text:
Eyeblink conditioning

Eyeblink conditioning (EBC) is a form of classical conditioning that has been used extensively to study neural structures and mechanisms that underlie learning and memory. The procedure is relatively simple and usually consists of pairing an auditory or visual stimulus (the conditioned stimulus (CS)) with an eyeblink-eliciting unconditioned stimulus (US) (e.g. a mild puff of air to the cornea or a mild shock). Naïve organisms initially produce a reflexive, unconditioned response (UR) (e.g. blink or extension of nictitating membrane) that follows US onset. After many CS-US pairings, an association is formed such that a learned blink, or conditioned response (CR), occurs and precedes US onset. The magnitude of learning is generally gauged by the percentage of all paired CS-US trials that result in a CR. Under optimal conditions, well-trained animals produce a high percentage of CRs (> 90%). The conditions necessary for, and the physiological mechanisms that govern, eyeblink CR learning have been studied across many mammalian species, including mice, rats, guinea pigs, rabbits, ferrets, cats, and humans. Historically, rabbits have been the most popular research subjects.

CS-US contingency
The order in which stimuli are presented is an important factor in all forms of classical conditioning. Forward conditioning describes a presentation format in which the CS precedes the US in time. That is, from the perspective of the research subject, experiencing the US is contingent upon having just experienced the CS. EBC is usually, but not always, conducted in this manner. Other stimulus contingencies include backward conditioning, in which US comes before CS, and simultaneous conditioning, in which CS and US are presented at the same time. In any case, the time between CS onset and US onset is the interstimulus interval (ISI). Animals are usually trained with a shorter ISI than humans, which can make interspecies comparisons difficult.

The delay and trace procedures
In delay EBC, the CS onset precedes the US onset and the two stimuli overlap and coterminate, with the stimuli converging in the cerebellar cortex and interpositus nucleus. In the trace EBC, the CS precedes the US and there is a stimulus free period (trace interval) between CS offset and US onset. While both of these procedures require the cerebellum, the trace procedure also requires the hippocampus and medial prefrontal cortex.

The blink reflex
When a US is delivered to the cornea of the eye, sensory information is carried to the trigeminal nucleus and relayed both directly and indirectly (via reticular formation) to the accessory abducens and abducens motor nuclei (see Cranial nerve nucleus). Output from these nuclei control various eye muscles that work synergistically to produce an unconditioned blink response to corneal stimulation (reviewed, Christian & Thompson, 2003). Electromyogram (EMG) activity of the orbicularis oculi muscle, which controls eyelid closure, is considered to be the most prominent and sensitive component of blinking (Lavond et al., 1990) and is, thus, the most common behaviorally-derived dependent variable in studies of EBC.

US pathway
The trigeminal nucleus also sends efferent projections to the inferior olive (IO), and this represents the US pathway for EBC. The critical region of the IO for eyeblink conditioning is the dorsal accessory olive (Brodal, 1981), and climbing fibers (CF) from this region send information about the US to the cerebellum (Brodal, Walberg & Hoddevik, 1975; Thompson, 1989). Climbing fibers ultimately project to both the deep cerebellar nuclei and Purkinje cells (PCs) in the cerebellar cortex.

The CS pathway
The pontine nuclei (PN) can support different CS modalities (auditory tone, light, etc.) for EBC as they receive projections from auditory, visual, somatosensory, and association systems (Glickstein et al., 1980; Brodal, 1981; Schmahmann & Pandya, 1989; 1991; 1993). When the CS is a tone, auditory information is received via the cochlear nuclei (Steinmetz & Sengelaub, 1992). The PN give rise to mossy fiber (MF) axons that carry CS-related information (Steinmetz et al., 1987; Lewis et al., 1987; Thompson et al., 1997) to the cerebellum via the middle cerebellar peduncle, and terminate in both the cerebellar nuclei, and at granule cells (GR) of the cerebellar cortex (Steinmetz & Sengelaub, 1992). Granule cells give rise to parallel fiber (PF) axons which synapse onto PCs.

CS-US convergence in the cerebellum
Two cerebellar sites of CS-US convergence are 1) cells of the deep nuclear region in the cerebellum, and 2) PCs of the cortex. In addition to receiving converging CS and US input via the PN and IO, respectively, cells of the cerebellar nuclei receive GABA-ergic inhibitory input from PCs of the cerebellar cortex. Output from the interpositus nucleus includes projections to the red nucleus, and the red nucleus sends projections to the facial and abducens nuclei. These nuclei supply the motor output component of the reflexive eyeblink. Therefore, in addition to being a site of stimulus convergence, the deep nuclei are also the cerebellum's output structure.

Critical role of the interposed nucleus
David A. McCormick, as a graduate student with Professor Richard F. Thompson, initially identified the cerebellum as the essential structure for learning and executing eyeblink CRs. Some scientists think that the interposed nucleus is the site critical to learning, retaining, and executing the conditioning blink response.

Lesion studies
The first evidence for the role of the cerebellum in EBC came from McCormick et al. (1981). They found that a unilateral cerebellar lesion which included both cortex and deep nuclei permanently abolished CRs. In subsequent studies, it was determined that lesions of the lateral interpositus and medial dentate nuclei were sufficient to prevent acquisition of CRs in naïve animals (Lincoln et al., 1982) and abolished CRs in well-trained animals (McCormick & Thompson, 1984). Finally, the use of Kainic acid lesions, which destroy neuronal cell bodies and spare passing fibers, provided evidence for a highly localized region of cerebellar nuclear cells that are essential for learning and performing CRs (Lavond et al., 1985). The population of cells critical for EBC appears to be restricted to a ~ 1 mm3 area of dorsolateral anterior INP ipsilateral to the conditioned eye. Lesions to this area of INP result in an inability to acquire eyeblink CRs in naïve animals. Additionally, the permanence of the localized lesion effect is remarkable. In well-trained animals, CRs abolished as a result of lesion are not reacquired, even after extensive training that spans over 8 months (Steinmetz et al., 1992). These results demonstrate that a highly localized region of cerebellum must be intact for CR learning to occur in EBC.

