can result in changes in higher brain function, especially learning and memory. However, as an emerging field in neuroscience, much of the knowledge about nonsynaptic plasticity is uncertain and still requires further investigation to better define its role in brain function and behavior.

Vs. synaptic plasticity

Neuroplasticity is the ability of a particular part or region of a neuron to change in strength over time. There are two largely recognized categories of plasticity: synaptic and nonsynaptic. Synaptic plasticity deals directly with the strength of the connection between two neurons, including amount of neurotransmitter released from the presynaptic neuron, and the response generated in the postsynaptic neuron. Nonsynaptic plasticity involves modification of neuronal excitability in the axon, dendrites, and soma of an individual neuron, remote from the synapse.

Synaptic plasticity

Synaptic plasticity is the ability of a synapse between two neurons to change in strength over time. Synaptic plasticity is caused by changes in use of the synaptic pathway, namely, the frequency of synaptic potentials and the receptors used to relay chemical signals. Synaptic plasticity plays a large role in learning and memory in the brain. Synaptic plasticity can occur through intrinsic mechanisms, in which changes in synapse strength occur because of its own activity, or through extrinsic mechanisms, in which the changes in synapse strength occur via other neural pathways. Short-term inhibitory synaptic plasticity often occurs because of limited neurotransmitter supply at the synapse, and long-term inhibition can occur through decreased receptor expression in the postsynaptic cell. Short-term complementary synaptic plasticity often occurs because of residual or increased ion flow in either the presynaptic or postsynaptic terminal, while long-term synaptic plasticity can occur through the increased production of AMPA and NMDA glutamate receptors, among others, in the postsynaptic cell.

Nonsynaptic plasticity

In comparison, nonsynaptic plasticity is a less well known and somewhat new and ongoing field of research in neuroscience. It is manifested through changes in the characteristics of nonsynaptic structures such as the soma (biology), the axon, or the dendrites. Nonsynaptic plasticity can have short-term or long-term effects. One way these changes occur is through modification of voltage-gated channels in the dendrites and axon, which changes the interpretation of excitatory or inhibitory potentials propagated to the cell. For example, axonal nonsynaptic plasticity can be observed when an action potential fails to reach the presynaptic terminal due to low conduction or buildup of ions. 

The neuronal soma, axon, and dendrites are involved in nonsynaptic plasticity and affect the plasticity at the synapse

Synergistic effects

General excitatory effects

Nonsynaptic and synaptic plasticity have been shown to work concurrently in a variety of ways to produce stimulating effects in the neuron. This includes spike generation, a product of nonsynaptic regulation of potassium and other presynaptic ion channels, which increase the response of the excitatory postsynaptic potential through neurotransmitter release and augmentation of the action potential. Nonsynaptic dendritic plasticity also adds to the effects of synaptic plasticity through widening of the action potential. As will be discussed further, brain-derived neurotrophic factor (BNDF) is produced by neurons to coordinate nonsynaptic and synaptic plasticity. Nonsynaptic changes in the somal body, axon, or dendrites of the neuron are inextricably linked to synaptic strength.

Integration in memory and learning

Although much more is known about the role of synaptic plasticity in memory and learning, both synaptic and nonsynaptic plasticity are essential to memory and learning in the brain. There is much evidence that the two mechanisms both work to achieve the observed effects synergistically. A key example of this is memory formation in the synapse, in which modification of presynaptic release mechanisms and postsynaptic receptors affects either long-term potentiation or depression. Continuous somal depolarization, on the other hand, has been proposed as a method for learned behavior and memory by nonsynaptic plasticity. Nonsynaptic plasticity also augments the effectiveness of synaptic memory formation by regulation of voltage-gated ion channels. Nonsynaptic plasticity is the mechanism responsible for modifications of these channels in the axon, leading to a change in strength of the neuronal action potential, invariably affecting the strength of synaptic mechanisms, and thus the depth and length of memory encoding. 

Regulation of synaptic plasticity

Nonsynaptic plasticity also has the ability to regulate the effects of synaptic plasticity through negative feedback mechanisms. Change in the number and properties of ion channels in the axon or dendrites has the ability to diminish the effects of a hyperstimulated synapse. In the case of extreme overexcitation of these ion channels, backwards flow of ions into the cell will occur, leading to excitotoxicity and cell death by apoptosis or necrosis.

Intrinsic mechanisms

Nonsynaptic neuronal areas such as the axon also have inherent qualities that affect the synapse. These essential mechanisms include the delay in depolarization that action potential undergoes while traveling down the axon. This intrinsic quality slows the propagation of action potentials and is due to the movement of depolarizing current down the cytoplasm and the intermittent placement of sodium channels on the Nodes of Ranvier. These mechanisms always exist, but may change depending on the conditions of the cell soma, axon, and dendrites at the time. Therefore, latency, or delay in propagation of action potentials or excitatory postsynaptic potentials, can be variable. Every excitatory postsynaptic potential that is propagated to a postsynaptic cell is first transmitted through the action potential down the axon in the presynaptic cell, and thus nonsynaptic plasticity inherently affects synaptic plasticity.

Types

Neurons interact in complex networks that affect the generation of action potentials in other neurons.

Intrinsic excitability of a neuron

The excitability of a neuron at any point depends on the internal and external conditions of the cell at the time of stimulation. Since a neuron typically receives multiple incoming signals at a time, the propagation of an action potential depends on the integration of all the incoming excitatory and inhibitory postsynaptic potentials arriving at the axon hillock. If the summation of all excitatory and inhibitory signals depolarize the cell membrane to the threshold voltage, an action potential is fired. Changing the intrinsic excitability of a neuron will change that neuron's function.

