Neural plate

The neural plate is a key developmental structure that serves as the basis for the nervous system. Opposite the primitive streak in the embryo, ectodermal tissue thickens and flattens to become the neural plate. The region anterior to the primitive knot can be generally referred to as the neural plate. Cells take on a columnar appearance in the process as they continue to lengthen and narrow. The ends of the neural plate, known as the neural folds, push the ends of the plate up and together, folding into the neural tube, a structure critical to brain and spinal cord development. This process as a whole is termed primary neurulation.
Signaling proteins are also important in neural plate development, and aid in differentiating the tissue destined to become the neural plate. Examples of such proteins include bone morphogenetic proteins and cadherins. Expression of these proteins is essential to neural plate folding and subsequent neural tube formation.
Involvement in primary neurulation.
Generally divided into four, the process of primary neurulation involves the neural plate in the first three steps. The formation and folding of the neural plate is the first step in primary neurulation. This is followed by the refinement and growth of neural plate cells. The third step of primary neurulation does not involve the neural plate per se, but rather the edges of the neural plate, which come together, turning the plate into the start of the neural tube. With the neural plate having folded into a tube, the neural folds come together to complete the fusion of the neural tube. This process is illustrated in the figure to the right, where the neural plate is shown in purple. The lime green marks the edges of the neural plate, which become the neural folds, involved in the folding of the plate to create the neural tube. The figure demonstrates the development of the neural plate into the neural tube, which is where the neural crest cells are derived from as well.
In primary neurulation, the layer of ectoderm divides into three sets of cells: the neural tube (future brain and spinal cord), epidermis (skin), and neural crest cells (connects epidermis and neural tube and will migrate to make neurons, glia, and skin cell pigmentation).
Development.
During the stage of neural plate formation the embryo consists of three cell layers: the ectoderm that eventually forms the skin and neural tissues, the mesoderm that forms muscle and bone, and the endoderm that will form the cells lining the digestive and respiratory tracts. The progenitor cells that make up the precursors to neural tissues in the neural plate are called neuroepithelial cells.
Stretched over the notochord, the ectodermal cells on the dorsal portion of the embryo are ultimately the ones that form the neural plate. Approximately half of those cells will be induced to remain ectoderm, while the other half will form the neural plate.
There are four stages of neural plate and neural tube formation: formation, bending, convergence, and closure.
The formation of the neural plate starts when dorsal mesoderm signals ectodermal cells above it to lengthen into columnar neural plate cells. This different shape distinguishes the cells of the presumptive neural plate from other pre-epidermal cells. If the neural plate is separated by itself, it will still develop to make a thinner plate but will not form a neural tube. If the region containing presumptive epidermis and neural plate tissue is isolated, small neural folds will form. Elongation that occurs throughout the formation of the neural plate and closure of the neural tube is vital; the closing areas of the neural tube are seen to have very increased elongation activity in the midline compared to already closed areas when the plate was beginning to shape itself into a tube.
The bending of the neural plate involves the formation of hinges, where the neural plate is connected to surrounding tissues. The midline of the neural plate is referred to the median hinge point (MHP). Cells in this area, known as medial hinge point cells because of their involvement with this structure, are stabilized and connected to the notochord. They are derived from the area of the neural plate anterior to primitive knot. The notochord will begin the shape changes in MHP cells. These cells will decrease in height and become wedge-shaped. Another type of hinge point occurs dorsal-laterally, referred to as dorsal-lateral hinge point (DLHP). These regions furrow and change shape in the same way as MHP cells do before connecting together to form the neural tube. It was seen in an experiment that without the notochord, the MHP characteristics did not develop correctly, so the neural plate and neural tube formation did not happen properly. The communication between the neural plate and the notochord is important for the future induction and formation of the neural tube.
Closure of the neural tube is completed when the neural folds are brought together, adhering to each other. While the cells that remain as the neural tube form the brain and spinal cord, the other cells that were part of the neural plate migrate away from the tube as neural crest cells. After an epithelial–mesenchymal transition, these cells form the autonomic nervous system and certain cells of the peripheral nervous system.
Cell signaling and essential proteins.
Critical to the proper folding and function of the neural plate is N-cadherin, a type of cadherin protein associated with the nervous system. N-cadherin is critical to holding neural plate cells together. Additionally, cells destined to become neural plate cells express nerve cell adhesion molecule (NCAM) to further neural plate cohesion. Another cadherin, E-cadherin, is expressed by ectodermal cells in the process of neural plate development.
Bone morphogenetic protein 4, or BMP4, is a transforming growth factor that causes the cells of the ectoderm to differentiate into skin cells. Without BMP4 the ectoderm cells would develop into neural cells. Axial mesoderm cells under the ectoderm secrete inhibitory signals called chordin, noggin and follistatin. These inhibitory signals prevent the action of BMP4, which would normally make the cells ectoderm; as a result, the overlying cells take their normal course and develop into neural cells. The cells in the ectoderm that circumscribe these neural cells do not receive the BMP4 inhibitor signals and as a result BMP4 induces these cells to develop into skin cells.
Neural plate border specifiers are induced as a set of transcription factors. Distalless-5, PAX3 and PAX7 prevent the border region from becoming either neural plate or epidermis. These induce a second set of transcription factors called neural crest specifiers, which cause cells to become neural crest cells.
In a newly formed neural plate, PAX3 mRNA, MSX1 mRNA, and MSX1/MSX2 proteins are expressed mediolaterally. When the neural plate begins to fold, rostral areas of the neural plate do not express Pax3 and MSX proteins. Areas caudal to neural tube closure have PAX3 and MSX expression restricted to lateral regions of the neural folds. These fluctuations in mRNA and protein expression allude to how they play a role in differentiation of neural plate cells.
Low pSMAD 1, 5, 8 levels allow a greater mobility at the median hinge point than in lateral neural plate cells. This flexibility allows for the pivoting and hinging that allows the buckling and lifting of the neural plate when formatting the neural tube. The neural plate has to be rigid enough for morphogenic movements to occur while being flexible enough to undergo shape and position changes for the transformation to the neural tube.
Other animals.
The neural tube closes differently in various species, the distinctions between humans and chickens being some of the most studied. In humans, the neural tube fuses together from a central region of the embryo and moves outwards. In chickens, neural tube closure begins at the future midbrain region and it closes in both directions. In birds and mammals, the closure does not occur at the same time.
In newt and general amphibian embryos, cell division is not a driving role in morphogenesis. Newt embryo cells are much larger and exhibit egg pigmentation to distinguish cells from each other. The newt neural plate doubles in length, decreases in apical width, and increases in thickness. The plate edges rise dorsally and fold toward the midline to form the neural tube. The apical surface area decreases.
In chicken embryos, while the neural plate increases in length and decreases in apical width, the thickness of the plate does not change drastically. As the neural plate progresses through the Hamburger-Hamilton stages, the plate thickens until about HH6-7, when the neural plate begins to fold into tube form. The apical surface area increases during neurulation, unlike amphibian embryos. In mouse embryos, there is a large convex-shaped curve to each side of the middle of the plate. This curve has to be reversed as the plate rolls together to form the neural tube.
Research.
Research on the neural plate began in earnest by looking into the determination of the ectoderm and its commitment to the neuronal path. With the development of research and laboratory techniques there have been major advances in the study of neurulation and the development and role of the neural plate in a growing embryo. The use of such techniques vary with the stage of development and overall research goals, but include such methods as cell labeling and grafting.
Cell labelling.
The process of in situ hybridization (ISH) follows the labeling of a DNA or RNA sequence to serve as an antisense mRNA probe, complementary to a sequence of mRNA within the embryo. Labeling with a fluorescent dye or radioactive tag allows for the visualization of the probe and their location within the embryo. This technique is useful as it reveals specific areas of gene expression in a tissue as well as throughout an entire embryo through whole-mount in situ hybridization. This technique is often used in determination of gene expression necessary for the proper development of the embryo. Marking certain genes in a developing embryo allows for the determination of the exact time and place in which the gene is activated, offering information in the role of the particular gene in development.
Similar to the process of in situ hybridization, immunofluorescence (IF) also allows for the determination of particular cell element's roles in development. In contrast to in situ hybridization however, immunofluorescence uses a fluorophore attached to an antibody with biomolecule target, such as proteins, rather than DNA and RNA sequences. The allows for the visualization of biomolecule elements of the cell. In the study of embryogenesis immunofluorescence may be used for purposes similar to hybridization, for the tracking of proteins that are involved in the development of the embryo and their specific time and place of production and use. Current research has expanded on the immunofluorescence technique to combined it with the methods of in situ hybridization, either fluorescent or radioactive. This combination is believed to increase specificity and take away for the limitations of each individual technique. For example, this method with enhance counterstaining in a tissue and multiple protein labeling.
Cell grafting.
Cell grafting in the early stages of embryo development has provided crucial information on cell fates and the processes of determination. Grafting at specific stages of neurulation has advanced research on the signaling necessary for the proper development of the neural plate and other structures. The grafting of the ectoderm and neural structures is very specialized and delicate procedure, requiring the removal and marking of a desired group of cells, followed by their transplantation, for example, into a new area of the embryo.
Grafting experiments done in "Xenopus" and chicken embryos show the neural plate's capability to induce other regions of cells, including the pre-placodal region, a group of ectodermal cells essential to the function of sensory organs.