Reversible inactivation studies
Reversible inactivation of the INP has provided further evidence for its role in EC. Methods used to temporarily inactivate nervous tissue include use of a cooling probe (< 10 °C), and locally infusing Muscimol or Lidocaine. These methods are advantageous primarily because the experimenter can essentially turn neutral tissue on and off, per se. The effect of each of these inactivation protocols on CR learning and execution has been tested throughout the cerebellum and associated brainstem structures. When applied to the INP, temporary inactivation completely prevents learning of CRs in naïve animals, and learning occurs normally during post-inactivation training (Clark et al., 1992; Krupa et al., 1993; Nordholm et al., 1993; Krupa & Thompson, 1997). Additionally, INP inactivation in well-trained animals results in a complete depression of conditioned responding, which returns to plateau levels when the INP comes back online (Clark et al., 1992).

Neural recording studies
Recordings of multiple-unit neuronal activity from rabbit INP during eyeblink conditioning have been possible with chronic electrode implants, and have revealed a population of cells that discharge prior to the initiation of the learned eyeblink CR and fire in a pattern of increased response frequency that predicted and modeled the temporal form of the behavioral CR (McCormick et al., 1981; 1982; 1983; Thompson, 1983; 1986; Foy et al., 1984; McCormick & Thompson, 1984a; b; Berthier & Moore, 1990; Gould & Steinmetz, 1996). Similar results were found in the rat INP (Freeman & Nicholson, 2000; Stanton & Freemen, 2000; Rogers et al., 2001), thus demonstrating that underlying circuitry for this form of learning may be conserved across species. Although samples of single-unit activity from the INP and surrounding nuclei have revealed a multitude of response patterns during EBC (Tracy, 1995), many of the cells in the anterior dorsolateral INP significantly increase their firing rate in a precise temporal pattern that is delayed from CS onset and precedes CR onset (Foy et al., 1984; Berthier & Moore, 1990). This pattern of responding is indicative of a structure that is capable of encoding learning and/or executing learned behavioral responses.

Critical sites for learning downstream
Alternative sites of synaptic plasticity critical to EBC have been posited to exist downstream from the cerebellum. Some proposed loci include the red nucleus (Tsukahara, Oda, and Notsu, 1981), the trigeminal nucleus and associated structures (Desmond & Moore, 1983), or the facial motor nucleus (Woody et al., 1974). All of these structures have been ruled out as potential sites of plasticity critical to learning the eyeblink CR (Krupa, Thompson, and Thompson, 1993; Clark and Lavond, 1996; Krupa, Weng, and Thompson, 1996).

Summary
Taken together, results from lesion, inactivation, and neural recording studies seem to demonstrate that the dorsolateral portion of the anterior interpositus nucleus (INP) of the cerebellum, ipsilateral to the trained eye, is an essential site for CR acquisition and expression in EBC (Lincoln et al., 1982; Lavond et al., 1984a,b). However recent studies (Nilaweera et al., 2006) found that temporary block of cerebellar output prevented normal acquisition of conditioned responses. The authors concluded that this form of associative learning in the rabbit eyeblink system requires extra-cerebellar learning and/or cerebellar learning that depends on the operation of cerebellar feedback loops.

Role of the cerebellar cortex
Two areas of cortex that are known to be involved in eyeblink conditioning are lobule HVI (Lavond et al., 1987; Lavond and Steinmetz, 1989; Yeo and Hardiman, 1992) and the anterior lobe ((ANT) Garcia, Steele, and Mauk, 1999). The importance of cerebellar cortex in EBC, relative to INP, is a matter of debate in the scientific community.

Lesion studies
Several studies have attempted to assess the role of the cerebellar cortex in eyeblink CR learning, and early studies focused on large aspiration lesions of cerebellar cortex. Lavond and Steinmetz (1989) completely removed lobules HVI/HVIIa and significant portions of ANT, sparing INP, and found significant acquisition deficits. Compared to controls, lesioned animals took seven times longer to reach learning criterion. Significant percentages of CRs were eventually reached by the cortically-lesioned animals, but the CRs were low in amplitude and poorly timed. Finally, large lesions of cerebellar cortex after learning do not abolish learned CRs (Lavond et al., 1987). One common factor in all of these cortical ablation studies was that portions of cortex were spared; making it possible to assume that other areas of cortex were compensating for the loss of tissue.

The pcd mouse
Classical conditioning of a Purkinje cell deficient mutant mouse strain helped to determine the extent to which spared regions in cerebellar cortex were compensating for lesioned regions in the studies mentioned above. These mice are born with PCs that die after about 3 weeks of life. Because PCs are the sole output neuron of the cortex, this model effectively lesions all of cerebellar cortex. Results of conditioning were similar to the cortical aspiration mice. Mice took significantly longer to produce CRs, and the timing and gain of the response were distorted (Chen et al., 1996). Therefore, although eyeblink CR learning deficits are associated with cerebellar cortex lesions, the structure does not appear, ultimately, to be essential for CR learning or retention.

Reversible inactivation studies
Results from cerebellar cortical inactivation studies are similar to those reported for lesion studies. For example, Krupa (1993) inactivated lobule HVI with the GABAA receptor agonist Muscimol and found significant acquisition deficits, but animals eventually learned. Clark et al. (1997) replicated these results with a cooling probe in HVI. Attwell, Rahman, and Yeo (2001) discovered similar disruption of with HVI inactivation. They infused the AMPA receptor antagonist CNQX into HVI during acquisition training and found that CNQX-infused rabbits did not learn the eyeblink CR. However, post-acquisition CNQX infusions did not affect retention. These results are perplexing, given that animals ultimately learned the eyeblink CR in all other cerebellar cortical lesion and inactivation studies. One reason why this effect is so strong may be that Attwell et al., (2001) trained animals for only 4 days at an ISI that is outside of a range known to be optimal for learning [150–300 ms is an optimal CS-US interval and the magnitude of learning decreases as the ISI is increased (Schneiderman and Gormezano, 1964; Smith, Coleman, and Gormezano, 1969)].

