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Molecular Biology: Genetics / MCB

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Addictions and recovery Mid‑importance

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Text and/or other creative content from this version of FOSB was copied or moved into Template:FOSB addiction table with this edit on July 17, 2016. The former page's history now serves to provide attribution for that content in the latter page, and it must not be deleted as long as the latter page exists.

Induction in D1/D2 MSNs by stimulus and ventral/dorsal striatal region

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834048/table/T1/

Ventral MSNs - mesolimbic pathway
Dorsal MSNs - nigrostriatal pathway

Seppi333 (Insert 2¢ | Maintained) 17:30, 16 February 2015 (UTC)[reply]

Review

G9a^[1] Seppi333 (Insert 2¢ | Maintained) 21:03, 16 February 2015 (UTC)[reply]

References

^ Nestler EJ (2014). "Epigenetic mechanisms of drug addiction". Neuropharmacology. 76 Pt B: 259–68. doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384. PMID 23643695. G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a). Interestingly, a prior history of cocaine exposure, followed by one month of withdrawal, leads to enhanced inducibility of the FosB gene in response to a subsequent cocaine challenge (Damez-Werno et al., 2012a). This priming is not associated with changes in the upstream signaling pathways that control FosB expression, thus pointing to a chromatin mechanism. Indeed, the priming is associated with reduced H3K9me2 binding at the FosB gene as well as with enrichment of a particular phosphorylated form of RNA polymerase II which has been associated with gene priming in cell culture systems (Damez-Werno et al., 2012a). FosB gene priming thus represents an important example of latent regulation that is mediated via chromatin mechanisms, although much further work is needed to understand the underlying mechanisms involved.

Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine's behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation. Our hypothesis is that the combination of cocaine and HDAC inhibition results in excessive hyperacetylation, which causes—as a classic negative feedback mechanism—induction of G9a to counteract the transcriptional-activating effects of increased acetylation (Fig. 5).

Antidepressant ∆FosB review

^[1]

Seppi333 (Insert 2¢) 15:23, 10 January 2016 (UTC)[reply]

References

^ Nestler EJ (2015). "∆FosB: a transcriptional regulator of stress and antidepressant responses". Eur. J. Pharmacol. 753: 66–72. doi:10.1016/j.ejphar.2014.10.034. PMID 25446562.

Collapsed transcluded

Seppi333, do you know how to collapse the table when it is transcluded? Sizeofint (talk) 06:32, 23 March 2016 (UTC)[reply]

{{:FOSB|Table title=Summary of addiction-related plasticity|class=wikitable mw-collapsible mw-collapsed}} Seppi333 (Insert 2¢) 06:37, 23 March 2016 (UTC)[reply]

Summary of addiction-related plasticity
Form of neuroplasticity or behavioral plasticity	Type of reinforcer						Sources
Form of neuroplasticity or behavioral plasticity	Opiates	Psychostimulants	High fat or sugar food	Sexual intercourse	Physical exercise (aerobic)	Environmental enrichment	Sources
ΔFosB expression in nucleus accumbens D1-type MSNsTooltip medium spiny neurons	↑	↑	↑	↑	↑	↑	^[1]
Behavioral plasticity
Escalation of intake	Yes	Yes	Yes				^[1]
Psychostimulant cross-sensitization	Yes	Not applicable	Yes	Yes	Attenuated	Attenuated	^[1]
Psychostimulant self-administration	↑	↑	↓		↓	↓	^[1]
Psychostimulant conditioned place preference	↑	↑	↓	↑	↓	↑	^[1]
Reinstatement of drug-seeking behavior	↑	↑			↓	↓	^[1]
Neurochemical plasticity
CREBTooltip cAMP response element-binding protein phosphorylation in the nucleus accumbens	↓	↓	↓		↓	↓	^[1]
Sensitized dopamine response in the nucleus accumbens	No	Yes	No	Yes			^[1]
Altered striatal dopamine signaling	↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3		↑DRD2	↑DRD2	^[1]
Altered striatal opioid signaling	No change or ↑μ-opioid receptors	↑μ-opioid receptors ↑κ-opioid receptors	↑μ-opioid receptors	↑μ-opioid receptors	No change	No change	^[1]
Changes in striatal opioid peptides	↑dynorphin No change: enkephalin	↑dynorphin	↓enkephalin		↑dynorphin	↑dynorphin	^[1]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens	↓	↑		↑			^[1]
Dendritic spine density in the nucleus accumbens	↓	↑		↑			^[1]

Thanks! Sizeofint (talk) 06:41, 23 March 2016 (UTC)[reply]

References

^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m Cite error: The named reference Natural and drug addictions was invoked but never defined (see the help page).