Corticomesencephalic tract

In neuroanatomy, corticomesencephalic tract is a descending nerve tract that originates in the frontal eye field (Brodmann area 8) and terminate in the midbrain. Its fibers mediate conjugate eye movement.
Structure.
The corticomesencephalic tract originates from the frontal eye field in the caudal part of the middle frontal gyrus and the inferior frontal gyrus (Brodmann's area 8). It runs rostral to the pyramidal tract in the posterior limb of the internal capsule. Then, it courses posteriorly toward the nuclei of the oculomotor nerve (III), trochlear nerve (IV) and abducens nerve (VI), the three cranial nerves that mediate eye movements. At the level of the caudal midbrain, corticomesencephalic fibers descend through the tegmentum in the medial lemniscus toward the oculomotor (III) and the trochlear (IV) nuclei on the contralateral (opposite) side. However, the fibers to the abducens (VI) nucleus do not terminate directly onto the nucleus. Instead, they terminate onto the paramedian pontine reticular formation (PPRF). The PPRF contains excitatory “burst” neurons that transmit the pulse to the ipsilateral (the same side of the body) abducens nucleus.
Function.
The fibers of the corticomesencephalic tracts are involved in the control of the conjugate eye movement. The fibers to the oculomotor (III) nucleus control the medial rectus, superior rectus, inferior rectus, and inferior oblique muscles. Fibers to the trochlear (IV) nucleus control the superior oblique muscle. Fibers to the paramedian pontine reticular formation (PPRF) project to the abducens (VI) nucleus, which controls the movement of the lateral rectus muscle. Also, fibers to the paramedian pontine reticular formation mediates the movements with the oculomotor (III) and trochlear (IV) nerves through the medial longitudinal fasciculus (MLF). The MLF coordinates the interaction between the oculomotor (III) and the abducens (VI) nuclei, which create bilateral conjugate horizontal eye movements.


Thoracic ganglia

The thoracic ganglia are paravertebral ganglia. The thoracic portion of the sympathetic trunk typically has 12 thoracic ganglia. Emerging from the ganglia are thoracic splanchnic nerves (the cardiopulmonary, the greater, lesser, and least splanchnic nerves) that help provide sympathetic innervation to abdominal structures. The thoracic part of sympathetic trunk lies posterior to the costovertebral pleura and is hence not a content of the posterior mediastinum
Also, the ganglia of the thoracic sympathetic trunk have both white and gray rami communicantes. The white rami communicantes carry sympathetic fibers arising in the spinal cord into the sympathetic trunk, while the gray rami communicantes carry postganglionic nerve fibers of the sympathetic nervous system back to the spinal nerves.


Jane Brick

Inger "Jane Brick" Lindström (12 June 1942 – 3 September 2016) was a Swedish television journalist.
Jane Brick worked for Swedish Television where she was a news anchor for the report, as well as a foreign correspondent. She was married twice with cartoonist Ove Lindström (born 1940), the first time from 1971 to 1982 and the second time in 1992 to his death. She had a son, Stefan.
She died of a brain tumor in Stockholm on 3 September 2016.


Histamine H3 receptor

Histamine H3 receptors are expressed in the central nervous system and to a lesser extent the peripheral nervous system, where they act as autoreceptors in presynaptic histaminergic neurons, and also control histamine turnover by feedback inhibition of histamine synthesis and release. The H3 receptor has also been shown to presynaptically inhibit the release of a number of other neurotransmitters (i.e. it acts as an inhibitory heteroreceptor) including, but probably not limited to dopamine, GABA, acetylcholine, noradrenaline, histamine and serotonin.
The gene sequence for H3 receptors expresses only about 22% and 20% homology with both H1 and H2 receptors respectively.
There is much interest in the histamine H3 receptor as a potential therapeutic target because of its involvement in the neuronal mechanism behind many cognitive disorders and especially its location in the central nervous system.
Function.
Like all histamine receptors, the H3 receptor is a G-protein coupled receptor. The H3 receptor is coupled to the Gi G-protein, so it leads to inhibition of the formation of cAMP. Also, the β and γ subunits interact with N-type voltage gated calcium channels, to reduce action potential mediated influx of calcium and hence reduce neurotransmitter release.
H3 receptors function as presynaptic autoreceptors on histamine-containing neurons.
The diverse expression of H3 receptors throughout the cortex and subcortex indicates its ability to modulate the release of a large number of neurotransmitters.
H3 receptors are thought to play a part in the control of satiety.
Isoforms.
There are at least six H3 receptor isoforms in the human, and more than 20 discovered so far. In rats there have been six H3receptor subtypes identified so far. Mice also have three reported isoforms. These subtypes all have subtle difference in their pharmacology (and presumably distribution, based on studies in rats) but the exact physiological role of these isoforms is still unclear.
Pharmacology.
Agonists.
There are currently no therapeutic products acting as selective agonists for H3 receptors, although there are several compounds used as research tools which are reasonably selective agonists. Some examples are:
Antagonists.
These include:
Therapeutic potential.
The H3-receptor is a promising potential therapeutical target for many (cognitive) disorders that are caused by a histaminergic H3R dysfunction, because it is linked to the central nervous system and its regulation of other neurotransmitters. Examples of such disorders are: sleep disorders (including narcolepsy), Tourette syndrome, Parkinson, OCD, ADHD, ASS and drug addictions.
This receptor has been proposed as a target for treating sleep disorders. The receptor has also been proposed as a target for treating neuropathic pain.
Because of its ability to modulate other neurotransmitters, H3 receptor ligands are being investigated for the treatment of numerous neurological conditions, including obesity (because of the histamine/orexinergic system interaction), movement disorders (because of H3 receptor-modulation of dopamine and GABA in the basal ganglia), schizophrenia and ADHD (again because of dopamine modulation) and research is underway to determine whether H3 receptor ligands could be useful in modulating wakefulness (because of effects on noradrenaline, glutamate and histamine).
There is also evidence that the H3-receptor plays an important role in Tourette syndrome. Mouse-models and other research demonstrated that reducing histamine concentration in the H3R causes tics, but adding histamine in the striatum decreases the symptoms. The interaction between histamine (H3-receptor) and dopamine as well as other neurotransmitters is an important underlying mechanism behind the disorder.


Cortical map

Cortical maps are collections (areas) of minicolumns in the brain cortex that have been identified as performing a specific information processing function (texture maps, color maps, contour maps, etc.).
Cortical maps.
Cortical organization, especially for the sensory systems, is often described in terms of maps. For example, sensory information from the foot projects to one cortical site and the projections from the hand target in another site. As the result of this somatotopic organization of sensory inputs to the cortex, cortical representation of the body resembles a map (or homunculus).
In the late 1970s and early 1980s, several groups began exploring the impacts of removing portions of the sensory inputs. Michael Merzenich and Jon Kaas and Doug Rasmusson used the cortical map as their dependent variable. They found—and this has been since corroborated by a wide range of labs—that if the cortical map is deprived of its input it will become activated at a later time in response to other, usually adjacent inputs. At least in the somatic sensory system, in which this phenomenon has been most thoroughly investigated, JT Wall and J Xu have traced the mechanisms underlying this plasticity. Re-organization is not cortically emergent, but occurs at every level in the processing hierarchy; this produces the map changes observed in the cerebral cortex.
Merzenich and William Jenkins (1990) initiated studies relating sensory experience, without pathological perturbation, to cortically observed plasticity in the primate somatosensory system, with the finding that sensory sites activated in an attended operant behavior increase in their cortical representation. Shortly thereafter, Ford Ebner and colleagues (1994) made similar efforts in the rodent whisker barrel cortex (also somatic sensory system). These two groups largely diverged over the years. The rodent whisker barrel efforts became a focus for Ebner, Matthew Diamond, Michael Armstrong-James, Robert Sachdev, Kevin Fox and great inroads were made in identifying the locus of change as being at cortical synapses expressing NMDA receptors, and in implicating cholinergic inputs as necessary for normal expression. However, the rodent studies were poorly focused on the behavioral end, and Ron Frostig and Daniel Polley (1999, 2004) identified behavioral manipulations as causing a substantial impact on the cortical plasticity in that system.
Merzenich and DT Blake (2002, 2005, 2006) went on to use cortical implants to study the evolution of plasticity in both the somatosensory and auditory systems. Both systems show similar changes with respect to behavior. When a stimulus is cognitively associated with reinforcement, its cortical representation is strengthened and enlarged. In some cases, cortical representations can increase two to threefold in 1–2 days at the time at which a new sensory motor behavior is first acquired, and changes are largely finished within at most a few weeks. Control studies show that these changes are not caused by sensory experience alone: they require learning about the sensory experience, and are strongest for the stimuli that are associated with reward, and occur with equal ease in operant and classical conditioning behaviors.
An interesting phenomenon involving cortical maps is the incidence of phantom limbs (see Ramachandran for review). This is most commonly described in people that have undergone amputations in hands, arms, and legs, but it is not limited to extremities. The phantom limb feeling, which is thought to result from disorganization in the brain map and the inability to receive input from the targeted area, may be annoying or painful. Incidentally, it is more common after unexpected losses than planned amputations. There is a high correlation with the extent of physical remapping and the extent of phantom pain. As it fades, it is a fascinating functional example of new neural connections in the human adult brain.
Norman Doidge, following the lead of Michael Merzenich, separates manifestations of neuroplasticity into adaptations that have positive or negative behavioral consequences. For example, if an organism can recover after a stroke to normal levels of performance, that adaptiveness could be considered an example of "positive plasticity". An excessive level of neuronal growth leading to spasticity or tonic paralysis, or an excessive release of neurotransmitters in response to injury which could kill nerve cells; this would have to be considered a "negative" plasticity. In addition, drug addiction and obsessive-compulsive disorder are deemed examples of "negative plasticity" by Dr. Doidge, as the synaptic rewiring resulting in these behaviors is also highly maladaptive.
A 2005 study found that the effects of neuroplasticity occur even more rapidly than previously expected. Medical students' brains were imaged during the period when they were studying for their exams. In a matter of months, the students' gray matter increased significantly in the posterior and lateral parietal cortex.