Neural recording studies
Electrophysiological recording studies of cerebellar cortex have helped to better understand the role that PCs play in the eyeblink CR learning process. McCormick and Thompson (1984b) recorded PC activity during eyeblink training and found cell populations that discharged in a pattern apparently related the behavioral CR, while other PC populations discharged in patterns that coincided with either presentation of the CS or US. Similar results were found by Berthier and Moore (1986) with single unit recording of PCs in lobule HVI. They found that populations of neurons fire in relation to various aspects of eyeblink training, including CS and US presentation and CR execution. (Berthier and Moore, 1986; Gould and Steinmetz, 1996). Recently, similar stimulus- and response-related PC activity has been found in ANT (Green and Steinmetz, 2005). Finally, electrophysiological recordings of PCs in HVI and ANT have revealed a difference in the overall population responses of PCs. The majority of PCs show excitatory patterns of activity during eyeblink conditioning in HVI (Berthier and Moore, 1986; Gould and Steinmetz, 1996; Katz and Steinmetz, 1997), and inhibitory patterns of activity in ANT (Green and Steinmetz, 2005). In a single unit recording study where the individual Purkinje cells were shown to be located in the area controlling blinks and to receive climbing fibre input on US presentations, only inhibitory responses were found. In a recent study of similarly characterized Purkinje cells which were followed for up to more than fifteen hours, it was found that repeated presentations of the CS and US caused the gradual development of a pause in Purkinje cell firing. This pause response, called a Purkinje cell CR, was also obtained when direct mossy fibre stimulation was used as the CS and direct climbing fibre stimulation as the US. Unpaired presentations of the CS and US caused extinction of the Purkinje cell CR. When paired presentations were reintroduced after extinction, Purkinje cell CRs reappeared rapidly, mirroring the "savings" phenomenon demonstrated at the behavioral level. Purkinje cell CRs were also adaptively timed.

Feedback control of learning
The deep cerebellar nuclei have been shown to inhibit the inferior olive and this inhibition probably serves a negative feedback control function. As learning proceeds, the olive becomes inhibited and it has been shown that this inhibition has temporal properties that makes ideally suited to serve as a feedback signal for controlling learning. Stimulating this pathway during paired CS - US presentations causes extinction. Recordings from Purkinje cells show that the olive is depressed during the Purkinje cell CR.

Summary
Taken together, results from lesion, inactivation, and neural recording studies seem to demonstrate that the cerebellar cortex is not essential for basic eyeblink CR learning or retention, but that significant contributions from cortex underlie normal learning.

Parallel fiber – Purkinje cell synapse
Long term depression (LTD) at the PF-PC synapse is hypothesized to have significant functional consequences for learning the behavioral CR in EBC (Ito, 1984). For example, as a result of training, INP cells discharge prior to CR execution and fire in a pattern of increased frequency of response that predicts the temporal form of the behavioral CR (McCormick & Thompson, 1984). This pattern of activity clearly indicates that the INP is capable a generating a conditioned response. Purkinje cells of the cerebellar cortex tonically inhibit deep nuclear cells. Therefore, an LTD-mediated decrease in PC activity at the appropriate time during a CS-US interval could release the INP from tonic inhibition and allow for execution of a CR. An increase in PC activity could have the opposite effect, prohibiting or limiting CR execution. It has been hypothesized that CRs are generated by the INP as a result of release from PC inhibition (i.e. Perrett et al., 1993).

title: Eyeblink conditioning


text:
Axiom (computer algebra system)

Axiom is a free, general-purpose computer algebra system. It consists of an interpreter environment, a compiler and a library, which defines a strongly typed hierarchy.

History
Two computer algebra systems named Scratchpad were developed by IBM. The first one was started in 1965 by James Griesmer at the request of Ralph Gomory, and written in Fortran. The development of this software was stopped before any public release. The second Scratchpad, originally named Scratchpad II, was developed from 1977 on, at Thomas J. Watson Research Center, under the direction of Richard Dimick Jenks.

The design is principally due to Richard D. Jenks (IBM Research), James H. Davenport (University of Bath), Barry M. Trager (IBM Research), David Y.Y. Yun (Southern Methodist University) and Victor S. Miller (IBM Research). Early consultants on the project were David Barton (University of California, Berkeley) and James W. Thatcher (IBM Research). Implementation included Robert Sutor (IBM Research), Scott C. Morrison (University of California, Berkeley), Christine J. Sundaresan (IBM Research), Timothy Daly (IBM Research), Patrizia Gianni (University of Pisa), Albrecht Fortenbacher (Universitaet Karlsruhe), Stephen M. Watt (IBM Research and University of Waterloo), Josh Cohen (Yale University), Michael Rothstein (Kent State University), Manuel Bronstein (IBM Research), Michael Monagan (Simon Fraser University), Jonathan Steinbach (IBM Research), William Burge (IBM Research), Jim Wen (IBM Research), William Sit (City College of New York), and Clifton Williamson (IBM Research)

Scratchpad II was renamed Axiom when IBM decided, circa 1990, to make it a commercial product. A few years later, it was sold to NAG. In 2001, it was withdrawn from the market and re-released under the Modified BSD License. Since then, the project's lead developer has been Tim Daly.

In 2007, Axiom was forked twice, originating two different open-source projects: OpenAxiom and FriCAS, following "serious disagreement about project goals". The Axiom project continued to be developed by Tim Daly.

The current research direction is "Proving Axiom Sane", that is, logical, rational, judicious, and sound.