Spike generation

Nonsynaptic plasticity has an excitatory effect on the generation of spikes. The increase in spike generation has been correlated with a decrease in the spike threshold, a response from nonsynaptic plasticity. This response can result from the modulation of certain presynaptic K⁺ (potassium ion) currents (I_A, I_K,Ca, and I_Ks), which work to increase the excitability of the sensory neurons, broaden the action potential, and enhance neurotransmitter release. These modulations of K⁺ conductances serve as common mechanisms for regulating excitability and synaptic strength.

Regulation of synaptic plasticity

Nonsynaptic plasticity has been linked with synaptic plasticity, via both synergistic and regulatory mechanisms. The degree of synaptic modification determines the polarity of nonsynaptic changes, affecting the change in cellular excitability. Moderate levels of synaptic plasticity produce nonsynaptic changes that will synergistically act with the synaptic mechanisms to strengthen a response. Conversely, more robust levels of synaptic plasticity will produce nonsynaptic responses that will act as a negative feedback mechanism. The negative feedback mechanisms work to protect against saturation or suppression of the circuit activity as a whole.

Axonal modulation

Axonal modulation is a type of plasticity in which the number, activity, or location of ion channels in the axon changes. This causes the neuron to behave differently when stimulated. The modulation of ion channels is a response to a change in the stimulation frequencies of a neuron.

Propagation plasticity

Action potential propagation animation

Because it is the summation of the action potentials that eventually results in the threshold polarization being crossed, the temporal relationship of different input signals is very important in determining if and when a post-synaptic neuron will fire. Over time, the time it takes an action potential to propagate down the length of a particular axon can change. In one experiment multielectrode arrays were used to measure the time it took for action potentials to travel from one electrode to another, called latency. The neurons were then stimulated and the value of the latency was recorded over time. The latency values changed over time, suggesting that axonal plasticity influenced the propagation of action potentials.

Shunting

Shunting is a process in which axonal ion channels open during the passive flow (not requiring an ion pump) of a subthreshold depolarization down the axon. Usually occurring at axonal branch points, the timing of these channels opening as the subthreshold signal arrives in the area causes a hyperpolarization to be introduced to the passively flowing depolarization. Therefore, the cell is able to control which branches of the axon the subthreshold depolarization current flows through, resulting in some branches of the axon being more hyperpolarized than others. These differing membrane potentials cause certain areas of the neuron to be more excitable than others, based on the specific location and occurrence of shunting.

High frequency stimulation

Short-term effects: High frequency stimulation of a neuron for a short period of time increases the excitability of the neuron by lowering the amount of voltage required to fire an action potential. High frequency stimulation leads to an increase in the intracellular concentration of sodium and calcium ions due to the repeated opening of voltage-gated sodium and calcium channels in the axon and terminal. As the frequency of stimuli increases, there is less time between each stimulus for the cell to repolarize and return to normal resting potential. Therefore, the resting potential becomes more depolarized, meaning a smaller depolarizing current is needed to fire an action potential.

However, this modulation is usually very short lived. If the stimulation ceases, the neuron will revert to its original resting potential as the ion channels and pumps have ample time to recover from the last stimulus.

Long-term effects: High frequency stimulation of a neuron over a long period of time causes two resulting neuronal changes. Initially, the neuron responds as it would during short-term stimulation, with an increase in excitability. Continuing the high frequency stimulation after this point, results in a drastic, non-reversible change in excitability. When sodium concentrations reach a high enough level in the axon, sodium/calcium pumps reverse their direction of flow, causing calcium to be imported into the cell as sodium is exported out. The increased calcium concentration (and subsequent depolarization of the membrane) inactivates sodium channels and targets them for endocytosis and lysosomal hydrolysis. This results in a major decrease in axonal sodium channels, which are necessary for action potential propagation. If the stimulation continues, eventually the neuron will stop transmitting action potentials and will die. Neuronal death due to overstimulation is called excitotoxicity.

Low frequency stimulation

Short-term effects: All living neurons have a basal rate of action potential propagation and synaptic release. Thus, low frequency stimulation of a neuron in the short term is similar to the activity of a neuron at rest in the brain. No major changes happen to the intrinsic excitability of the neuron.

Long-term effects: Low frequency stimulation of a neuron for a long period of time decreases the excitability of the neuron by activating calcium-dependent phosphatases that tag AMPA receptors for internalization. Low frequency stimulation leads to low levels of calcium in the cell. When calcium concentrations are low, active calcium-dependent phosphatases dominate over calcium-dependent kinases. As more phosphatases are activated, they tag more AMPA receptors for internalization through endocytosis. Since AMPA receptors are one of the main excitatory receptors on neurons, removing them from the cell membrane effectively depresses the cell (if the cell cannot react to excitatory signals, it cannot generate an action potential of its own). In this way low frequency stimulation can actually reverse the effects of long-term potentiation, however these concepts are generally considered types of synaptic plasticity.