Sympathetic nervous system

The sympathetic nervous system (SNS) is one of the three divisions of the autonomic nervous system, the others being the parasympathetic nervous system and the enteric nervous system.
The autonomic nervous system functions to regulate the body's unconscious actions. The sympathetic nervous system's primary process is to stimulate the body's fight or flight response. It is, however, constantly active at a basic level to maintain homeostasis. The sympathetic nervous system is described as being antagonistic to the parasympathetic nervous system which stimulates the body to "feed and breed" and to (then) "rest-and-digest".
Structure.
There are two kinds of neurons involved in the transmission of any signal through the sympathetic system: pre-ganglionic and post-ganglionic. The shorter preganglionic neurons originate in the thoracolumbar division of the spinal cord specifically at T1 to L2~L3, and travel to a ganglion, often one of the paravertebral ganglia, where they synapse with a postganglionic neuron. From there, the long postganglionic neurons extend across most of the body.
At the synapses within the ganglia, preganglionic neurons release acetylcholine, a neurotransmitter that activates nicotinic acetylcholine receptors on postganglionic neurons. In response to this stimulus, the postganglionic neurons release norepinephrine, which activates adrenergic receptors that are present on the peripheral target tissues. The activation of target tissue receptors causes the effects associated with the sympathetic system. However, there are three important exceptions:
Organization.
Sympathetic nerves arise from near the middle of the spinal cord in the intermediolateral nucleus of the lateral grey column, beginning at the first thoracic vertebra of the vertebral column and are thought to extend to the second or third lumbar vertebra. Because its cells begin in the thoracolumbar division – the thoracic and lumbar regions of the spinal cord - the sympathetic nervous system is said to have a "thoracolumbar outflow". Axons of these nerves leave the spinal cord through the anterior root. They pass near the spinal (sensory) ganglion, where they enter the anterior rami of the spinal nerves. However, unlike somatic innervation, they quickly separate out through white rami connectors (so called from the shiny white sheaths of myelin around each axon) that connect to either the paravertebral (which lie near the vertebral column) or prevertebral (which lie near the aortic bifurcation) ganglia extending alongside the spinal column.
To reach target organs and glands, the axons must travel long distances in the body, and, to accomplish this, many axons relay their message to a second cell through synaptic transmission. The ends of the axons link across a space, the synapse, to the dendrites of the second cell. The first cell (the presynaptic cell) sends a neurotransmitter across the synaptic cleft where it activates the second cell (the postsynaptic cell). The message is then carried to the final destination.
Presynaptic nerves' axons terminate in either the paravertebral ganglia or prevertebral ganglia. There are four different paths an axon can take before reaching its terminal. In all cases, the axon enters the paravertebral ganglion at the level of its originating spinal nerve. After this, it can then either synapse in this ganglion, ascend to a more superior or descend to a more inferior paravertebral ganglion and synapse there, or it can descend to a prevertebral ganglion and synapse there with the postsynaptic cell.
The postsynaptic cell then goes on to innervate the targeted end effector (i.e. gland, smooth muscle, etc.). Because paravertebral and prevertebral ganglia are relatively close to the spinal cord, presynaptic neurons are generally much shorter than their postsynaptic counterparts, which must extend throughout the body to reach their destinations.
A notable exception to the routes mentioned above is the sympathetic innervation of the suprarenal (adrenal) medulla. In this case, presynaptic neurons pass through paravertebral ganglia, on through prevertebral ganglia and then synapse directly with suprarenal tissue. This tissue consists of cells that have pseudo-neuron like qualities in that when activated by the presynaptic neuron, they will release their neurotransmitter (epinephrine) directly into the bloodstream.
In the sympathetic nervous system and other components of the peripheral nervous system, these synapses are made at sites called ganglia. The cell that sends its fiber is called a preganglionic cell, while the cell whose fiber leaves the ganglion is called a postganglionic cell. As mentioned previously, the preganglionic cells of the sympathetic nervous system are located between the first thoracic segment and third lumbar segments of the spinal cord. Postganglionic cells have their cell bodies in the ganglia and send their axons to target organs or glands.
The ganglia include not just the sympathetic trunks but also the cervical ganglia (superior, middle and inferior), which send sympathetic nerve fibers to the head and thorax organs, and the celiac and mesenteric ganglia, which send sympathetic fibers to the gut.
Information transmission.
Messages travel through the sympathetic nervous system in a bi-directional flow. Efferent messages can trigger changes in different parts of the body simultaneously. For example, the sympathetic nervous system can accelerate heart rate; widen bronchial passages; decrease motility (movement) of the large intestine; constrict blood vessels; increase peristalsis in the oesophagus; cause pupillary dilation, piloerection (goose bumps) and perspiration (sweating); and raise blood pressure. One exception is with certain blood vessels such as those in the cerebral and coronary arteries, which dilate (rather than constrict) with an increase in sympathetic tone. This is because of a proportional increase in the presence of β2 adrenergic receptors rather than α1 receptors. β2 receptors promote vessel dilation instead of constriction like α1 receptors. An alternative explanation is that the primary (and direct) effect of sympathetic stimulation on coronary arteries is vasoconstriction followed by a secondary vasodilation caused by the release of vasodilatory metabolites due to the sympathetically increased cardiac inotropy and heart rate. This secondary vasodilation caused by the primary vasoconstriction is termed functional sympatholysis, the overall effect of which on coronary arteries is dilation.
The target synapse of the postganglionic neuron is mediated by adrenergic receptors and is activated by either norepinephrine (noradrenaline) or epinephrine (adrenaline).
Function.
The sympathetic nervous system is responsible for up- and down-regulating many homeostatic mechanisms in living organisms. Fibers from the SNS innervate tissues in almost every organ system, providing at least some regulation of functions as diverse as pupil diameter, gut motility, and urinary system output and function. It is perhaps best known for mediating the neuronal and hormonal stress response commonly known as the "fight-or-flight response". This response is also known as "sympatho-adrenal response" of the body, as the preganglionic sympathetic fibers that end in the adrenal medulla (but also all other sympathetic fibers) secrete acetylcholine, which activates the great secretion of adrenaline (epinephrine) and to a lesser extent noradrenaline (norepinephrine) from it. Therefore, this response that acts primarily on the cardiovascular system is mediated directly via impulses transmitted through the sympathetic nervous system and indirectly via catecholamines secreted from the adrenal medulla.
The sympathetic nervous system is responsible for priming the body for action, particularly in situations threatening survival. One example of this priming is in the moments before waking, in which sympathetic outflow spontaneously increases in preparation for action.
Sympathetic nervous system stimulation causes vasoconstriction of most blood vessels, including many of those in the skin, the digestive tract, and the kidneys. This occurs as a result of activation of alpha-1 adrenergic receptors by norepinephrine released by post-ganglionic sympathetic neurons. These receptors exist throughout the vasculature of the body but are inhibited and counterbalanced by beta-2 adrenergic receptors (stimulated by epinephrine release from the adrenal glands) in the skeletal muscles, the heart, the lungs, and the brain during a sympathoadrenal response. The net effect of this is a shunting of blood away from the organs not necessary to the immediate survival of the organism and an increase in blood flow to those organs involved in intense physical activity.
Sensation.
The afferent fibers of the autonomic nervous system, which transmit sensory information from the internal organs of the body back to the central nervous system (or CNS), are not divided into parasympathetic and sympathetic fibers as the efferent fibers are. Instead, autonomic sensory information is conducted by general visceral afferent fibers.
General visceral afferent sensations are mostly unconscious visceral motor reflex sensations from hollow organs and glands that are transmitted to the CNS. While the unconscious reflex arcs normally are undetectable, in certain instances they may send pain sensations to the CNS masked as referred pain. If the peritoneal cavity becomes inflamed or if the bowel is suddenly distended, the body will interpret the afferent pain stimulus as somatic in origin. This pain is usually non-localized. The pain is also usually referred to dermatomes that are at the same spinal nerve level as the visceral afferent synapse.
Relationship with the parasympathetic nervous system.
Together with the other component of the autonomic nervous system, the parasympathetic nervous system, the sympathetic nervous system aids in the control of most of the body's internal organs. Reaction to stress—as in the flight-or-fight response—is thought to counteract the parasympathetic system, which generally works to promote maintenance of the body at rest. The comprehensive functions of both the parasympathetic and sympathetic nervous systems are not so straightforward, but this is a useful rule of thumb.
Disorders.
In heart failure, the sympathetic nervous system increases its activity, leading to increased force of muscular contractions that in turn increases the stroke volume, as well as peripheral vasoconstriction to maintain blood pressure. However, these effects accelerate disease progression, eventually increasing mortality in heart failure.
 Sympathicotonia is a stimulated condition of the sympathetic nervous system, marked by vascular spasm, elevated blood pressure, and goose bumps. A recent study has shown the expansion of Foxp3+ natural Treg in the bone marrow of mice after brain ischemia and this myeloid Treg expansion is related to sympathetic stress signaling after brain ischemia.
History and etymology.
The name of this system can be traced to the concept of sympathy, in the sense of "connection between parts", first used medically by Galen. In the 18th century, Jacob B. Winslow applied the term specifically to nerves.