Design
In Axiom, each object has a type. Examples of types are mathematical structures (such as rings, fields, polynomials) as well as data structures from computer science (e.g., lists, trees, hash tables).

A function can take a type as argument, and its return value can also be a type. For example,  is a function, that takes an   as argument, and returns the field of fractions of its argument. As another example, the ring of $$4\times 4$$ matrices with rational entries would be constructed as. Of course, when working in this domain,  is interpreted as the identity matrix and   would give the inverse of the matrix , if it exists.

Several operations can have the same name, and the types of both the arguments and the result are used to determine which operation is applied (cf. function overloading).

Axiom comes with an extension language called SPAD. All the mathematical knowledge of Axiom is written in this language. The interpreter accepts roughly the same language.

Features
Within the interpreter environment, Axiom uses type inference and a heuristic algorithm to make explicit type annotations mostly unnecessary.

It features 'HyperDoc', an interactive browser-like help system, and can display two and three dimensional graphics, also providing interactive features like rotation and lighting. It also has a specialized interaction mode for Emacs, as well as a plugin for the TeXmacs editor.

Axiom has an implementation of the Risch algorithm for elementary integration, which was done by Manuel Bronstein and Barry Trager. While this implementation can find most elementary antiderivatives and whether they exist, it does have some non-implemented branches, and raises an error when such cases are encountered during integration.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Axiom (computer algebra system)


text:
User talk:Roadkill

Hi there. Welcome to Wikipedia! Drop us a note at New user log to introduce yourself.

If you need editing help, visit How does one edit a page. For format questions, visit our manual of style

Some time when you're bored, you can read through our policies and guidelines. If you made any edits before you got an account, you might be interested in assigning those to your username.

If you have any other questions about the project then check out Help or add a question to the Village pump. You can also drop me a question on my talk page.

Happy editing, Isomorphic 08:12, 25 Feb 2004 (UTC)

title: User talk:Roadkill


text:
Fear conditioning

Pavlovian fear conditioning is a behavioral paradigm in which organisms learn to predict aversive events. It is a form of learning in which an aversive stimulus (e.g. an electrical shock) is associated with a particular neutral context (e.g., a room) or neutral stimulus (e.g., a tone), resulting in the expression of fear responses to the originally neutral stimulus or context. This can be done by pairing the neutral stimulus with an aversive stimulus (e.g., an electric shock, loud noise, or unpleasant odor ). Eventually, the neutral stimulus alone can elicit the state of fear. In the vocabulary of classical conditioning, the neutral stimulus or context is the "conditional stimulus" (CS), the aversive stimulus is the "unconditional stimulus" (US), and the fear is the "conditional response" (CR).

Fear conditioning has been studied in numerous species, from snails to humans. In humans, conditioned fear is often measured with verbal report and galvanic skin response. In other animals, conditioned fear is often measured with freezing (a period of watchful immobility) or fear potentiated startle (the augmentation of the startle reflex by a fearful stimulus). Changes in heart rate, breathing, and muscle responses via electromyography can also be used to measure conditioned fear. A number of theorists have argued that conditioned fear coincides substantially with the mechanisms, both functional and neural, of clinical anxiety disorders. Research into the acquisition, consolidation and extinction of conditioned fear promises to inform new drug based and psychotherapeutic treatments for an array of pathological conditions such as dissociation, phobias and post-traumatic stress disorder.

Scientists have discovered that there is a set of brain connections that determine how fear memories are stored and recalled. While studying rats' ability to recall fear memories, researchers found a newly identified brain circuit is involved. Initially, the pre-limbic prefrontal cortex (PL) and the basolateral amygdala (BLA) were identified in memory recall. A week later, the central amygdala (CeA) and the paraventricular nucleus of the thalamus (PVT) were identified in memory recall, which are responsible for maintaining fear memories. This study shows how there are shifting circuits between short term recall and long term recall of fear memories. There is no change in behavior or response, only change in where the memory was recalled from.

In addition to the amygdala, the hippocampus and the anterior cingulate cortex are important in fear conditioning. Fear conditioning in the rat is stored at early times in the hippocampus, with alterations in hippocampal gene expression observed at 1 hour and 24 hours after the event. In the mouse, changed gene expression is also seen in the hippocampus at one hour and 24 hours after fear conditioning. These changes are transient in the hippocampal neurons, and almost none are present in the hippocampus after four weeks. By 4 weeks after the event, the memory of the fear conditioning event is more permanently stored in the anterior cingulate cortex.

Neuronal gene expression
As shown in the rodent brain, neuronal gene expression is dynamically changed in response to fear conditioning. In particular, the expressions of immediate early genes (IEGs) such as Egr1, c-Fos, and Arc are rapidly and selectively up-regulated in subsets of neurons in specific brain regions associated with learning and memory formation.

A review in 2022 describes multiple steps in up-regulating the IEGs in neurons in the hippocampus during fear conditioning. IEGs are similarly up-regulated in the amygdala during fear conditioning. The multiple steps in up-regulating IEGs include activation of transcription factors, formation of chromatin loops, interaction of enhancers with promoters in chromatin loops and topoisomerase II beta-initiated temporary DNA double-strand breaks.

At least two IEGs up-regulated by fear conditioning, Egr1 and Dnmt3A2 (shown to be an IEG by Oliveira et al. ) affect DNA methylation, and thus expression, of many genes. Up-regulated EGR1 proteins associate with pre-existing nuclear TET1 proteins, and the EGR1 proteins bring TET1 proteins to hundreds of genes, allowing TET1 to initiate DNA demethylation of those genes. DNMT3A2 protein is a de novo DNA methyltransferase, adding methylation to cytosines in DNA. Expression of DNMT3A2 proteins in hippocampus neurons in culture preferentially targeted the addition of new methylation to more than 200 genes involved in synaptic plasticity. Expressions of IEGs are a source of the dynamic changes in subsequent neuronal gene expression in response to fear conditioning.