Homeostatic and Hebbian plasticity

Central nervous system (CNS) neurons integrate signals from many neurons. In the short term, it is important to have changes in activity of the neuron because this is how information is conveyed in the nervous system (Hebbian plasticity). However, for long-term sustainability, drift towards excitability or inexcitability will disturb the circuit's ability to convey information (homeostatic plasticity). Long-term potentiation (LTP) induces a higher firing rate in post synaptic neurons. It has been hypothesized that the intrinsic properties of a neuron should be arranged to make the most of the dynamic range, acting as a homeostatic mechanism. However, it was shown that intrinsic excitability follows a lognormal distribution which requires active, Hebbian learning to be kept up. In vitro studies have found that when the spontaneous activity of neuronal cultures is inhibited, the neurons become hyper excitable and that when an increase in activity is induced for long periods, the firing rates of the culture drop. In contrast, there is a wealth of evidence that the opposite form of regulation, Hebbian learning or LTP-IE/LTD-IE, also occurs and theoretical arguments show that Hebbian plasticity must be the dominant form of plasticity for intrinsic excitability as well. Since homeostatic plasticity also occurs between individual synapses, an earlier view suggesting that homeostatic plasticity and intrinsic plasticity are linked was shown to be inconsistent with evidence.

Mechanism

One mechanism for preserving the dynamic range of a neuron is synaptic scaling, a homeostatic form of plasticity that restores neuronal activity to its normal 'baseline' levels by changing the postsynaptic response of synapses of a neuron as a function of activity. Homeostatic modulation of the intrinsic excitability of a neuron is another way to maintain stability. The regulation of ionic conductances can be achieved in a number of ways, mostly through the release of neuromodulators like dopamine, serotonin etc. Another way is through the controlled release of brain-derived neurotrophic factor (BDNF). BDNF has also been found to influence synaptic scaling, suggesting that this neurotrophic factor may be responsible for the coordination of synaptic and nonsynaptic mechanisms in homeostatic plasticity.

Dendritic excitability

The dendrites are the regions responsible for the integration of the inputs from other neurons. One way that neurons manipulate the integration properties of the dendrites is by changing the number and properties of voltage gated ion channels. Inducing Long-term potentiation (LTP) in a particular synapse, results in an increase in excitability of the dendritic branches specific to that synapse. Dendritic excitability is important for the propagation and integration of synaptic signals. Dendritic excitability is thought to contribute to E-S potentiation, or an increase in the probability that a given input will result in the firing of an action potential.

It is known that changes in dendritic excitability affect action potential back propagation. Action potentials begin near the axon hillock and propagate down the length of the axon, but they also propagate backward through the soma into the dendritic arbor. Active back propagation is dependent on ion channels and changing the densities or properties of these channels can influence the degree to which the signal is attenuated. Plasticity of back-propagation in the dendrites occurs in less than one minute and lasts longer than 25 minutes. Back propagation is a method of signaling to the synapses that an action potential was fired. This is important for spike-timing-dependent plasticity. Fast dendritic adaptation on timescales of few seconds was experimentally observed indicating a potential meaningful global learning mechanism. 

Intrinsic plasticity

Intrinsic plasticity is a form of activity-dependent plasticity distinct from synaptic plasticity, which involves changes at the synapse between two neurons rather than changes in the electrical properties within a single neuron. There are some closely related phenomena that can affect a neuron's excitability – such as neuromodulation, structural plasticity, short-term plasticity due to channel kinetics, and neural development.  There is no consensus on the quantity that intrinsic plasticity regulates, e.g. the firing rate of a neuron, its gain or its internal calcium concentration. Functionally, intrinsic plasticity might allow neurons to learn the intensity of stimuli and represent those intensity statistics in their excitabilities.  Intrinsic plasticity contributes to encoding memory and complements other forms of activity-dependent plasticity including synaptic plasticity.

Higher brain function

Long-term associative memory

Experimental evidence

The experiment of Kemenes et al. demonstrated that in an extrinsic modulatory neuron, nonsynaptic plasticity influences the expression of long-term associative memory. The relationship between nonsynaptic plasticity and memory was assessed using cerebral giant cells (CGCs). Depolarization from conditioned stimuli increased the neuronal network response. This depolarization lasted as long as the long-term memory. Persistent depolarization and behavioral memory expression occurred more than 24 hours after training, indicating long-term effects. In this experiment, the electrophysiological expression of the long-term memory trace was a conditioned stimulus induced feeding response. CGCs were significantly more depolarized in the trained organisms than the control group, indicating association with learning and excitability changes. When CGCs were depolarized, they showed an increased response to the conditional stimuli and a stronger fictive feeding response. This demonstrated that the depolarization is enough to produce a significant feeding response to the conditioned stimuli. Additionally, no significant difference was observed in the feeding rates between conditioned organisms and ones that were artificially depolarized, reaffirming that depolarization is sufficient to generate the behavior associated with long-term memory.

Memory storage

Nonsynaptic activity in the cell is usually expressed as changes in neuronal excitability. This occurs through modulation of membrane components, such as resting and voltage-gated channels and ion pumps. Nonsynaptic processes are thought to be involved in memory storage. One possible mechanism of this action involves marking a neuron that has been recently active with changes in excitability. This would help to link temporally separated stimuli. Another potential mechanism comes from a computational model that indicates that nonsynaptic plasticity may prime circuits for modification in learning because excitability changes may regulate the threshold for synaptic plasticity.

The storage capacity of synaptic-based memory storage systems is very large, making it an attractive mechanism to study. There are approximately 10⁴ synapses per neuron and 10¹¹ neurons in the human brain. Nonsynaptic plasticity is often overlooked simply because its storage capacity is not as high. Regulating the density of ion channels in the axon and soma of a neuron would change the throughput and affect all of the synapses. Therefore, its storage capacity would be significantly less than that of synaptic plasticity.