Gliogenesis

Gliogenesis is the generation of non-neuronal glia populations derived from multipotent neural stem cells.
Overview.
Gliogenesis results in the formation of non-neuronal glia populations from neuronal cells. In this capacity, glial cells provide multiple functions to both the central nervous system (CNS) and the peripheral nervous system (PNS). Subsequent differentiation of glial cell populations results in function-specialized glial lineages. Glial cell-derived astrocytes are specialized lineages responsible for modulating the chemical environment by altering ion gradients and neurotransmitter transduction. Similarly derived, oligodendrocytes produce myelin, which insulates axons to facilitate electric signal transduction. Finally, microglial cells are derived from glial precursors and carry out macrophage-like properties to remove cellular and foreign debris within the central nervous system ref. Functions of glial-derived cell lineages are reviewed by Baumann and Hauw. Gliogenesis itself, and differentiation of glial-derived lineages are activated upon stimulation of specific signaling cascades. Similarly, inhibition of these pathways is controlled by distinct signaling cascades that control proliferation and differentiation. Thus, elaborate intracellular-mechanisms based on environmental signals are present to regulate the formation of these cells. As regulation is much more known in the CNS, its mechanisms and components will be focused on here. Understanding the mechanisms in which gliogenesis is regulated provides the potential to harness the ability to control the fate of glial cells and, consequently, the ability to reverse neurodegenerative diseases.
Gliogenesis induction.
Following the generation of neural stem cells, an option is presented to proceed to enter neurogenesis and form new neurons within the CNS, shift into gliogenesis, or remain in a pluripotent cell state. The mechanisms determining the ultimate fate of neural stem cells are conserved among both invertebrate and vertebrate species and are determined from extracellular cues generated from neighboring cells. Most work to derive such mechanisms, however, began with invertebrate models. Conclusions reached from these studies have directed attention to specific signaling molecules and effector pathways that are responsible for mediating the cellular events required for maintaining or changing the neural stem cell fate.
Signaling effectors.
Notch signaling is known to mediate prominent cellular events that result in gliogenesis. The Notch family proteins are transmembrane receptors that are ligand activated. In the presence of ligand effectors, the intracellular domain of the receptor is cleaved and sequestered to the nucleus where it acts to influence expression of transcription factors required for gliogenesis. Transcription factors synthesized as a result of the Notch signaling cascade bind to promoters of genes responsible for glial determination. Additionally, Notch signaling also acts to downregulate many genes responsible for neuronal development, thus inhibiting a neuron phenotype from arising. Both actions collectively function to promote glial fate.
In certain CNS tissue, JAK/STAT signaling is also known to promote gliogenesis Significant levels of the ciliary neurotrophic factor (CNTF) are expressed immediately preceding gliogensis in response to environmental cues allowing the activation of the JAK-STAT signaling pathway. Kinase activity phosphorylates STAT proteins which then are recruited by transcription factors. The STAT complex is targeted to promoters of genes responsible for gliogenesis activation. It is important to recognize that when isolated, receptor-mediated signaling cascades can produce distinct actions, however, when in vivo coopertivity often exists among receptor pathways and results in much more complicated cellular actions.
Signaling molecules.
The receptor-proteins responsible for gliogenic pathways are often ligand activated. Upon binding of Delta or "Jagged", the notch-mediated signaling cascades are activated leading to gliogenic transcription factor production as discussed above. As noted for receptor-proteins, in vivo interactions among different growth factor responsible for gliogenesis and other cell fates produce very different roles than when isolated.
Gliogenesis regulation.
To ensure proper temporal differentiation as well as correct quantities of glial cell formation, gliogenesis is subjected to stringent regulatory mechanisms. Proneural factors are expressed in high concentrations during times in which glial cells are not to form or neuron development is needed. These protein signals function to inhibit many of the signals utilized during the induction of gliogenesis. Additionally, the properties and abundance of receptor molecules that mediate gliogenesis are altered, consequently disrupting propagation of induction signals.
Signaling inhibition.
During periods in which glial cell formation is discouraged, neural stem cells have the option to remain pluripotent or switch pathway lineages and begin forming neurons during neurogenesis. If neuron development is instructed, neurogenic factors, i.e. BMPs, are present to induce expression of proneural transcription factors like Neurogenin and ASCL1. These transcription factors function to interact with transcription factors generated from Notch signaling. Consequently, this complex is sequestered away from promoters activating gliogenesis and now directed to promoters that influence activity directed for neuron development. Neurogenin proteins regulate JAK/STAT signaling by similar mechanisms.
Receptor insensitivity.
Recently, an alternative mechanism to regulate differentiation has been proposed in addition to inhibition through growth factors. Changes in local sensitivity of neural stem cells have been shown to modulate the differentiation capacity of growth factors. Over developmental time, neural stem cells lose the ability to respond to growth factors that influence differentiation as intrinsic changes occur to receptor structure and function of these cells. It has been shown Notch receptors require 50-fold higher concentrations of ligand effectors to initiate differentiation responses similar to that of developmentally earlier neural stem cells. Decrease in sensitivity of Notch receptors reduces the activity of Notch-signaling required for gliogenesis to occur. Consequently, neural stem cells have developed a general mechanism limiting further differentiation after intense specialization during the early developmental periods.
Receptor internalization.
The internalization, or endocytosis, of receptor proteins from the cell’s plasma membrane contributes to yet another mode of regulation of cellular function. While receptor internalization has the potential to regulate cellular functions in both a positive and negative fashion, internalization of the Notch receptor is shown to down-regulate the events leading to gliogenesis as this process is Notch-signaling dependent
During repression of gliogenesis, expression of the Notch-binding protein, Numb, is elevated. Numb is suggested to function in two manners: 1) When expressed, Numb will interact with specific endocytic proteins and create a link between the notch receptor and the endocytic vesicles. The vesicle-receptor complex generated will be targeted back to the cell membrane and the membrane receptor will be recycled to the cell surface never reaching the nucleus. Alternatively, 2) Numb is suggested to recruit additional molecules other than endocytic proteins. In particular, ubiquitin ligases are shown to be recruited by Numb in mammals. The ubiquitin ligases ubiquitinates Notch and targets it for degradation Whatever the mechanism of Numb, the Notch receptor does not reach the nucleus and the transcription factors required for gliogenesis are not generated.
Gliogenic-associated pathology.
Recent work has demonstrated abnormalities in the signaling pathways responsible for gliogenesis and neurogenesis could contribute to the pathogenesis of neurodegenerative diseases and tumor development within the nervous system. Recognizing the distinct pathways controlling neural stem fate, as discussed above, provides one the opportunity to intervene in the pathogenesis of these diseases.
Gliogenesis and neurodegenerative disease.
The pathology of neurodegenerative diseases is associated with the disruption of gliogenic pathways and has been recently reviewed. The subventricular zone (SVZ) of the forebrain is of special interest when evaluating errant gliogenic pathways as it is the largest store of neural stem cells in the brain. In multiple sclerosis (MS) patients, lesions in this area are frequently observed and often extend outward toward the lateral ventricles of the brain. Immune cells infiltrate the gliogenic regions within the SVZ adjacent to the lesions and initiate inflammatory response mechanisms in response to damage in this region. It is suggested that cytokine release during the inflammatory response reduces, foremost, the inherent neural stem cell populations, and jointly the potential of the remaining neural stem cell to differentiate to glial-fates. Consequently, a reduction of glial-derived oligodendroctyes, among others, compromise maintenance of myelin production for axon insulation, a hallmark phenotype among MS patients.
Consequences of gliogenesis disruption among other neurodegenerative diseases, such as Huntington's, Parkinson's, and Alzheimer's Diseases are currently being investigated and strong mechanistic evidence is shown for pathogenesis similar to MS.
Gliogenesis and glial tumors.
Disruption of controlled glial generation subsequently results in tumorigenesis and glioma formation within the central nervous system. Loss of contact inhibition, cellular migration, and unregulated proliferation are characteristic of gliomas. Consistent with other tissues, these malignant phenotypes result most commonly from chromosome deletions, translocations, and point mutations. Linskey reviews both the genetic contributions and phenotypic observations of glioma
In non-carcinogenic neural stem cells, key regulatory mechanisms prevent uncontrolled gliogenic proliferation. However, such mechanisms are disrupted upon genetic damage. Studies now suggest glioma formation may result from cellular insensitivity to regulatory growth factors and cell signals, like neurogenin, that would normally inhibit further proliferation of glial cells. Conformational changes in receptor proteins are thought to occur, leaving the cell constitutively proliferating.
Therapeutic intervention of gliogenic-derived pathogenesis.
Understanding the pathology of these neurodegenerative diseases and establishment of therapeutic interventions require recognition of the processes of induction and inhibition of gliogenesis and the regulating mechanisms coordinating the intricate system established from both actions. Cell replacement strategies are now intensely studied as a possible therapeutic intervention of glial associated neurodegenerative disorders and glial tumors. Similar to any novel strategy, however, set-backs and liabilities accompany the promises this technique withholds. For cell replacement to function efficiently and demonstrate robust results, introduced cells must be 1) generated in sufficient yield and 2) immunocompatible with the host and 3) able to sustain self-growth. New perspectives within stem cell biology and gliogenesis regulation have provided new insights within the past decade to begin addressing these challenges. Reprogramming terminally differentiated neural lineages back to neural stem cells permits regeneration of a multipotent self-lineage that can be redirected to cellular-fates affected during neurogenerative diseases, oligodendrocytes with MS patients or astrocytes in those affected with Alzheimer's, in the presence of proper environmental signals.
It can be expected that as the signaling pathways discussed are shown as prominent regulators during glial cell generation, these same pathways will become therapeutic targets for glial-derived and other CNS cancers. In medulloblastomas, in vivo studies have begun targeting notch pathways by blocking Notch receptors with specific inhibitors preventing further differentiation. When used, pathway inhibitors provided 10-fold greater sensitivity to apoptotic induction in medulloblastoma cells Recognition of the regulatory mechanisms of gliogenesis provide new direction for intervention of neurogenic disorders.