Amygdala
Fear conditioning is thought to depend upon an area of the brain called the amygdala. The amygdala is involved in acquisition, storage, and expression of conditioned fear memory. Lesion studies have revealed that lesions drilled into the amygdala before fear conditioning prevent the acquisition of the conditioned response of fear, and lesions drilled in the amygdala after conditioning cause conditioned responses to be forgotten. Electrophysiological recordings from the amygdala have demonstrated that cells in that region undergo long-term potentiation (LTP), a form of synaptic plasticity believed to underlie learning. Pharmacological studies, synaptic studies, and human studies also implicate the amygdala as chiefly responsible for fear learning and memory. Additionally, inhibition of neurons in the amygdala disrupts fear acquisition, while stimulation of those neurons can drive fear-related behaviors, such as freezing behavior in rodents. This indicates that proper function of the amygdala is both necessary for fear conditioning and sufficient to drive fear behaviors. The amygdala is not exclusively the fear center, but also an area for responding to various environmental stimuli. Several studies have shown that when faced with unpredictable neutral stimuli, amygdala activity increases. Therefore, even in situations of uncertainty and not necessarily fear, the amygdala plays a role in alerting other brain regions that encourage safety and survival responses.

In the mid-1950s Lawrence Weiskrantz demonstrated that monkeys with lesions of amygdala failed to avoid an aversive shock while the normal monkeys learned to avoid them. He concluded that a key function of the amygdala was to connect external stimuli with aversive consequences. Following Weiskrantz's discovery many researchers used avoidance conditioning to study neural mechanisms of fear.

Joseph E. LeDoux has been instrumental in elucidating the amygdala's role in fear conditioning. He was one of the first to show that the amygdala undergoes long-term potentiation during fear conditioning, and that ablation of amygdala cells disrupts both learning and expression of fear.

Hippocampus
Some types of fear conditioning (e.g. contextual and trace) also involve the hippocampus, an area of the brain believed to receive affective impulses from the amygdala and to integrate those impulses with previously existing information to make it meaningful. Some theoretical accounts of traumatic experiences suggest that amygdala-based fear bypasses the hippocampus during intense stress and can be stored somatically or as images that can return as physical symptoms or flashbacks without cognitive meaning.

The hippocampus is one of the brain regions that undergoes major alterations in gene expression after contextual fear conditioning. Contextual fear conditioning applied to a rat causes about 500 genes to be up-regulated (possibly due to DNA demethylation of CpG sites) and about 1,000 genes to be down-regulated (observed to be correlated with DNA methylation at CpG sites in promoter regions) (see Regulation of transcription in learning and memory). By 24 hours after the event, 9.17% of the genes in the genomes of rat hippocampus neurons are differentially methylated. The pattern of induced and repressed genes within hippocampal neurons appears to provide a molecular basis for forming the early transient memory of contextual fear conditioning in the hippocampus. When similar contextual fear conditioning was applied to a mouse, one hour after contextual fear conditioning there were 675 demethylated genes and 613 hypermethylated genes in the hippocampus region of the mouse brain. These changes were transient in the hippocampal neurons, and almost none of these DNA methylation alterations were present in the hippocampus after four weeks. However, in mice subjected to contextual fear conditioning, after four weeks there were more than 1,000 differentially methylated genes and more than 1,000 differentially expressed genes in the mouse anterior cingulate cortex where long-term memories are stored.

Double-strand breaks
More than 100 DNA double-strand breaks occur, both in the hippocampus and in the medial prefrontal cortex (mPFC), in two peaks, at 10 minutes and at 30 minutes after contextual fear conditioning. This appears to be earlier than the DNA methylations and demethylations of neuron DNA in the hippocampus that were measured at one hour and 24 hours after contextual fear conditioning (described above in the section Hippocampus).

The double strand breaks occur at known memory-related immediate early genes (among other genes) in neurons after neuron activation. These double-strand breaks allow the genes to be transcribed and then translated into active proteins.

One immediate early gene newly transcribed after a double-strand break is EGR1. EGR1 is an important transcription factor in memory formation. It has an essential role in brain neuron epigenetic reprogramming. EGR1 recruits the TET1 protein that initiates a pathway of DNA demethylation. Removing DNA methylation marks allows the activation of downstream genes (see Regulation of gene expression. EGR1 brings TET1 to promoter sites of genes that need to be demethylated and activated (transcribed) during memory formation.  EGR-1, together with TET1, is employed in programming the distribution of DNA demethylation sites on brain DNA during memory formation and in long-term neuronal plasticity.

DNMT3A2 is another immediate early gene whose expression in neurons can be induced by sustained synaptic activity. DNMTs bind to DNA and methylate cytosines at particular locations in the genome. If this methylation is prevented by DNMT inhibitors, then memories do not form. If DNMT3A2 is over-expressed in the hippocampus of young adult mice it converts a weak learning experience into long-term memory and also enhances fear memory formation.

Intra-amygdala circuit
Neurons in the basolateral amygdala are responsible for the formation of conditioned fear memory. These neurons project to neurons in the central amygdala for the expression of a conditioned fear response. Damage to these areas in the amygdala would result in disruption of the expression of conditioned fear responses. Lesions in the basolateral amygdala have shown severe deficits in the expression of conditioned fear responses. Lesions in the central amygdala have shown mild deficits in the expression of conditioned fear responses.

NMDA receptors and glutamate
One of the major neurotransmitters involved in conditioned fear learning is glutamate. It has been suggested that NMDA receptors (NMDARs) in the amygdala are necessary for fear memory acquisition, because disruption of NMDAR function disrupts development of fear responses in rodents. In addition, the associative nature of fear conditioning is reflected in the role of NMDARs as coincident detectors, where NMDAR activation requires simultaneous depolarization by US inputs combined with concurrent CS activation.