While its storage capacity is too low to make it the sole mechanism for storage, nonsynaptic plasticity could contribute to synaptic storage methods. It has been shown that the modulation of ion channels can occur in regions as small as specific dendrites. This specificity makes the storage capacity of nonsynaptic plasticity larger than if it were taken to be whole neuron modulation. Procedural memories are a good fit for this type of storage system because they do not require the high specificity that declarative memories do. Generalization of motor tasks and conditioned stimuli could be an efficient way to store this information.

Learning

Changes in excitability from learning that act as part of the memory trace do so as primers to initiate further changes in the neurons or by a short-term storage mechanism for short-term memory. Nonsynaptic plasticity can emerge during learning as a result of cellular processes, although the timing, persistence, and the relationship between nonsynaptic plasticity and synaptic output are all poorly understood. Studies have shown that nonsynaptic plasticity plays an indirect but important role in the formation of memories. Learning-induced nonsynaptic plasticity is associated with soma depolarization.

Classical conditioning

Experiments have revealed that nonsynaptic changes take place during conditional learning. Woody et al. demonstrated that eyeblink conditioning (EBC), a form of classical conditioning for studying neural structures and mechanisms underlying learning and memory, in a cat is associated with increased excitability and input in the neurons in sensorimotor cortical areas and in the facial nucleus. It was observed that increasing excitability from classical conditioning continued after the response stopped. This suggests that increased excitability may function as a mechanism for memory storage.

In eyeblink conditioning in rabbits, nonsynaptic changes occurred throughout the dorsal hippocampus. This indicates that although excitability changes alone are not enough to explain memory storage processes, nonsynaptic plasticity might be a storage mechanism for phases of memory limited by time. Nonsynaptic changes influence other types of plasticity involved with memory. For example, a nonsynaptic change such as depolarization of the resting membrane potential resulting from conditional learning could cause synaptic plasticity in future learning.

Rule learning and savings

The ability to learn rules is dependent on nonsynaptic plasticity. One study sought to teach rats to discriminate between various odors, and it took several days to teach them to distinguish between a first pair of smells. However, after learning this, the rat was able to learn to distinguish between different odors much faster. Changes in excitability of the pyramidal neurons in these rats were observed for three days after training. These changes faded eventually, suggesting that the neurons were involved in learning the rules, not in storing memory. Daoudal and Debanne attempted to determine if the same learning rules and induction mechanisms defined for synaptic plasticity also applied to nonsynaptic plasticity affecting ion channels. They determined that nonsynaptic and synaptic plasticity share common learning rules and induction pathways, e.g., NMDA receptor dependent long-term potentiation (LTP) and long-term depression (LTD). They also showed that nonsynaptic and synaptic plasticity synergistically form a coherent engram to store memory traces.

Savings is the ability to relearn forgotten information much faster than it was learned originally. Nonsynaptic plasticity is a possible mechanism for this savings effect. During training procedures many neurons experience an increase in intrinsic excitability. This increase in excitability persists even after the memory fades.

Substance dependence

Drugs of abuse typically affect the mesolimbic system, or more specifically, the reward pathway of the nervous system. Amongst the common drugs of abuse, nicotine is one of the strongest agonists at the nicotinic cholinergic synapse. Nicotine, competing with acetylcholine (ACh), acts through the nonsynaptic, preterminal, nicotinic acetylcholine receptor (nAChRs) to initiate a membrane potential change and propagate an intracellular Ca²⁺ signal, thus encouraging the release of neurotransmitters. The specific and characteristic role of calcium current mediated nAChR activity has a different voltage-dependence than other Ca²⁺ permeable ion channels, as well as different temporal and spatial distribution and as a result, the nonsynaptic nAChR activity enhances the induction of synaptic potentiation, promoting the learning of substance dependence.

Applications to disease

After damage

Nonsynaptic plasticity can function to alleviate the effects of brain damage. When one of the vestibular nerves is damaged, disparity in the firing rates of neurons in the vestibular nuclei causes unnecessary vestibular reflexes. The symptoms of this damage fade over time. This is likely due to modifications of intrinsic excitability in the neurons of the vestibular nucleus.

Seizure activity

Nonsynaptic plasticity also plays a key role in seizure activity. Febrile seizures, seizures due to fever early in life, can lead to increased excitability of hippocampal neurons. These neurons become highly sensitized to convulsant agents. It has been shown that seizures early in life can predispose one to more seizures through nonsynaptic mechanisms.

Trauma, including stroke that results in cortical injury, often results in epilepsy. Increased excitability and NMDA conductances result in epileptic activity, suggesting that nonsynaptic plasticity may be the mechanism through which epilepsy is induced after trauma.

Autism

Valproic acid (VPA) is a treatment for epilepsy, migraines, and bipolar disorder that has been linked to many conditions including autism. An animal model of autism exists in which pregnant rats are given VPA. The offspring have traits similar to those of humans with autism. Shortly after birth, these animals exhibit decreased excitability and increased NMDA currents. These effects are corrected at later stages in life. The changes in intrinsic excitability in these animals helped to offset the effects of increased NMDA currents on network activity, a form of homeostatic plasticity. It is believed that this helps mediate the detrimental effects that the increased NMDA currents would have.