Rostral migratory stream

The rostral migratory stream (RMS) is a specialized migratory route found in the brain of some animals along which neuronal precursors that originated in the subventricular zone (SVZ) of the brain migrate to reach the main olfactory bulb (OB). The importance of the RMS lies in its ability to refine and even change an animal's sensitivity to smells, which explains its importance and larger size in the rodent brain as compared to the human brain, as our olfactory sense is not as developed. This pathway has been studied in the rodent, rabbit, and both the squirrel monkey and rhesus monkey. When the neurons reach the OB they differentiate into GABAergic interneurons as they are integrated into either the granule cell layer or periglomerular layer.
Although it was originally believed that neurons could not regenerate in the adult brain, neurogenesis has been shown to occur in mammalian brains, including those of primates. However, neurogenesis is limited to the hippocampus and SVZ, and the RMS is one mechanism neurons use to relocate from these areas.
Brief history.
The RMS was named and discovered by J. Altman in 1969 using 3H-thymidine autoradiography in the rat brain. He traced the migration of labeled cells from the SVZ, which is situated throughout the lateral walls of the lateral ventricles, rostrally to the main olfactory bulb. He also quantitatively studied the effect of age on the size of the RMS. There is still some ongoing debate about the extent of the RMS and adult SVZ neurogenesis of new neurons in humans.
Cell biology.
Vascular cells.
Vascular cells are known to play a prominent role in regulating proliferation of adult neural precursors. In the adult subgranular zone (SGZ), dense clusters of dividing cells were found to be anatomically close to the vasculature, especially capillaries. Contacts between adult SVZ neuronal precursors and blood vessels are unusually permeable and frequently devoid of astrocyte and pericyte interferences, suggesting that blood-derived cues are gaining direct access to adult neural precursors and their progeny. The vasculature also provides the substrate for new neuron migration after injury in the adult striatum.
In the RMS, vascular cells are arranged parallel to the route of the migrating cells and provide a scaffolding. Glial cells are also associated with the blood vessels; communication between these cells may be important for RMS migration, for example, in BDNF (brain-derived neurotrophic factor), a growth factor that is thought to module RMS migration.
Astrocytes.
Astrocytes form gap junctions and are closely associated with the vasculature and its basal lamina in the adult SVZ and subsequently in the RMS. They may serve as an interface to modulate influences of endothelial and circulation-derived factors as well as the availability of cytokines and growth factors in this system. In addition, astrocytes derived from the neurogenic hippocampus and SVZ, but not from the non-neurogenic spinal cord, promote proliferation and neuronal fate commitment of multipotent adult neural stem cells in culture, suggesting a role in the RMS. Astrocytes express a number of secreted and membrane-attached factors both "in vitro" and "in vivo" that are known to regulate proliferation and fate specification of adult neural precursors as well as neuronal migration, maturation, and synapse formation. In the adult SVZ, astrocytes express Robo receptors and regulate the rapid migration of SLIT1-expressing neuroblasts through the RMS. Additionally, it has been proposed that the neuroblasts themselves play a role in modulating the astrocytes through Slit-Robo interactions. In the absence of Slit, astrocytic processes do not align correctly, or create the "tubes", instead running across the migrating neurons. Adult SVZ astrocytes also appear to release glutamate to regulate the survival of neuroblasts. Unique to the adult SVZ, ependymal cells lining the ventricular wall are in close association with neural precursors and their progeny, acting like a shield to protect the "neurogenic niche", a zone in which stem cells are retained after embryonic development for the production of new cells of the nervous system.
Other glial cells.
Ependymal cells actively regulate neuronal fate specification of adult neural precursors through release of Noggin. Beating of the cilia of ependymal cells appears to set up concentration gradients of guidance molecules, such as cytokines TNF-α (tumor necrosis factor) and IGF-1 (insulin-like growth factor), to direct migration of neuroblasts, such as in the RMS. Microglia also actively regulate adult neurogenesis. Under basal conditions, apoptotic corpses of newly generated neurons are rapidly phagocytosed from the niche by unactivated microglia in the adult SGZ. Under inflammatory conditions, reactivated microglia can have both beneficial and detrimental effects on different aspects of adult neurogenesis, depending on the balance between secreted molecules with pro- and anti-inflammatory action. In one study, the activation of microglia and recruitment of T cells were suggested to be required for enriched environment-induced SGZ neurogenesis, suggesting a possible role in the RMS.
Migration mechanics.
Cells in the RMS are believed to move by "chain migration". These neuroblasts are connected by membrane specializations including gap junctions and adherens junctions, moving along each other towards the olfactory bulb through glial tubes. The pathway and mechanisms behind this movement are a ventriculo-olfactory neurogenic system (VONS), a glial framework, and a chemotaxic cell signalling system.
Ventriculo-olfactory neurogenic system (VONS).
The olfactory system is made up in part of the RMS which stretches from the subventricular zone in the wall of the lateral ventricle, through the basal forebrain, to the olfactory bulb (OB). "VONS" is the name given to this pathway, and it consists of the subventricular zone, the RMS, the olfactory tract and the olfactory bulb. Developing neurons leave the subventricular zone and enter the RMS and travel caudally and ventrally along the undersurface of the caudate nucleus; this is referred to as the descending limb. Upon reaching the ventral side of the caudate nucleus, the neurons follow the rostral limb and travel ventrally and rostrally, entering the anterior olfactory cortex (AOC). The AOC gives rise to the olfactory tract, which ends in the olfactory bulb.
Glial framework.
Developing neurons travel toward the olfactory bulb along the RMS via glial tubes, which mark the division between the differentiated nervous tissue and the tissue with embryonic characteristics. Uniquely, the cells travel tangential to the brain surface, parallel to the pial surfaces rather than radially like most developing neurons. Neurons that migrate tangentially are typically believed to migrate independently of radial glia but in the RMS researchers believe this is not the case. Adult rat glial tubes have been observed via light and electron microscopy and described as a meshwork of astrocytic bodies and processes. They have been determined to be astrocytes based on the typical expression of GFAP (glial fibrillary acidic protein) and more specifically as protoplasmic astrocytes based on their morphology. Furthermore, these glial cells were found to be positive for vimentin expression, a protein commonly found in embryonic or immature glial cells. The developing neurons are identified by their expression of the cell surface molecule, a polysialylated (PSA) embryonic form of the neural cell adhesion molecule (NCAM) called PSA-NCAM, as well as β-tubulin, a protein often found in postmitotic neuroblasts, proving the cells of RMS are committed to developing into neurons and will do so upon entry into the olfactory bulb. With the removal of NCAM, the neuroblasts scatter, proving the importance of NCAM in chain formation. The neurons form both clusters and chains along the lumen of these glial tubes.
Once the developing neurons reach the core of the olfactory bulb, they detach from the RMS, which is initiated by Reelin and tenascin and move radially toward glomeruli, this migration is dependent on tenascin-R, and differentiate into subtypes of interneurons. These neurons have been studied "in vivo" via electrophysiology and confocal imaging.
Cell signaling.
The nature of the molecular cues involved in the correct targeting of the migrating precursors remains a question. The secretion of a chemoattractant factor by the OB appears as a possibility. Chemoattractants and repellants act on the migrating neurons by inducing changes in the growth cone to direct them. Nevertheless, tissue derived from this structure had no directive influence on the migration. On the other hand, a septum-derived secreted factor showed a repulsive effect on the SVZ cells. More recently, it has been shown that the secreted molecule SLIT shows such a repelling effect on SVZ-derived precursors. Furthermore, integrins have been demonstrated to have a regulatory influence on precursor cell chain-migration and regulation of their divisions.
PSA-NCAM appears as another candidate. Mice lacking NCAM show a dramatically size-reduced OB and an accumulation of migrating precursors along the RMS. It is possible that lack of NCAM results in agitation of neuron–glia interactions, and modifications in these interactions might in turn be responsible for the inhibition of migration in the RMS. It has been demonstrated that a cross talk exists between neurons and glial cells and data in favor of an active role of PSA–NCAM in this process has been presented. The lack of PSA–NCAM on the surface of migrating precursors might alter the proliferative properties of this glial cell population, a scenario that appears reminiscent of astrogliosis occurring in neurodegenerative diseases even before any signs of neuronal damage.
Current research.
Existence in humans.
The presence of an analogous RMS in humans has been difficult to identify, possibly because the olfactory bulb is significantly less developed in humans than in rodents and thus harder to study, and much of the previous scientific work has been called into question concerning the RMS in humans. In the developing fetal brain and in young postnatal infants, chains of immature neurons typical of the RMS were observed. However, there was little evidence for the existence of a migrating chain along the SVZ or olfactory peduncle to the bulb in the adult human brain, even though there was a distinct population of adult neuronal stem cells in the SVZ. These researchers studied subjects from 0 to 84 years of age by analyzing brain sections that had been removed during surgery or during autopsies. They discovered that cells that expressed DCX (doublecortin) and PSA-NCAM are present in the brain sections taken from infants, but have disappeared by 18 months. Yet further studies indicated the presence of a small population of migrating immature neurons, which originate solely from the SVZ. These neuroblasts appear singly or in pairs without forming chains, in contrast to the elongated chains of neuroblasts observed in the rodent RMS. This suggests that the RMS is drastically reduced beyond infancy and especially into adulthood, but is not absent. However, a direct correlation between stem cell quiescence and age has not yet been defined due to a high level of variability between individuals. Thus an RMS analogous structure in the adult human brain remains highly controversial.
Age-related decline.
The extent of age-related RMS decline in humans has been the subject of significant debate. The decline of neurogenesis in and migration from the hippocampus in humans has already been well documented. Furthermore, age-related declines in the activities of SVZ stem cells, which migrate to the OB via the RMS, are in place by middle age in rodents. In elderly mice, studies showed that the population of actively dividing SVZ cells and the rate of interneuron replacement in the OB are both drastically reduced, indicating an age-related decline in neuronal proliferation and migration through the RMS. This decline was shown to be due to neuronal stem cell quiescence in the SVZ even by middle age, and not destruction, much like in the hippocampus.
Pharmaceuticals.
Another topic in current RMS research pertains to pharmaceuticals. Scientists are still trying to tackle the difficult task of administering drugs into the brain and getting them past the selective blood–brain barrier. In a recent study, researchers tested the role of the RMS in “intranasal delivery of drugs into the CNS”. In this study, the experimenters disrupted the RMS in mice, which obstructed “the uptake of intranasally administered radioligands into the CNS.” Fluorescent tracers were also used to track the medicine throughout the brain. It was found that the medicine spread to all regions of the brain, including the olfactory bulb. The study concluded that the RMS was extremely prevalent and necessary in the central nervous system in order to deliver drugs intranasally. The study also noted that this research on the RMS is not sufficient, but instead needs to be expanded. Some of the limits and capabilities of the RMS are still unknown, as well as some of the hazards of it. If drugs are to be administered into the CNS through the RMS, all of the details of the RMS must be known in order to ensure safe delivery of the drugs to the brain.
α6β1 integrin.
A study was conducted testing a specific integrin, alpha-six-beta-one, and the role it plays in the RMS. The study researched the principle that chemoattractive molecules may play an important role in neuroblast migration in the RMS. The study of this one particular integrin was conducted in mice. By using antibodies to bind to α6β1 integrin subunits, found on the neuroblasts, the researchers observed that the migration was disrupted. Furthermore, they investigated the mechanism through which α6β1 integrin functions and determined it was via the chemoattractant laminin. This was completed by injecting laminin perpendicular to the RMS and observing that doing so drew “neuroblasts away from their normal course of migration”. The researchers concluded with the idea that this research could prove useful for therapeutics purposes in that neuroblasts could potentially be drawn to locations of injury or disease.