Role in addiction

Is this paragraph linguistically correct? Especially the phrase "like drugs of abuse". "ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[6][12] Natural rewards, like drugs of abuse, induce gene expression of ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ΔFosB overexpression.[6][7][12] Consequently, ΔFosB is the key mechanism involved in addictions to natural rewards (i.e., behavioral addictions) as well;[6][7][12] in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward.[12]" --Igenno (talk) 18:46, 30 April 2016 (UTC)[reply]

"Drugs of abuse" is a very vague term, but it is a term that is consistently used in some of these sources as a substitute for the term "addictive drugs". I probably wouldn't have used it in the article if not for the sources that were cited. Seppi333 (Insert 2¢) 19:29, 30 April 2016 (UTC)[reply]

The problem with the sentence is the word "like," which in this construction in American English usually means "such as." This presents "drugs of abuse" as an example of natural rewards. The reader has to translate to the other meaning of like which is "similar to." To make the sentence clearer just use "similar to." — Preceding unsigned comment added by Flkevin (talk • contribs) 15:18, 4 January 2019 (UTC)[reply]

Table template and onlyinclude tags (originally called FOSB table)

Moved from User talk:Pppery

To clarify what I meant in the edit summary, if you were to go to a page revision which used the article transclusion, like special:permalink/727552968, without the onlyinclude tags in the current page, the whole article would be transcluded in that page revision instead of the table itself. Seppi333 (Insert 2¢) 20:15, 21 July 2016 (UTC)[reply]

@Seppi333: ... and why does that matter. According to Help:Page history#Linking to a specific version of a page:

A permalink does not necessarily reproduce the historical version of the page as it originally appeared. This is because images, templates (transcluded text and images), and time-based variables (such as CURRENTTIME) may have changed in the interim; they appear in their current state, not their historical state

(emphasis mine). Why is it worth keeping transclusion markup in untranscluded pages just for the sake of old revisions? To support my point, {{Persondata}}, which was once used on more than one million pages and probably tens of millions of old revisions, was deleted less than a month ago. Pppery (talk) 20:40, 21 July 2016 (UTC)[reply]

I care because it fucks up old page revisions to articles which I actively edit, making it a pain in the ass when I need to look through a old revision. Let me pose the same question to you: why do you care if an onlyinclude tag is in an article? Seppi333 (Insert 2¢) 20:44, 21 July 2016 (UTC)[reply]

@Seppi333: To me, having an onlyinclude tag in an article is a problem because, as I stated in the previous discussion at Talk:Amphetamine, including them on articles produces counterintuitive transclusion results. (I, actually, was confused when I first encountered onlyinclude tags and selective transclusion - it was on Wikipedia:Categories for discussion/Speedy transcluding Wikipedia:Criteria for speedy deletion). Really, though it is just needless noise that goes against my belief that articles and templates should be kept seperate. Pppery (talk) 21:22, 21 July 2016 (UTC)[reply]

I am moving this discussion to Talk:FOSB as it is more about the article than about me. Pppery (talk) 21:24, 21 July 2016 (UTC)[reply]

Can you clarify what you mean by produces counterintuitive transclusion results? I generally agree that transclusion should occur from the template space and not article space, but there are times when it really is much simpler to transclude from 1 article to another. I'm sure you'd agree that it would be needlessly decentralized and much more complicated to transclude in all the sections currently in amphetamine to amphetamine and the transcluded articles from templates for those sections as opposed to transcluding from that article. Seppi333 (Insert 2¢) 21:27, 21 July 2016 (UTC)[reply]

What I mean by produces counterintuitive transclusion results is that it seems counterintuitive for someone (who doesn't know about the onlyinclude tags) types {{:FOSB}}, the fact that only some table (which is a tiny part of the article) is transcluded would be very confusing. (This actually happened to me, although the onlyinclude-using page was Wikipedia:Criteria for speedy deletion). I agree that it would needlessly decentralized to move the transcluded parts of Amphetamine to template space, which is why I (attempted to) convert it to labeled section transclusion rather than splitting off to a template. Pppery (talk) 21:57, 21 July 2016 (UTC) @Seppi333: Also, it is not nice to use swear words (It fucks up old revisions) Pppery (talk) 22:12, 21 July 2016 (UTC)[reply]

@Pppery: The onlyinclude tags that are currently in the article only serve to fix historical page revisions - they're not there to transclude the table by transcluding from this article. While it is possible to do this with the onlyinclude tags being present, it'd be needlessly complicated for someone to figure out where the table actually is located if this article is transcluded instead since it's like transcluding from a redirect which has other content on the page. I don't intend to transclude from this page so there shouldn't be an issue with {{:FOSB}} occurring in any articles in the future; I merely want to fix historical page revisions with the onlyinclude tags. Seppi333 (Insert 2¢) 22:16, 21 July 2016 (UTC)[reply]

Orphaned references in FOSB

Bot message

I check pages listed in Category:Pages with incorrect ref formatting to try to fix reference errors. One of the things I do is look for content for orphaned references in wikilinked articles. I have found content for some of FOSB's orphans, the problem is that I found more than one version. I can't determine which (if any) is correct for this article, so I am asking for a sentient editor to look it over and copy the correct ref content into this article.