Current and future research

Additional research is needed to obtain a broader understanding of nonsynaptic plasticity. Topics that should be further explored as of January 2010 include:

• Local versus global excitability changes in neuronal networks and maintenance of the memory trace
• Specificity of induction of learning-dependent excitability changes
• Manipulation of learning-dependent excitability changes by pharmaceutical products or genetic mutations and their effects on the memory trace
• Similarities between the molecular mechanisms of synaptic and nonsynaptic plasticity
• Comparison of in vivo patterns of nonsynaptic plasticity with in vitro results
• Alterations in gene expression produced by neural activity

Neural backpropagation

From Wikipedia, the free encyclopedia

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

Neural backpropagation is the phenomenon in which, after the action potential of a neuron creates a voltage spike down the axon (normal propagation), another impulse is generated from the soma and propagates towards the apical portions of the dendritic arbor or dendrites (from which much of the original input current originated). In addition to active backpropagation of the action potential, there is also passive electrotonic spread. While there is ample evidence to prove the existence of backpropagating action potentials, the function of such action potentials and the extent to which they invade the most distal dendrites remain highly controversial.

Mechanism

Methods of neural backpropagation. Left: action potential forms in axon and travels towards soma. Right: Regular action potential generates an echo that backpropagates through the dendritic tree.

When the graded excitatory postsynaptic potentials (EPSPs) depolarize the soma to spike threshold at the axon hillock, first, the axon experiences a propagating impulse through the electrical properties of its voltage-gated sodium and voltage-gated potassium channels. An action potential occurs in the axon first as research illustrates that sodium channels at the dendrites exhibit a higher threshold than those on the membrane of the axon (Rapp et al., 1996). Moreover, the voltage-gated sodium channels on the dendritic membranes having a higher threshold helps prevent them triggering an action potential from synaptic input. Instead, only when the soma depolarizes enough from accumulating graded potentials and firing an axonal action potential will these channels be activated to propagate a signal traveling backwards (Rapp et al. 1996). Generally, EPSPs from synaptic activation are not large enough to activate the dendritic voltage-gated calcium channels (usually on the order of a couple milliamperes each) so backpropagation is typically believed to happen only when the cell is activated to fire an action potential. These sodium channels on the dendrites are abundant in certain types of neurons, especially mitral and pyramidal cells, and quickly inactivate. Initially, it was thought that an action potential could only travel down the axon in one direction (towards the axon terminal where it ultimately signaled the release of neurotransmitters). However, recent research has provided evidence for the existence of backwards-propagating action potentials (Staley 2004).

This diagram displays how the dendritic voltage spike comes after the depolarization of the axon and soma.

To elaborate, neural backpropagation can occur in one of two ways. First, during the initiation of an axonal action potential, the cell body, or soma, can become depolarized as well. This depolarization can spread through the cell body towards the dendritic tree where there are voltage-gated sodium channels. The depolarization of these voltage-gated sodium channels can then result in the propagation of a dendritic action potential. Such backpropagation is sometimes referred to as an echo of the forward propagating action potential (Staley 2004). It has also been shown that an action potential initiated in the axon can create a retrograde signal that travels in the opposite direction (Hausser 2000). This impulse travels up the axon eventually causing the cell body to become depolarized, thus triggering the dendritic voltage-gated calcium channels. As described in the first process, the triggering of dendritic voltage-gated calcium channels leads to the propagation of a dendritic action potential.

It is important to note that the strength of backpropagating action potentials varies greatly between different neuronal types (Hausser 2000). Some types of neuronal cells show little to no decrease in the amplitude of action potentials as they invade and travel through the dendritic tree while other neuronal cell types, such as cerebellar Purkinje neurons, exhibit very little action potential backpropagation (Stuart 1997). Additionally, there are other neuronal cell types that manifest varying degrees of amplitude decrement during backpropagation. It is thought that this is due to the fact that each neuronal cell type contains varying numbers of the voltage-gated channels required to propagate a dendritic action potential.

Regulation and inhibition

Generally, synaptic signals that are received by the dendrite are combined in the soma in order to generate an action potential that is then transmitted down the axon toward the next synaptic contact. Thus, the backpropagation of action potentials poses a threat to initiate an uncontrolled positive feedback loop between the soma and the dendrites. For example, as an action potential was triggered, its dendritic echo could enter the dendrite and potentially trigger a second action potential. If left unchecked, an endless cycle of action potentials triggered by their own echo would be created. In order to prevent such a cycle, most neurons have a relatively high density of A-type K+ channels.

A-type K+ channels belong to the superfamily of voltage-gated ion channels and are transmembrane channels that help maintain the cell's membrane potential (Cai 2007). Typically, they play a crucial role in returning the cell to its resting membrane following an action potential by allowing an inhibitory current of K+ ions to quickly flow out of the neuron. The presence of these channels in such high density in the dendrites explains their inability to initiate an action potential, even during synaptic input. Additionally, the presence of these channels provides a mechanism by which the neuron can suppress and regulate the backpropagation of action potentials through the dendrite (Vetter 2000). Pharmacological antagonists of these channels promoted the frequency of backpropagating action potentials which demonstrates their importance in keeping the cell from excessive firing (Waters et al., 2004). Results have indicated a linear increase in the density of A-type channels with increasing distance into the dendrite away from the soma. The increase in the density of A-type channels results in a dampening of the backpropagating action potential as it travels into the dendrite. Essentially, inhibition occurs because the A-type channels facilitate the outflow of K+ ions in order to maintain the membrane potential below threshold levels (Cai 2007). Such inhibition limits EPSP and protects the neuron from entering a never-ending positive-positive feedback loop between the soma and the dendrites.