Channelopathy

Channelopathies are diseases caused by disturbed function of ion channel subunits or the proteins that regulate them. These diseases may be either congenital (often resulting from a mutation or mutations in the encoding genes) or acquired (often resulting from autoimmune attack on an ion channel).
There are many distinct dysfunctions known to be caused by ion channel mutations. The genes for the construction of ion channels are highly conserved amongst mammals and one condition, hyperkalemic periodic paralysis, was first identified in the descendants of Impressive, a registered Quarter Horse.
The channelopathies of human skeletal muscle include hyper- and hypokalemic (high and low potassium blood concentrations) periodic paralysis, myotonia congenita and paramyotonia congenita.
Channelopathies affecting synaptic function are a type of synaptopathy.
Types.
The types in the following table are commonly accepted. Channelopathies currently under research, like Kir4.1 potassium channel in multiple sclerosis, are not included.
External links.
VIDEO Channel Surfing in Pediatrics by Carl E. Stafstrom, M.D., at the UW-Madison Health Sciences Learning Center.


Rushdy Abaza

Rushdy Said Bughdady Abaza () (August 1926 – 27 July 1980) was an Egyptian actor. He was a member of the wealthy Abaza family. He was considered one of the most charming actors in the Egyptian film industry. He died of brain cancer at the age of 53.
Family.
Rushdy Abaza was born in Mansoura, Egypt, to Egyptian father, Said Abaza, belonging to one of Egypt's richest and most well-known families, the Abaza family, and Italian mother Teresa (Tereza) Luigi. Rushdy attended school at Collège Saint Marc in Alexandria.
From his father's side he had three half-sisters, Ragaa, Mounira, Zeinab and one half-brother, Fikri (an actor). From his mother's side, he had one half-brother, Hamed. His only child is a daughter, Qismat.
Filmography.
He appeared in more than 100 films from 1948 to 1980; many of which in starring or co-starring roles with the most notable Arabic actors and actresses such as 1972 film titled "My Dear Daughter" (in Arabic - "Ebnati al-Aziza") 1 Najat Al Saghira;
1948
1949
1950
1951
1952
1953
1954
1955
1956
1957
1958
1959
1960
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971
1972
1973
1974
1975
1976
1977
1978
1979
1980


Zotepine

Zotepine is an atypical antipsychotic drug indicated for acute and chronic schizophrenia. It has been used in Germany since 1990 (although it has been discontinued in Germany) and Japan since 1982.
Zotepine is not approved for use in the United States, United Kingdom, Australia, Canada or New Zealand.
Medical uses.
Zotepine's primary use is as a treatment for schizophrenia although clinical trials have been conducted (with positive results) into its efficacy as an antimanic agent in patients with acute bipolar mania. In a 2013 study in a comparison of 15 antipsychotic drugs in effectivity in treating schizophrenic symptoms, zotepine demonstrated medium-strong effectivity. Less effective than clozapine, slightly less effective than olanzapine and risperidone, approximately as effective as paliperidone, and slightly more effective than haloperidol, quetiapine, and aripiprazole.
Pharmacology.
Pharmacodynamics.
The antipsychotic effect of zotepine is thought to be mediated through antagonist activity at dopamine and serotonin receptors. Zotepine has a high affinity for the D1 and D2 receptors. It also affects the 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors. In addition, its active metabolite, norzotepine, serves as a potent norepinephrine reuptake inhibitor.
Names.
Brand names include Losizopilon , Lodopin , Setous , Zoleptil ; where † indicates a formulation that has been discontinued.


Journal of Integrative Neuroscience

The Journal of Integrative Neuroscience is a peer-reviewed scientific journal of neuroscience. It was published by World Scientific from 2002 to 2016, then IOS Press in 2017, and is now published by IMR Press since 2018. The journal is edited by Roman R. Poznanski.
Abstracting and indexing.
The journal is abstracted and indexed in:
According to the "Journal Citation Reports", the journal has a 2018 impact factor of 1.139.


Mark H. Schoenfisch

Mark H. Schoenfisch ( ) is an American Analytical Chemist. He is the Peter A. Ornstein Distinguished Professor of Chemistry at the University of North Carolina at Chapel Hill and is jointly appointed with the institution's Schools of Medicine and Pharmacy. His research interests include analytical sensors, biomaterials, and the development of macromolecular nitric oxide release scaffolds as novel therapeutics. Intellectual property originating from his research group is the basis of technology being commercialized by Novan, Diabetic Health, and Vast Therapeutics located in the Research Triangle Park.
Early life and education.
Mark H. Schoenfisch was born in Elgin, Illinois. He attended William Fremd High School in Palatine, Illinois (class of 1988) and graduated from the University of Kansas in 1992 with a B.A. in Chemistry and Germanic Languages & Literature. Schoenfisch went on to receive his Ph.D. in Chemistry at the University of Arizona in 1997.
Career.
In 1998, Schoenfisch worked as a NIH Postdoctoral Fellow under the Department of Chemistry at the University of Michigan. He moved to Chapel Hill, North Carolina, and began his independent research career as an Assistant Professor of Chemistry at the University of North Carolina at Chapel Hill in 2000. He was promoted to Associate Professor in 2005, and Full Professor in 2009. He was appointed as Peter A. Ornstein Distinguished Professor in 2018.
Research.
The Schoenfisch group works at the interface analytical chemistry, materials science, biomedical engineering, and pharmacology. Research within the Schoenfisch group is currently focused on four main areas:
Awards and honors.
In 1998, Schoenfisch received the National Institutes of Health Postdoctoral Fellowship. He received the Society for Analytical Chemists of Pittsburgh Young Investigator Award in 2001, the Eli Lilly and Company Young Investigator Award in 2002, the National Science Foundation CAREER Award in 2004 and the International Union of Pure and Applied Chemistry Young Observer Award in 2005. Schoenfisch was recognized as a prominent professor in 2007 when he received the John L. Sanders Award for Distinguished Undergraduate Teaching and Service. In 2015, he received both the Chapman Family Teaching Award for Distinguished Teaching of Undergraduates as well as the Institute for the Arts and Humanities Faculty Fellowship. In 2018, he received UNC's Office of Commercialization and Economic Development Inventor of the Year Award.
Commercialization interests.
Schoenfisch is a cofounder of Novan, Inc. (2006). The public pharmaceutical company focuses primarily on the development of nitric oxide release-based therapies for dermatological indications. One lead product is an anti-acne drug, which has completed Phase 3 clinical trial. At least three other drugs are being developed, including topical anti-virals for the treatment of molluscum contagiosum (Phase 3) and external genital warts caused by the human papillomavirus (Phase 2), and a topical for the treatment of onychomycosis (Phase 2).
Schoenfisch is also a cofounder of KnowBIO, LLC and Vast Therapeutics, Inc., 2017. Vast focuses on the development of water-soluble nitric oxide-releasing biopolymers for treating chronic respiratory infections.


Academic audit

In academia, an audit is an educational term for the completion of a course of study for which no assessment of the performance of the student is made nor grade awarded. Some institutions may record a grade of "audit" to those who have elected not to receive a letter grade for a course in which they are typically awarded.
In this case, 'audit' indicates that the individual merely has received teaching, rather than being evaluated as having achieved a given standard of knowledge of the subject. The term 'audit' is Latin, translating as, 'he/she hears'. In other words, the audit student has experienced the course, but has not been assessed.
Some students audit a class merely for enjoyment, including purposes of self-enrichment and academic exploration, with no need or desire of academic credit. Sometimes this technique is employed by individuals who wish to take a specific course without the risk of under-performance resulting in a poor or failing grade. This may be helpful when reviewing a long-unstudied subject, or when first beginning or exploring the study of a discipline where one has little experience or confidence.
Auditing is generally an option at institutions of higher learning, such as colleges and universities, rather than grammar school or secondary school.