Epigenetics
Conditioned fear may be inherited transgenerationally. In one experiment, mice were conditioned to fear an acetophenone odor and then set up to breed subsequent generations of mice. Those subsequent generations of mice also showed a behavioral sensitivity to acetophenone, which was accompanied by neuroanatomical and epigenetic changes that are believed to have been inherited from the parents' gametes.

Across development
The learning involved in conditioned fear, as well as the underlying neurobiology, changes dramatically from infancy, across childhood and adolescence, into adulthood and aging. Specifically, infant animals show an inability to develop fear associations, whereas their adult counterparts develop fear memories much more readily.

Previous research has indicated that adolescents show hampered fear extinction learning compared to children and adults. This finding may have clinical implications, as one of the most widely used treatments for anxiety disorders is exposure based therapy, which builds on the principles of fear extinction. The exact mechanisms underlying the developmental differences in fear extinction learning have not yet been discovered, although it has been suggested that age related differences in connectivity between the amygdala and medial prefrontal cortex can be one of the biological mechanisms underpinning the developmental change in fear extinction learning.

Prior experience with stress
A history of stressors preceding a traumatic event increases the effect of fear conditioning in rodents. This phenomenon, named Stress-Enhanced Fear Learning (SEFL), has been demonstrated in both young (e.g. Poulos et al. 2014 ) and adult (e.g. Rau et al. 2009 ) rodents. Biological mechanisms underpinning SEFL have not yet been made clear, though it has been associated with a rise in corticosterone, the stress hormone, following the initial stressor.

title: Fear conditioning


text:
Talk:Roland TB-303

It is definitely sawtooth and square. Sawtooth is definitely the more popular of the two, at least for acid. Somebody mentioned that "production lasted only 18 months, resulting in 10,000 units" I find that very hard to believe that only 10,000 have been made. IT would seem that such a popular instrument would have been a bit more available at the time... Then again, I don't see many people toting their 808's either! --HL-SDK 19:03, 11 August 2006 (UTC)

I corrected (I believe) the fact that the oscillator could be switched between sawtooth and square waveforms. The previous version claimed cosine (?) and square (as a variation of sawtooth), but searching everywhere (including the unit's markings and user manual) seemed to only confirm that that the waveforms were sawtooth and square. Hoping my "correction" isn't an error... Ds13 08:16, 2004 Feb 25 (UTC)

Vote for removing the list of musicians
Do we need a list of musicians that use the TB-303? That's like listing all the musicians that use the electric guitar in their songs.

I too vote for removing the list of musicians having used the TB-303 since first of all it isn't very relevant, and second of all it isn't accurate. Many many more artists have used the TB-303.
 * I removed it. --Grm wnr 21:30, 3 Feb 2005 (UTC)

It's still there. Perhaps somebody re-animated it without taking a look at this talk-page. I vote for removing it too. I don't see the need for all of these massive and pointless lists. Not all information is relevant, interesting or helps understanding the subject, even if there's plenty of it :) --mie vaan 13:52, 3 Sep 2005 (UTC)

Remove it. --Robert Merkel 09:20, 4 September 2005 (UTC)

I am now removing it once again, adding a comment that people should consult the talk page before reinstating it. --Mereman 10:02, 23 November 2005 (UTC)

-I agree with this removal, even though it has already happened.--ДрakюлaTalk 03:30, 22 December 2005 (UTC)

It reappeared and I removed it again. -- Phlake 01:21, 30 May 2007 (UTC)

Example Sound
If there's anybody out there with one of these who can record an characteristic bassline with it, that would be a great addition to the page. --Robert Merkel 4 July 2005 06:31 (UTC)

 * Hi. Yes I could do this. Just a short monotonous and simple example, maybe a few notes and some filter tweaking. With or without beat? I made some examples already for the Roland MC-202. http://en.wikipedia.org/wiki/Image:Mc202example.ogg and http://en.wikipedia.org/wiki/Image:Discobotter.ogg It's really plain without any effects. Would something like this be fine? --audioschotter.net 01:38, 5 October 2005 (UTC)

 * That would be wonderful. If I had the instrument and the skill, what I'd add to the page myself is the following:
 * a melody line played "straight" on the 303
 * the same melody used as an "acidline" (is that the correct term?) where the effects are used in the characteristic style of acid house.
 * the above "acidline" in the context of a track (with drums and whatever other voices you might put over the top).

 * Also, note that a full-length track is quite unnecessary; 20-30 seconds is almost certainly more than enough to illustrate the point.

 * But, in any case, anything you feel like adding would be much, much better than nothing. --Robert Merkel 02:18, 5 October 2005 (UTC)

 * By the way, did you add links to those audio files you've already uploaded to the relevant articles? If they're not linked, nobody will find them :(--Robert Merkel 02:21, 5 October 2005 (UTC)

Rebirth
The long paragraph on Rebirth has no place in the TB-303 article. Won't somebody start a Rebirth article, so the paragraph can be reduced to a mere sentence with a link to the Rebirth article? Joyrex 20:12, 29 August 2005 (UTC)

A RB338 article is already here by the way: http://en.wikipedia.org/wiki/ReBirth
 * Well, some of the information is valid IMHO as the RB338 sort of reanimated the style. And products like the Audiorealism Bassline plugin show that there's still demand for these sounds as Hardware gets rare.

Here's a suggestion:

1) Keep this information: "By 1997 software synthesisers were just starting to break into the music world with massive popularity at retail music stores around the world. One notable program at this time was made by Propellerhead Software called ReBirth. The software became very popular, as it provided a cheap and easy way for musicians to reproduce the classic 303, as well as 808 (and later 909) sounds."

2) Maybe the software clone section could continue mentioning Muon Tau and Audiorealism Bassline plugins for VST. Also Roland itself made an emulation available for the V-Synth.

3) Add the remaining information given in this article to RB338 article.