History

Since the 1950s, evidence has existed that neurons in the central nervous system generate an action potential, or voltage spike, that travels both through the axon to signal the next neuron and backpropagates through the dendrites sending a retrograde signal to its presynaptic signaling neurons. This current decays significantly with travel length along the dendrites, so effects are predicted to be more significant for neurons whose synapses are near the postsynaptic cell body, with magnitude depending mainly on sodium-channel density in the dendrite. It is also dependent on the shape of the dendritic tree and, more importantly, on the rate of signal currents to the neuron. On average, a backpropagating spike loses about half its voltage after traveling nearly 500 micrometres.

Backpropagation occurs actively in the neocortex, hippocampus, substantia nigra, and spinal cord, while in the cerebellum it occurs relatively passively. This is consistent with observations that synaptic plasticity is much more apparent in areas like the hippocampus, which controls spatial memory, than the cerebellum, which controls more unconscious and vegetative functions.

The backpropagating current also causes a voltage change that increases the concentration of Ca²⁺ in the dendrites, an event which coincides with certain models of synaptic plasticity. This change also affects future integration of signals, leading to at least a short-term response difference between the presynaptic signals and the postsynaptic spike.

Functions

While many questions have yet to be answered in regards to neural backpropagation, there exists a number of hypotheses regarding its function. Some proposed function include involvement in synaptic plasticity, involvement in dendrodendritic inhibition, boosting synaptic responses, resetting membrane potential, retrograde actions at synapses and conditional axonal output. Backpropagation is believed to help form LTP (long term potentiation) and Hebbian plasticity at hippocampal synapses. Since artificial LTP induction, using microelectrode stimulation, voltage clamp, etc. requires the postsynaptic cell to be slightly depolarized when EPSPs are elicited, backpropagation can serve as the means of depolarization of the postsynaptic cell.

Backpropagating action potentials can induce Long-term potentiation by behaving as a signal that informs the presynaptic cell that the postsynaptic cell has fired. Moreover, Spike-Time Dependent Plasticity is known as the narrow time frame for which coincidental firing of both the pre and post synaptic neurons will induce plasticity. Neural backpropagation occurs in this window to interact with NMDA receptors at the apical dendrites by assisting in the removal of voltage sensitive Mg2+ block (Waters et al., 2004). This process permits the large influx of calcium which provokes a cascade of events to cause potentiation.

Current literature also suggests that backpropagating action potentials are also responsible for the release of retrograde neurotransmitters and trophic factors which contribute to the short-term and long-term efficacy between two neurons. Since the backpropagating action potentials essentially exhibit a copy of the neurons axonal firing pattern, they help establish a synchrony between the pre and post synaptic neurons (Waters et al., 2004).

Importantly, backpropagating action potentials are necessary for the release of Brain-Derived Neurotrophic Factor (BDNF). BDNF is an essential component for inducing synaptic plasticity and development (Kuczewski N., Porcher C., Ferrand N., 2008). Moreover, backpropagating action potentials have been shown to induce BDNF-dependent phosphorylation of cyclic AMP response element-binding protein (CREB) which is known to be a major component in synaptic plasticity and memory formation (Kuczewski N., Porcher C., Lessmann V., et al. 2008).

Algorithm

While a backpropagating action potential can presumably cause changes in the weight of the presynaptic connections, there is no simple mechanism for an error signal to propagate through multiple layers of neurons, as in the computer backpropagation algorithm. However, simple linear topologies have shown that effective computation is possible through signal backpropagation in this biological sense.

Synaptic plasticity

From Wikipedia, the free encyclopedia

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

In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuits in the brain, synaptic plasticity is one of the important neurochemical foundations of learning and memory (see Hebbian theory).

Plastic change often results from the alteration of the number of neurotransmitter receptors located on a synapse. There are several underlying mechanisms that cooperate to achieve synaptic plasticity, including changes in the quantity of neurotransmitters released into a synapse and changes in how effectively cells respond to those neurotransmitters. Synaptic plasticity in both excitatory and inhibitory synapses has been found to be dependent upon postsynaptic calcium release.

Historical discoveries

In 1973, Terje Lømo and Tim Bliss first described the now widely studied phenomenon of long-term potentiation (LTP) in a publication in the Journal of Physiology. The experiment described was conducted on the synapse between the perforant path and dentate gyrus in the hippocampi of anaesthetised rabbits. They were able to show a burst of tetanic (100 Hz) stimulus on perforant path fibres led to a dramatic and long-lasting augmentation in the post-synaptic response of cells onto which these fibres synapse in the dentate gyrus. In the same year, the pair published very similar data recorded from awake rabbits. This discovery was of particular interest due to the proposed role of the hippocampus in certain forms of memory.

Biochemical mechanisms

Two molecular mechanisms for synaptic plasticity involve the NMDA and AMPA glutamate receptors. Opening of NMDA channels (which relates to the level of cellular depolarization) leads to a rise in post-synaptic Ca²⁺ concentration and this has been linked to long-term potentiation, LTP (as well as to protein kinase activation); strong depolarization of the post-synaptic cell completely displaces the magnesium ions that block NMDA ion channels and allows calcium ions to enter a cell – probably causing LTP, while weaker depolarization only partially displaces the Mg²⁺ ions, resulting in less Ca²⁺ entering the post-synaptic neuron and lower intracellular Ca²⁺ concentrations (which activate protein phosphatases and induce long-term depression, LTD).

These activated protein kinases serve to phosphorylate post-synaptic excitatory receptors (e.g. AMPA receptors), improving cation conduction, and thereby potentiating the synapse. Also, these signals recruit additional receptors into the post-synaptic membrane, stimulating the production of a modified receptor type, thereby facilitating an influx of calcium. This in turn increases post-synaptic excitation by a given pre-synaptic stimulus. This process can be reversed via the activity of protein phosphatases, which act to dephosphorylate these cation channels.