Dentate nucleus

The dentate nucleus is a cluster of neurons, or nerve cells, in the central nervous system that has a dentate – tooth-like or serrated – edge. It is located within the deep white matter of each cerebellar hemisphere, and it is the largest single structure linking the cerebellum to the rest of the brain. It is the largest and most lateral, or farthest from the midline, of the four pairs of deep cerebellar nuclei, the others being the globose and emboliform nuclei, which together are referred to as the interposed nucleus, and the fastigial nucleus. The dentate nucleus is responsible for the planning, initiation and control of voluntary movements. The dorsal region of the dentate nucleus contains output channels involved in motor function, which is the movement of skeletal muscle, while the ventral region contains output channels involved in nonmotor function, such as conscious thought and visuospatial function.
Development.
The dentate nucleus is highly convoluted, with gyri (ridges on the cerebral cortex) and sulci (furrows or grooves on the cerebral cortex). Its formation is coincident with a critical period of extensive growth in the fetal dentate. The dentate nucleus becomes visible in the cerebellar white matter as early as 11–12 weeks of gestation, containing only smooth lateral (towards the side(s) or away from the midline) and medial (towards the midline) surfaces. During this time, the neurons of the dentate nucleus are similar in shape and form, being mainly bipolar cells.
During 22–28 weeks of gestation, which is the critical period in fetal development of the dentate nucleus, gyral formation occurs extensively over the entire surface. Here, neurons mature into various forms of multipolar cells, and the most frequent neuronal types are medium sized to large neurons.
Structure.
Location.
The architecture of cerebellum has a form that resembles the structure of a crystal, so a slice anywhere in the cerebellum gives repeated architecture. The eight cerebellar nuclei, located within the deep white matter of each cerebellar hemisphere, are grouped into pairs, with one of each pair in each of the two hemispheres. As a chunk of tissue, the dentate nucleus with overlying cerebellar cortex makes up a functional unit called the cerebrocerebellum. Thus, there is a part of cerebellum that communicates exclusively with the dentate nucleus.
Deep cerebellar nuclei.
The deep cerebellar nuclei receive the final output from the cerebellar cortex via Purkinje cells in the form of inhibition. Neurons in the cerebellar nuclei generate spontaneous action potentials despite ongoing inhibition from Purkinje cells. The cerebellar nuclei receive afferent projections from the inferior olive, lateral reticular nucleus, upper cervical and lumbar spinal segments, and the Pontine nuclei. Together, the deep cerebellar nuclei form a functional unit that provides feedback control of the cerebellar cortex by cerebellar output.
Morphology.
The dentate nucleus is highly convoluted and can be divided into dorsal (motor) and ventral (nonmotor) domains. The ventral half is much more developed in humans than in great apes, and it appears to play an important role in fiber connection. Further, the ventral domain mediates higher cerebellar functions, such as language and cognition, as well as versatile and coordinated finger movement. While it is generally accepted that the ventral region is more recent on an evolutionary timescale, current 3-Dimensional imaging raises questions regarding this assumption, as a third axis, the rostrocaudal axis, can now be analyzed. In addition, current images show that the ventral region is not physically larger than the dorsal region in humans, as would be predicted if size increases with cognitive function.
The neurons of the adult dentate are divided based on size, morphology, and function into large principal and small local circuit neurons.
Large principal neurons.
The large principal neurons have been classified into four primary types according to position within the dentate, shape of soma (cell body), and dendritic branching. These neurons are responsible for communication between the dentate nucleus and the cerebellar cortex.
Small local circuit neurons.
Small local circuit neurons include signaling pathways that are contained within the dentate. These neurons provide feedback to the dentate and allow for fine control of signaling. Currently, less research has been conducted on the specific shape and role of these neurons, as the dentate nucleus is composed primarily of large principal neurons.
Function.
Projections.
The dentate contains anatomically separate and functionally distinct motor and nonmotor domains (dorsal and ventral, respectively), and projections are organized from the dentate nucleus to distinct areas in the ventrolateral thalamus. In addition, the dorsal parts of the dentate project to the primary motor and premotor areas of the cerebral cortex, while the ventral parts of the dentate project to prefrontal and posterior parietal areas of the cerebral cortex. The motor and nonmotor domains make up approximately 50–60 percent and 20 percent, respectively, of the dentate. It is estimated that the human dentate proportions are comparable. All cerebral cortical areas that are targeted by the dentate project back on the cerebellum via efferents to Pontine nuclei, and cortical areas that do not project onto the cerebellum are not targets of dentate output.
The motor domain in the dorsal portion of the dentate contains output channels that control both generation and control of movement, as well as neurons that innervate premotor areas in the frontal lobe.
The nonmotor domain contains output channels involved in cognition and visuospatial function, and projections to the prefrontal and posterior parietal cortical areas within this region are clustered into distinct regions with little overlap. These areas are activated during tasks involving short-term working memory, rule-based learning, and higher executive function-like planning. Although the ventral aspect of the dentate has been shown to be involved in acquisition of information, whether it is involved in retention and storage remains unclear.
Pathways.
There are three distinct routes from the dentate nucleus to the ventrolateral thalamus, including a direct, posterior, and anterior route. The direct route passes in the anterolateral direction under the thalamus and enters from the ventral side. Axons following the posterior pathway turn dorsally from the midline at the posterior side of the thalamus, entering the thalamus from various positions. Axons following the anterior route pass laterally in the subthalamus and enter the external medullary lamina. Within the lamina, fibers turn posteriorly and enter the dorsal side of the thalamus. Therefore, as a result of these various pathways, the neurons of the dentate nucleus are able to traverse all thalamic nuclei, with the exception of those at the midline and anterior nuclear groups.
Dentate nucleus axons can be divergent or convergent. Convergent branches include those that originate from entirely different axons and traverse different routes, yet overlap on the same terminal field. Divergent pathways originate from the same axon but travel different routes and target different terminal fields. Although no point-to-point connectivity has been observed between the dentate nucleus and the thalamus, it is believed that there is a pre-wired connectivity between a single dentate site and several body part representations in the thalamus.
Three modalities are received by cerebellum, including proprioception, nociception, and somatic input, and all of these stimulate the dentate nucleus. The dentate nucleus is mostly responsible for planning and execution of fine movement. Since any motor function requires sensory information, it can be assumed that the dentate nucleus receives and modulates this sensory information, though the specific mechanism of this remains unclear. For example, the act of lifting an object requires sensory input, such as the size of the object and where it is located in space. While the primary role of the dentate nucleus is control of the movement, it does play a role in sensory processing as well.
Role.
The role of the dentate nucleus can be described in two basic tenets:
The dentate nucleus is responsible for the planning, initiation and control of voluntary movements. The dorsal region of the dentate contains output channels involved in motor function, while the ventral region contains output channels involved in nonmotor function, such as cognition and visuospatial function. The dentate nucleus sends commands and information to the motor and premotor areas in the forebrain.
Clinical significance.
Several pathological processes involve the dentate nucleus including metabolic, genetic, and neurodegenerative disorders, as well as some infections.
Metabolic disorders.
Maple syrup urine disease (MSUD): An inherited disorder of amino acid metabolism in newborns, MSUD results in neurological deterioration. Myelin edema is seen in the cerebellum, including the dentate nucleus, brain stem, and corticospinal tracts.
Leigh disease: Clinical and pathological symptoms usually appear in the first year of life and include psychomotor retardation and brain stem dysfunction. Bilaterally symmetric defects are seen in the periaqueductal grey matter, brain stem, basal ganglia, and dentate nucleus.
Glutaric aciduria type 1 (GA1): An autosomal recessive disease, GA1 is due to glutaryl-coenzyme A dehydrogenase deficiency. Abnormalities are seen in the basal ganglia and dentate nucleus.
Canavan's disease: Canavan's disease is a white matter disease due to aspartoacylase deficiency. The dentate nucleus is not affected until late in disease progression.
Miscellaneous disorders.
Neurofibromatosis type 1 (NF1): NF1 is an autosomal dominant neurocutaneous disorder. The hallmark of NF1 is the development of numerous tumors. Cerebellar white matter and dentate nucleus lesions usually occur in children less than ten years of age.
Langerhans cell histiocytosis (LCH): LCH is an aggressive disorder due to proliferation of Langerhans cell hystiocytes, and the dentate nucleus is believed to be involved in up to 40 percent of patients.
Alzheimer's disease (AD) with myoclonus: There is an increase in mean volume of large neurons and a decrease in mean volume of small neurons in the dentate nucleus in AD with myoclonus. Morphological changes in the dentate nucleus may contribute to the pathological substrate of myoclonus in AD.


Tentorial notch

The tentorial notch (also known as the tentorial incisure or incisura tentorii) refers to the anterior opening between the free edge of the cerebellar tentorium and the clivus for the passage of the brainstem.
The midbrain continues with the thalamus of the diencephalon through the tentorial notch.
Structure.
The tentorial notch is located between the tentorial edges and communicates the supratentorial and infratentorial spaces. This area can be divided into three spaces: "anterior", "middle" (lateral to), and "posterior" to the brainstem. The middle incisural space is close to the midbrain and the upper pons at the level of the pontomesencephalic sulcus. Medial temporal lobe structures such as the uncus, the parahippocampal gyrus and the hippocampal formation, are also intimately related to the incisura. The principal vascular structures coursing along the middle incisural space are the posterior cerebral artery and the superior cerebellar artery which pass around the brainstem, parallel to the free tentorial edge. The incisura has also a close relationship with the first 6 cranial nerves.
Clinical significance.
If intracranial pressure superior to the cerebellar tentorium is increased, it may force part of the temporal lobe through this notch. This is referred to as a tentorial brain herniation. The consequences are unconsciousness, widening of the pupil of the affected side, and hemiparesis on the opposite side.


Principle of univariance

The principle of univariance states that one and the same visual receptor cell can be excited by different combinations of wavelength and intensity, so that the brain cannot know the color of a certain point of the retinal image. One individual photoreceptor type can therefore not differentiate between a change in wavelength and a change in intensity. Thus the wavelength information can be extracted only by comparing the responses across different types of receptors. The principle of univariance was first described by W. A. H. Rushton (p. 4P).
Both cone monochromats (those who only have 1 cone type) and rod monochromats (those with no cones) suffer from the principle of univariance.The principle of univariance can be seen in situations where a stimulus can vary in two dimensions, but a cell's response can vary in one. For example, a coloured light may vary in both wavelength and in luminance. However, the brain's cells can only vary in the rate at which action potentials are fired. Therefore, a cell tuned to red light may respond the same to a dim red light as to a bright yellow light. To avoid this, the response of multiple cells is compared.