Sven --audioschotter.net 01:32, 5 October 2005 (UTC)

Artists
The section entitled "List of musicians who use the TB-303" is highly suspicious. Many of the names appear to be album titles, not musicians. Someone should go through them and remove unsubstantiated claims.

well, The TB-303 was used by Daft Punk to make the song "Da Funk", in their album Homework. now that can be proved if you listen to remakes on the 303, it sounds exactly the same. I remember reading it in an interview of them however i can't bring myself to find it. I own a 303 as well, it sounds completely the same. (EDIT 12/13/11: I found some proof, sounds like patterns i can make on my 303. http://www.youtube.com/watch?v=yOOl8jO8TD4&feature=related  about 0:48)  — Preceding unsigned comment added by 68.82.240.199 (talk) 00:08, 11 November 2011 (UTC)

In my opinion there is no place in an encyclopedic article for speculation about what might have happened had someone released an unreleased record. Either it did influence the American House and Techno scene, or it didn't.

Merge from Acid machine
This following text from that article, to be merged in. Marasmusine 22:39, 14 September 2006 (UTC) Acid Machine - a colloquial term, used by musicians and listeners alike, for the Roland TB-303 Bassline which formed a large part of almost all early Acid House music. This 1980's instrument consisted of a small pushbutton keyboard and was intended to play pre-programmed basslines in conjunction with one of the variety of Roland drum machines of the time, as an accompaniment to more traditional instrumentation. However, it had two features that changed its usage forever. Firstly, because the 303 could not be played in the normal manner like a piano, but had to be 'step programmed' beforehand, it was possible to produce unusual repetative melodies. Secondly and most importantly, the selection of controls for altering the tone of the 303's sound could be adjusted live, while the programmed melody was replaying. This distinctive feature meant that a single melody line could be repeated endlessly and variations in the sonic tone would ensure that the sound kept mutating rather than staying the same in the traditional manner of a bassline. A well known emulator of the TB-303 is the Rebirth RB-338 software produced by Propellerheads. Original 303's are much sought-after by collectors and musicians.

number of units
Is there any reliable source on the number of units made? Most internet sources quote 20000 units rather than 10000 units. —The preceding unsigned comment was added by 129.215.220.113 (talk) 15:13, 23 March 2007 (UTC).

Filter not that unusual
The filter circuit is in fact very similar to Moog's diode ladder circuit, except that transistors are used. The base and collectors of each are connected together, so they behave like diodes, conducting as soon as the voltage reaches a certain point. I never understood why they "wasted" more expensive transistors in this way, but possibly it was to get around patent issues. 213.173.165.130 15:32, 25 July 2007 (UTC)

Filter slope should be 24dB
The article incorrectly states the filter slope is 64dB/oct when in fact it is a 4th-order, 4-pole, 24dB/octave filter. There is a common misconception that it is a 18dB 3-pole which is incorrect. There is a detailed analysis here.. http://www.timstinchcombe.co.uk/synth/diode_18_24/diode.html —Preceding unsigned comment added by 218.186.9.236 (talk) 10:31, 12 December 2009 (UTC)

False Information Under Usage
Orange Juice's "Rip it Up" was not the first UK hit to feature the synthesizer, "In the Heat of the Night" by Imagination which was released in 1982 and reached #22 on the UK pop chart precedes it by a year or so. I'm not saying "In the Heat of the Night" was the first, but "Rip it Up" was definitely not. The source may be wrong, it might be worth checking out. InTechnicolour (talk) 06:10, 12 March 2013 (UTC)

Open Source Software
The open source software section reads like ad copy. — Preceding unsigned comment added by 71.171.44.231 (talk) 00:58, 24 December 2016 (UTC)

External links modified
Hello fellow Wikipedians,

I have just modified 3 external links on Roland TB-303. Please take a moment to review my edit. If you have any questions, or need the bot to ignore the links, or the page altogether, please visit this simple FaQ for additional information. I made the following changes:
 * Added archive https://web.archive.org/web/20110723023341/http://rebirthapp.com/rebirth-for-ipad/ to http://rebirthapp.com/rebirth-for-ipad/
 * Added archive https://web.archive.org/web/20130424014239/http://www.x0xclones.com/review-cyclone-analogic-bass-bot-tt-303/ to http://www.x0xclones.com/review-cyclone-analogic-bass-bot-tt-303/
 * Corrected formatting/usage for http://www.tb-303.org/

When you have finished reviewing my changes, you may follow the instructions on the template below to fix any issues with the URLs.

Cheers.— InternetArchiveBot  (Report bug) 17:18, 26 July 2017 (UTC)

Volca Bass not a TB-303 clone, but has Accent through MIDI
Can we take the Volca Bass out of the list of commercial clones? Or at least mention at the end, that it is not a clone despite the looks? (Since people will keep on adding it.)

Yes, the Volca is an acid bass synth and it has some design clues clearly pointing to the TB-303, however. It is not designed to replicate the TB-303 sound. This said, it is an amazing synth in its own right. It might even have the potential to become a legendary synth itself.

Also, I want to clarify, that while Accent can not be programed on the device itself, it can be played through MIDI (max. velocity). — Preceding unsigned comment added by GreenBlinkingLED (talk • contribs) 01:21, 13 January 2018 (UTC)

Added London Underground Acid link
My link was taken out as it needed a source. But I linked the wiki page which states:

'' In London, the acid techno scene developed via illegal network of parties; the 1997 compilation It’s Not Intelligent…And It’s Not From Detroit…But It’s F**king ‘Avin It was subtitled The Sound of London’s Acid Techno Underground and helped to solidify the genre in the underground consciousness.[3]

The term Acid specifically refers to the harsh "acidic" sound of layered 303s.[3][5]''

And if you read the ref [3] in the above, it's an interview with the Liberator crew and others talking about the 303, the party scene and the unique sound of their London Underground sound.