The second mechanism depends on a second messenger cascade regulating gene transcription and changes in the levels of key proteins at pommel synapses such as CaMKII and PKAII. Activation of the second messenger pathway leads to increased levels of CaMKII and PKAII within the dendritic spine. These protein kinases have been linked to growth in dendritic spine volume and LTP processes such as the addition of AMPA receptors to the plasma membrane and phosphorylation of ion channels for enhanced permeability. Localization or compartmentalization of activated proteins occurs in the presence of their given stimulus which creates local effects in the dendritic spine. Calcium influx from NMDA receptors is necessary for the activation of CaMKII. This activation is localized to spines with focal stimulation and is inactivated before spreading to adjacent spines or the shaft, indicating an important mechanism of LTP in that particular changes in protein activation can be localized or compartmentalized to enhance the responsivity of single dendritic spines. Individual dendritic spines are capable of forming unique responses to presynaptic cells. This second mechanism can be triggered by protein phosphorylation but takes longer and lasts longer, providing the mechanism for long-lasting memory storage. The duration of the LTP can be regulated by breakdown of these second messengers. Phosphodiesterase, for example, breaks down the secondary messenger cAMP, which has been implicated in increased AMPA receptor synthesis in the post-synaptic neuron.

Long-lasting changes in the efficacy of synaptic connections (long-term potentiation, or LTP) between two neurons can involve the making and breaking of synaptic contacts. Genes such as activin ß-A, which encodes a subunit of activin A, are up-regulated during early stage LTP. The activin molecule modulates the actin dynamics in dendritic spines through the MAP-kinase pathway. By changing the F-actin cytoskeletal structure of dendritic spines, spine necks are lengthened producing increased electrical isolation. The end result is long-term maintenance of LTP.

The number of ion channels on the post-synaptic membrane affects the strength of the synapse. Research suggests that the density of receptors on post-synaptic membranes changes, affecting the neuron's excitability in response to stimuli. In a dynamic process that is maintained in equilibrium, N-methyl D-aspartate receptor (NMDA receptor) and AMPA receptors are added to the membrane by exocytosis and removed by endocytosis. These processes, and by extension the number of receptors on the membrane, can be altered by synaptic activity. Experiments have shown that AMPA receptors are delivered to the synapse through vesicular membrane fusion with the postsynaptic membrane via the protein kinase CaMKII, which is activated by the influx of calcium through NMDA receptors. CaMKII also improves AMPA ionic conductance through phosphorylation. When there is high-frequency NMDA receptor activation, there is an increase in the expression of a protein PSD-95 that increases synaptic capacity for AMPA receptors. This is what leads to a long-term increase in AMPA receptors and thus synaptic strength and plasticity.

If the strength of a synapse is only reinforced by stimulation or weakened by its lack, a positive feedback loop will develop, causing some cells never to fire and some to fire too much. But two regulatory forms of plasticity, called scaling and metaplasticity, also exist to provide negative feedback. Synaptic scaling is a primary mechanism by which a neuron is able to stabilize firing rates up or down.

Synaptic scaling serves to maintain the strengths of synapses relative to each other, lowering amplitudes of small excitatory postsynaptic potentials in response to continual excitation and raising them after prolonged blockage or inhibition. This effect occurs gradually over hours or days, by changing the numbers of NMDA receptors at the synapse (Pérez-Otaño and Ehlers, 2005). Metaplasticity varies the threshold level at which plasticity occurs, allowing integrated responses to synaptic activity spaced over time and preventing saturated states of LTP and LTD. Since LTP and LTD (long-term depression) rely on the influx of Ca²⁺ through NMDA channels, metaplasticity may be due to changes in NMDA receptors, altered calcium buffering, altered states of kinases or phosphatases and a priming of protein synthesis machinery. Synaptic scaling is a primary mechanism by which a neuron to be selective to its varying inputs. The neuronal circuitry affected by LTP/LTD and modified by scaling and metaplasticity leads to reverberatory neural circuit development and regulation in a Hebbian manner which is manifested as memory, whereas the changes in neural circuitry, which begin at the level of the synapse, are an integral part in the ability of an organism to learn.

There is also a specificity element of biochemical interactions to create synaptic plasticity, namely the importance of location. Processes occur at microdomains – such as exocytosis of AMPA receptors is spatially regulated by the t-SNARE STX4. Specificity is also an important aspect of CAMKII signaling involving nanodomain calcium. The spatial gradient of PKA between dendritic spines and shafts is also important for the strength and regulation of synaptic plasticity. It is important to remember that the biochemical mechanisms altering synaptic plasticity occur at the level of individual synapses of a neuron. Since the biochemical mechanisms are confined to these "microdomains," the resulting synaptic plasticity affects only the specific synapse at which it took place.

Theoretical mechanisms

A bidirectional model, describing both LTP and LTD, of synaptic plasticity has proved necessary for a number of different learning mechanisms in computational neuroscience, neural networks, and biophysics. Three major hypotheses for the molecular nature of this plasticity have been well-studied, and none are required to be the exclusive mechanism:

1. Change in the probability of glutamate release.
2. Insertion or removal of post-synaptic AMPA receptors.
3. Phosphorylation and de-phosphorylation inducing a change in AMPA receptor conductance.