Equivalence point

The equivalence point, or stoichiometric point, of a chemical reaction is the point at which chemically equivalent quantities of reactants have been mixed. For an acid-base reaction the equivalence point is where the moles of acid and the moles of base would neutralize each other according to the chemical reaction. This does not necessarily imply a 1:1 molar ratio of acid:base, merely that the ratio is the same as in the chemical reaction. It can be found by means of an indicator, for example phenolphthalein or methyl orange.
The endpoint (related to, but not the same as the equivalence point) refers to the point at which the indicator changes color in a colorimetric titration.
Methods to determine the equivalence point.
Different methods to determine the equivalence point include:


Norepinephrine reuptake inhibitor

A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline) by blocking the action of the norepinephrine transporter (NET). This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine and therefore can increase adrenergic neurotransmission.
NRIs are commonly used in the treatment of conditions like ADHD and narcolepsy due to their psychostimulant effects and in obesity due to their appetite suppressant effects. They are also frequently used as antidepressants for the treatment of major depressive disorder, anxiety and panic disorder. Additionally, many addictive substances such as cocaine and methylphenidate possess NRI activity, though it is important to mention that NRIs without combined dopamine reuptake inhibitor (DRI) properties are not significantly rewarding and hence are considered to have a negligible potential for addiction. However, norepinephrine has been implicated as acting synergistically with dopamine when actions on the two neurotransmitters are combined (e.g., in the case of NDRIs) to produce rewarding effects in psychostimulant addictive substances.
A meta analysis published in BMJ in 2011 concluded that the selective NRI reboxetine is indistinguishable from placebo in the treatment of depression. A second review by the European Medicines Agency concluded that reboxetine was significantly more effective than placebo, and that its risk/benefit ratio was positive. The latter review, also examined the efficacy of reboxetine as a function of baseline depression, and concluded that it was effective in severe depression and panic disorder but did not show effects significantly superior to placebo in mild depression.
A closely related type of drug is a norepinephrine releasing agent (NRA).
List of selective NRIs.
Many NRIs exist, including the following:
Note: Only NRIs selective for the NET greater than the other two monoamine transporters (MATs) are listed here. For a list of NRIs that act at multiple MATs, see the other monoamine reuptake inhibitor pages such as NDRI, SNRI, and SNDRI.


Splanchnic nerves

The splanchnic nerves are paired visceral nerves (nerves that contribute to the innervation of the internal organs), carrying fibers of the autonomic nervous system (visceral efferent fibers) as well as sensory fibers from the organs (visceral afferent fibers). All carry sympathetic fibers except for the pelvic splanchnic nerves, which carry parasympathetic fibers.
Types.
The term "splanchnic nerves" can refer to:


Tripartite synapse

Tripartite synapse refers to the functional integration and physical proximity of the presynaptic membrane, postsynaptic membrane, and their intimate association with surrounding glia as well as the combined contributions of these three synaptic components to the production of activity at the chemical synapse. Tripartite synapses occur at a number of locations in the central nervous system with astrocytes and may also exist with Muller glia of retinal ganglion cells and Schwann cells at the neuromuscular junction. The term was first introduced in the late 1990s to account for a growing body of evidence that glia are not merely passive neuronal support cells but, instead, play an active role in the integration of synaptic information through bidirectional communication with the neuronal components of the synapse as mediated by neurotransmitters and gliotransmitters.
Evidence of the Tripartite Synapse.
Evidence for the role of astrocytes in the integration and processing of synaptic integration presents itself in a number of ways:


Fuzz bass

Fuzz bass, also called "bass overdrive" or "bass distortion", is a style of playing the electric bass or modifying its signal that produces a buzzy, distorted, overdriven sound, which the name implies in an onomatopoetic fashion. Overdriving a bass signal significantly changes the timbre, adds higher overtones (harmonics), increases the sustain, and, if the gain is turned up high enough, creates a "breaking up" sound characterized by a growling, buzzy tone.
One of the earliest examples may be the 1961 Marty Robbins Country and Western song "Don't Worry." By the mid- to late-1960s, a number of bands began to list "fuzz bass" in addition to "electric bass" on their album credits. Two well-known examples are the Beatles' 1965 song "Think for Yourself" (from "Rubber Soul"), which marked the first instance of a bass guitar being recorded through a distortion unit, and the 1966 Rolling Stones song "Under My Thumb". Album or performance credits for fuzz bass can be found from every decade since then (see examples below).
Fuzz bass can be produced by overloading a bass amp's tube or transistor preamplifier, by using a bass fuzz or bass overdrive effect pedal, or for the most powerful effect, by combining both approaches. In the 1960s and early 1970s fuzz bass was associated with the psychedelic music (e.g., Edgar Broughton Band), progressive rock (e.g., Genesis), and psychedelic soul/funk (e.g., Sly and the Family Stone) styles, and it tended to be a "warmer", "smoother", and "softer" overdrive-type sound caused by soft, symmetrical clipping of the audio signal that "round[ed] off the signal peaks rather than razor-slicing" them and filtered out the harsher high harmonics.
In the 1980s and 1990s, overdriven bass tended to be associated with hardcore punk (e.g., Stormtroopers of Death), death metal (e.g., Mortician), grindcore (e.g., Napalm Death) and Industrial bands (e.g., Ministry), and the tone tended to be heavier, more metallic and more grinding. This is achieved by hard clipping of the bass signal, which leaves in "harsher high harmonics that can result in sounds that are heard as jagged and spiky." Fuzz bass has been used by indie, alternative rock and hard rock bands such as Muse and Royal Blood.
Approaches.
In the context of electric guitars, the terms "distortion", "overdrive" and "fuzz" are often used interchangeably, but they have subtle differences in meaning.
A fuzz bass sound can be created by turning up the volume of a tube amp or transistor amp to the point that preamplifier tube (or transistor preamp) clipping" occurs. In practice, when a bass amp is "cranked" to its maximum volume, the fuzz tone will also include some power amplifier clipping. While some musicians seek out the additional "grit" provided by power amp clipping, audio engineers and bass technicians recommend avoiding power amp clipping, as it can blow speakers.
Fuzz bass can be produced by using an electric guitar fuzz, distortion or overdrive pedal. The downside of using a pedal designed for the electric guitar is that the lower-end bass tone is mostly lost when the signal is heavily clipped.
Clipping is a form of waveform distortion that occurs when an amplifier is overdriven and attempts to deliver an output voltage or current beyond its maximum capability. Driving an amplifier into clipping may cause it to output power in excess of its published ratings. Clipping is a non-linear process that produces frequencies not originally present in the audio signal.
These frequencies can either be "harmonic", meaning they are whole number multiples of the signal's original frequencies, or "inharmonic", meaning dissonant odd-order overtones. Harmonic distortion produces harmonically related overtones while intermodulation distortion produces inharmonic overtones. "Soft clipping" gradually flattens the peaks of a signal and de-emphasizes higher odd harmonics. "Hard clipping" flattens peaks abruptly, resulting in harsh-sounding, high amplitude odd harmonics.
Since the late 1980s, manufacturers have been producing bass overdrive pedals specifically designed for the electric bass, and in many cases they found a way to keep the low fundamental pitch in along with the buzzy overdrive tone. One early model was the Ibanez "Bass Stack" bass overdrive pedal, which was sold in the late 1980s.
1980s grindcore groups, such as Napalm Death in the sound clip to the right, used a very heavy, distorted bass tone that resembles the sound of a grinding buzz saw.
The simplest fuzz bass pedals have knobs for controlling the volume level, the tone, and the fuzz or overdrive effect. More complex pedals have different distortion effects (e.g., overdrive and fuzz), gates to trigger the volume at which sounds will get overdriven, mixers to mix the natural and fuzzed sound in the player's desired proportions, and multiple band equalizers (typically for low and high frequencies). Boutique fuzz bass pedals even have unusual effects such as a "starve" effect, which mimics the distortion sound a pedal gives with a dying battery, a diode selector (either silicon or germanium) for selecting the transistor overdrive tone, and an octave selector (above or below the pitch being played).
While fuzz bass pedals are most commonly used by bass players, some electric guitar players use bass overdrive units. Buzz Osborne, electric guitarist from the Melvins, uses a BOSS Bass Overdrive ODB-3 pedal.
Overdrive built into amplifiers.
Some bass amplifiers have an "overdrive" or distortion effect built into the unit. The Peavey Century 200 has an onboard "distortion" effect on the second channel. The Peavey VB-2 also has built-in overdrive. Aguilar Amplification's AG 500 bass head is a two-channel amplifier, one of which offers a "saturation" control for overdrive. A variety of BOSS combo amplifiers have a built-in "drive" effect. Gallien-Krueger's bass amp heads have a "boost" control that provides a simulated tube overdrive effect. The Behringer Ultrabass BVT5500H Bass Amplifier Head has a built-in limiter and overdrive. The LowDown LD 150 bass amp has a range of overdrive sounds, from a slight hint to heavy distortion. The CUBE-20XL BASS amp includes built-in overdrive.
The 75W Fender Rumble 75 Bass Combo Amp can produce an overdrive effect by using the gain and blend controls, giving overdrive sounds ranging from "mellow warmth [to] heavy distorted tones". The Fender SuperBassman is a 300-watt tube head that has a built-in overdrive channel. The Fender Bronco 40 includes a range of effects including modern bass overdrive, vintage overdrive and fuzz.
The MESA Bigblock 750 has a built-in overdrive channel. The Mesa M2000 has a high gain switch that can be engaged with a footswitch. The Marshall MB450 head and combo bass amplifiers have a tube pre-amp on the "Classic" channel that can be overdriven. The Ashdown ABM 500 EVO III 575W Bass amp head has a built-in overdrive effect. Overdrive is also available on many Crate bass amplifiers. The Yamaha BBT500H has three types of built-in drive effects: overdrive, distortion and fuzz. The Ampeg B5R Bass Amplifier has two channels: clean and overdrive, with the ability to combine the two.
The Orange has introduced a new line of bass amplifiers(OB 1 series) with a built in fuzz.
Verellen, a boutique amp company, produces a bass amplifier with a built in overdrive channel.
Selected songs.
The following section gives examples of songs that feature fuzz bass.