Surely that's enough? Or should I put it back as it was - London Underground Acid linking to the wiki Acid_techno page but with that reference with it?

That explains the importance of the 303 to the unique London Underground sound. Ganpati23 (talk) 20:20, 16 September 2019 (UTC)
 * The reference needs to be added to the claim in the article directly. See WP:CITE.
 * However, on reflection, I don't think we need any subgenres in the lead anyway. Chicago house is a subgenre of house; acid techno is a subgenre of techno; etc. Just citing techno and house is sufficient for the lead. Popcornduff (talk) 21:08, 16 September 2019 (UTC)

"according to forbes...."
that well-known music magazine.... who cares what a business mag thought of the sound? or at least, let's have the name of the writer involved, so that we can assess whether they have any (ahem) business commenting on the veracity or otherwise of this bass instrument.

duncanrmi (not signed in) 139.47.66.35 (talk) 08:42, 7 July 2023 (UTC)

 * The author's name is given in the citation. Popcornfud (talk) 09:27, 7 July 2023 (UTC)

title: Talk:Roland TB-303


text:
Talk:Jim Guy Tucker

Jim Guy Tucker
I wondered if he is still active in politics. I haven't heard of him in recent years. Jack Tucker  jackfran@peoplpc.com 206.148.96.115

Edited to add pertinent material from Conason and Lyons' "The Hunting of the President." 72.150.175.35 14:43, 27 May 2006 (UTC)Black Max

-I deleted this portion from the article discussing what Tucker is doing today. It's disgustingly biased and unsourced, pointless flattery and rhetoric that looks like it was added by his Aunt:

"In spite of his becoming ensnared by the Whitewater scandal, seen by many as an extraordinary irony since he had nothing to do with the Clintons' business dealings and had remained an outspoken Clinton policy critic, he is widely thought of as having been a moderately progressive governor who strove to improve public services, particularly in the areas of highway maintenance and secondary education." A procrastinator 23:07, 25 August 2007 (UTC)

The sidebar should include his time as Lieutenant governor, with predecessor, successor etc... —Preceding unsigned comment added by 63.243.18.186 (talk) 16:47, 4 June 2010 (UTC)

Old washed out cracker. — Preceding unsigned comment added by 141.116.212.32 (talk) 19:50, 18 June 2012 (UTC)

Unknown references
Does anybody know what sections of the article these references apply to?Alan.ca 10:29, 10 December 2006 (UTC)

 * Clinton, Bill (2005). My Life. Arrow Books. ISBN 1-4000-3003-X.

 * Conason, Joe and Lyons, Gene. The Hunting of the President.  Thomas Dunne Books.  ISBN 0-312-24547-5.

Acting Governor
Should Tucker be listed as Acting Governor, December 1992 to January 1995? Isn't the Arkansas gubernatorial succession, the same as Massachusetts? GoodDay (talk) 19:02, 17 March 2008 (UTC)

No. —Preceding unsigned comment added by 72.204.87.71 (talk) 07:24, 12 July 2009 (UTC)

Post-Politics
Jim Guy spent a lot of time in Indonesia and Hong Kong in the late 1990s and early 2000s, in the telecommunications business. DOR (HK) (talk) 01:28, 3 September 2009 (UTC)

Mike Huckabees Account
In Mike Huckabee's book on Character, he makes the rescindal of Mr. Tucker's resignation sound like it caused this serious constitutional crisis in Arkansas. The article here really just talks about in passing. If it was that serious, should that be looked at? 96.250.83.177 (talk) 03:05, 14 August 2010 (UTC)

External links modified
Hello fellow Wikipedians,

I have just modified one external link on Jim Guy Tucker. Please take a moment to review my edit. If you have any questions, or need the bot to ignore the links, or the page altogether, please visit this simple FaQ for additional information. I made the following changes:
 * Added archive https://web.archive.org/web/20150106074211/http://www.oldstatehouse.com/exhibits/virtual/governors/the_new_south/tucker.aspx to http://www.oldstatehouse.com/exhibits/virtual/governors/the_new_south/tucker.aspx

When you have finished reviewing my changes, you may follow the instructions on the template below to fix any issues with the URLs.

Cheers.— InternetArchiveBot  (Report bug) 14:44, 22 April 2017 (UTC)

External links modified
Hello fellow Wikipedians,

I have just modified 2 external links on Jim Guy Tucker. Please take a moment to review my edit. If you have any questions, or need the bot to ignore the links, or the page altogether, please visit this simple FaQ for additional information. I made the following changes:
 * Added archive https://web.archive.org/web/20110913060154/http://www.arkmilitaryheritage.com/exhibits/HallGuys.htm to http://www.arkmilitaryheritage.com/exhibits/HallGuys.htm
 * Added archive https://web.archive.org/web/20071007115439/http://www.oldstatehouse.com/exhibits/virtual/governors/the_new_south/tucker.asp to http://www.oldstatehouse.com/exhibits/virtual/governors/the_new_south/tucker.asp

When you have finished reviewing my changes, you may follow the instructions on the template below to fix any issues with the URLs.

Cheers.— InternetArchiveBot  (Report bug) 13:27, 25 November 2017 (UTC)

External links modified
Hello fellow Wikipedians,

I have just modified one external link on Jim Guy Tucker. Please take a moment to review my edit. If you have any questions, or need the bot to ignore the links, or the page altogether, please visit this simple FaQ for additional information. I made the following changes:
 * Added archive https://web.archive.org/web/20070929135417/http://www.courttv.com/archive/legaldocs/government/whitewater/tucker.html to http://www.courttv.com/archive/legaldocs/government/whitewater/tucker.html

When you have finished reviewing my changes, you may follow the instructions on the template below to fix any issues with the URLs.

Cheers.— InternetArchiveBot  (Report bug) 21:51, 9 December 2017 (UTC)

title: Talk:Jim Guy Tucker