Of these, the latter two hypotheses have been recently mathematically examined to have identical calcium-dependent dynamics which provides strong theoretical evidence for a calcium-based model of plasticity, which in a linear model where the total number of receptors are conserved looks like

${\displaystyle \frac{d{W}_i(t)}{dt}=\frac{1}{\tau ([C{a}^{2+}{]}_i)}\left(\mathrm{\Omega }([C{a}^{2+}{]}_i)-W_i\right),}$

where

• ${\displaystyle W_i}$ is the synaptic weight of the ${\displaystyle i}$th input axon,
• ${\displaystyle [C{a}^{2+}]}$ is the concentration of calcium,
• ${\displaystyle \tau }$ is a time constant dependent on the insertion and removal rates of neurotransmitter receptors, which is dependent on ${\displaystyle [C{a}^{2+}]}$, and
• ${\displaystyle \mathrm{\Omega }=\beta A_m^{\mathrm{f}\mathrm{p}}}$ is also a function of the concentration of calcium that depends linearly on the number of receptors on the membrane of the neuron at some fixed point.

Both ${\displaystyle \mathrm{\Omega }}$ and ${\displaystyle \tau }$ are found experimentally and agree on results from both hypotheses. The model makes important simplifications that make it unsuited for actual experimental predictions, but provides a significant basis for the hypothesis of a calcium-based synaptic plasticity dependence.

Short-term plasticity

Short-term synaptic plasticity acts on a timescale of tens of milliseconds to a few minutes unlike long-term plasticity, which lasts from minutes to hours. Short term plasticity can either strengthen or weaken a synapse.

Synaptic enhancement

Short-term synaptic enhancement results from an increased probability of synaptic terminals releasing transmitters in response to pre-synaptic action potentials. Synapses will strengthen for a short time because of an increase in the amount of packaged transmitter released in response to each action potential. Depending on the time scales over which it acts synaptic enhancement is classified as neural facilitation, synaptic augmentation or post-tetanic potentiation.

Synaptic depression

Synaptic fatigue or depression is usually attributed to the depletion of the readily releasable vesicles. Depression can also arise from post-synaptic processes and from feedback activation of presynaptic receptors. heterosynaptic depression is thought to be linked to the release of adenosine triphosphate (ATP) from astrocytes.

Long-term plasticity

Long-term depression (LTD) and long-term potentiation (LTP) are two forms of long-term plasticity, lasting minutes or more, that occur at excitatory synapses. NMDA-dependent LTD and LTP have been extensively researched, and are found to require the binding of glutamate, and glycine or D-serine for activation of NMDA receptors. The turning point for the synaptic modification of a synapse has been found to be modifiable itself, depending on the history of the synapse. Recently, a number of attempts have been made to offer a comprehensive model that could account for most forms of synaptic plasticity.

Long-term depression

Brief activation of an excitatory pathway can produce what is known as long-term depression (LTD) of synaptic transmission in many areas of the brain. LTD is induced by a minimum level of postsynaptic depolarization and simultaneous increase in the intracellular calcium concentration at the postsynaptic neuron. LTD can be initiated at inactive synapses if the calcium concentration is raised to the minimum required level by heterosynaptic activation, or if the extracellular concentration is raised. These alternative conditions capable of causing LTD differ from the Hebb rule, and instead depend on synaptic activity modifications. D-serine release by astrocytes has been found to lead to a significant reduction of LTD in the hippocampus. Activity-dependent LTD was investigated in 2011 for the electrical synapses (modification of Gap Junctions efficacy through their activity).. In the brain, cerebellum is one of the structures where LTD is a form of neuroplasticity.

Long-term potentiation

Long-term potentiation, commonly referred to as LTP, is an increase in synaptic response following potentiating pulses of electrical stimuli that sustains at a level above the baseline response for hours or longer. LTP involves interactions between postsynaptic neurons and the specific presynaptic inputs that form a synaptic association, and is specific to the stimulated pathway of synaptic transmission. The long-term stabilization of synaptic changes is determined by a parallel increase of pre- and postsynaptic structures such as axonal bouton, dendritic spine and postsynaptic density. On the molecular level, an increase of the postsynaptic scaffolding proteins PSD-95 and Homer1c has been shown to correlate with the stabilization of synaptic enlargement.

Modification of astrocyte coverage at the synapses in the hippocampus has been found to result from the induction of LTP, which has been found to be linked to the release of D-serine, nitric oxide, and the chemokine, s100B by astrocytes. LTP is also a model for studying the synaptic basis of Hebbian plasticity. Induction conditions resemble those described for the initiation of long-term depression (LTD), but a stronger depolarization and a greater increase of calcium are necessary to achieve LTP. Experiments performed by stimulating an array of individual dendritic spines, have shown that synaptic cooperativity by as few as two adjacent dendritic spines prevents LTD, allowing only LTP.

Synaptic strength

The modification of synaptic strength is referred to as functional plasticity. Changes in synaptic strength involve distinct mechanisms of particular types of glial cells, the most researched type being astrocytes.

Computational use of plasticity

Every kind of synaptic plasticity has different computational uses. Short-term facilitation has been demonstrated to serve as both working memory and mapping input for readout, short-term depression for removing auto-correlation. Long-term potentiation is used for spatial memory storage while long-term depression for both encoding space features, selective weakening of synapses and clearing old memory traces respectively. Forward spike-timing-dependent plasticity is used for long range temporal correlation, temporal coding and spatiotemporal coding. The reversed spike-timing-dependent plasticity acts as sensory filtering.