Reference named "Cellular basis":

From NF-κB: Nestler EJ (Dec 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–43. PMC 3898681. PMID 24459410.
From Methylphenidate: Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin. Neurosci. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.⁴¹. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.4
From Striatum: Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin. Neurosci. 15 (4): 431–443. PMC 3898681. PMID 24459410.
From Opioid use disorder: Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin Neurosci. 15 (4): 431–443. PMC 3898681. PMID 24459410. DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement
From Ethanol: Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin Neurosci. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the Importance of Numerous Psychosocial Factors, at its Core, Drug Addiction Involves a Biological Process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement
From Alternative splicing: Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin. Neurosci. 15 (4): 431–443. PMC 3898681. PMID 24459410. DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement
From Disease theory of alcoholism: Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin. Neurosci. 15 (4): 431–443. PMC 3898681. PMID 24459410. DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.⁴¹ Many other ΔFosB targets have been shown to mediate the ability of certain drugs of abuse to induce synaptic plasticity in the NAc and associated changes in the dendritic arborization of NAc medium spiny neurons, as will be discussed below.

I apologize if any of the above are effectively identical; I am just a simple computer program, so I can't determine whether minor differences are significant or not. AnomieBOT ⚡ 08:20, 8 January 2017 (UTC)[reply]

State IEG instead of gene in the intro sentence?

@Boghog: given that it's a more precise statement, wouldn't it be better to refer to FOSB as an IEG instead of a gene in the first lead sentence? I.e., writing something like "... is a protein that, in humans, is encoded by the immediate early gene FOSB" instead of "... is a protein that, in humans, is encoded by the FOSB gene". I normally would just be bold and change this without discussion, but I don't have a sufficient background knowledge of genetics to know whether or not this might be an incomplete, inaccurate, or otherwise incorrect description. Or more simply, I don't know what I don't know about genetics. Seppi333 (Insert 2¢) 03:56, 25 January 2019 (UTC)[reply]

Also, I don't know much about alternative splicing so I'm not sure if my understanding of the term "truncated splice variant" is correct: does this mean that the overall amino acid sequence of the truncated protein is missing a sub-sequence which is present in the full-length protein? Assuming that's right, could a truncated protein be missing a sub-sequence at the C-terminus end, N-terminus end, and/or the interior of the full-length protein's amino acid sequence, or only at the C-terminus and/or N-terminus ends? Seppi333 (Insert 2¢) 04:27, 25 January 2019 (UTC)[reply]

Hi Seppi. An IEG (immediate early gene) describes when the gene is expressed and is a rather specialized topic. I also think it is important to keep the lead sentence dead simple and there should be nothing in the lead that is not discussed in more detail in the body of the article. This type of detail would be more appropriate in a new section on regulation/mechanism. There are different type of alternative splicing, involving either truncation and/or incorporation of alternative stretches of amino acid residues. Truncation can in principle occur anywhere (N-terminus, C-terminus, or in the interior). Boghog (talk) 05:48, 25 January 2019 (UTC)[reply]

In the case of human FOSB, there are 10 splice variants that have been detected which involve truncation in either the N-terminus and/or one or more of four different interior sites. Boghog (talk) 05:59, 25 January 2019 (UTC)[reply]

Thanks for clarifying that. I suppose I'll just go ahead and mention it in the body but not the lead then. Seppi333 (Insert 2¢) 06:04, 25 January 2019 (UTC)[reply]

[Nestler_2014_epigenetics-1] Nestler EJ (2014). "Epigenetic mechanisms of drug addiction". Neuropharmacology. 76 Pt B: 259–68. doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384. PMID 23643695. G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a). Interestingly, a prior history of cocaine exposure, followed by one month of withdrawal, leads to enhanced inducibility of the FosB gene in response to a subsequent cocaine challenge (Damez-Werno et al., 2012a). This priming is not associated with changes in the upstream signaling pathways that control FosB expression, thus pointing to a chromatin mechanism. Indeed, the priming is associated with reduced H3K9me2 binding at the FosB gene as well as with enrichment of a particular phosphorylated form of RNA polymerase II which has been associated with gene priming in cell culture systems (Damez-Werno et al., 2012a). FosB gene priming thus represents an important example of latent regulation that is mediated via chromatin mechanisms, although much further work is needed to understand the underlying mechanisms involved.

Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine's behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation. Our hypothesis is that the combination of cocaine and HDAC inhibition results in excessive hyperacetylation, which causes—as a classic negative feedback mechanism—induction of G9a to counteract the transcriptional-activating effects of increased acetylation (Fig. 5).

[Antidepressant-2] Nestler EJ (2015). "∆FosB: a transcriptional regulator of stress and antidepressant responses". Eur. J. Pharmacol. 753: 66–72. doi:10.1016/j.ejphar.2014.10.034. PMID 25446562.

[Natural_and_drug_addictions-3] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m Cite error: The named reference Natural and drug addictions was invoked but never defined (see the help page).

[1]

[1]

[1]