Up c-fos to increase brain learning/unlearning?

C-fos increases in the brain right after administration of drugs such as cocaine (http://www.pnas.org/content/87/17/6912.full.pdf), and it appears to be elevated in some brain areas when the brain is "unlearning" a previous memory pattern, such as in this study looking at c-fos levels in rats just after they brought about extinction of a previously-reinforced behavior (i.e., it's as though they stopped feeding Pavlov's dog after ringing bells, observed how long it took for the dog to stop salivating after bell ringing, then examined the dog's brain tissue) (https://www.ncbi.nlm.nih.gov/pubmed/24315832):

Taking into account that c-Fos activity reflects the last part of this process of extinction in this study, we cannot preclude the possibility of a new inhibitory learning taking place at the time. According to some authors, the extinguished memory is not erased but inhibited, so that the observed c-Fos changes may reflect this new learning process that could be occurring at the end of the extinction procedure.

Researchers seem reluctant to say that c-fos is a causative part of making the neuronal assemblies associated with addiction, but they do find a strong correlational link:

The described neurochemical and molecular biological mechanisms all support the idea that c-fos promoter activation is an indicator of strong and persistent calcium influx into synapses of MSNs that received the most excitatory glutamatergic input. Drug-induced dopamine can synergistically enhance c-fos promoter activation in these strongly activated MSNs. It should be noted that a lack of Fos expression in a neuron does not imply a complete lack of neural activity, only that it is not depolarized strongly or persistently enough to produce enough intracellular calcium to activate the ERK signaling pathway. The earlier section describing in vivo electrophysiology and cellular imaging studies indicate that the neurons receiving the most excitatory glutamatergic input are determined by the context and cues present during drug administration. Altogether these data support the hypothesis that Fos-expressing neurons in corticostriatal circuitry can act together as a unit to form neuronal ensembles that encode and mediate conditioned drug behaviors. It is important to note that we treat c-fos and Fos only as markers of activated neurons in this hypothesis and do not imply that these molecules are directly involved in neuronal ensemble function. 

(https://www.ncbi.nlm.nih.gov/pubmed/25446457)

Suppose someone wants to learn a new behavior or lessen the pull of a learned, unhelpful behavior. Might it be helpful to increase c-fos somehow during the learning/unlearning period? Delta-fosB, which I discussed in previous posts, accumulates in addiction and represses c-fos, which repression could be preventing addiction-breaking learning/unlearning. That gives support to the idea that not increasing c-fos is unhelpful when overcoming an addiction. But it does not logically follow that increasing c-fos will therefore be helpful in overcoming an addiction. I'll have to look and see if there are studies done specifically on that.

There are studies that look at how to increase c-fos expression. Three tested ways to increase c-fos expression are forskolin (an herbal supplement already in use by some as a weight loss help), BDNF (brain-derived neurotrophic factor, a protein), and membrane depolarization (brought about via neurotransmitters or KCl) (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696896/). BDNF is being looked at as a possible aid in cocaine addiction (https://www.ncbi.nlm.nih.gov/pubmed/26923993), and forskolin seems able to induce a strengthening of synapses involved in memory formation (but the effect is much smaller in older rat brain tissue--https://www.ncbi.nlm.nih.gov/pubmed/15911893). Glutamate is a neurotransmitter, and monosodium glutamate (MSG) is known to evoke c-fos activity (https://www.ncbi.nlm.nih.gov/pubmed/26762887); a quick Google search finds that many people feel MSG is addictive for them, for what that's worth.

Here's a fun idea to test whether upping c-fos helps develop new brain pathways associated with memory and addiction. Try a new activity that you would like to become slightly addicted to, and eat Nacho Cheese Doritos while you do it.  Nacho Cheese Doritos are a good source of MSG. Then see if you are more fixated on the new activity afterward than you would have expected. Even if the experiment bombs, you'll have gotten to eat Doritos in the name of science!

C-fos, addiction, and eros

Another molecule connected to addiction is c-fos (https://en.wikipedia.org/wiki/C-Fos), production of which is increased after using cocaine, methamphetamine (https://www.ncbi.nlm.nih.gov/pubmed/2118661), and other such drugs and possibly after mating (c-fos increases have been found in rats after mating--https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834303/). Various articles in the past few years have claimed that falling in love is the same to the brain as getting high on crack cocaine (e.g., http://www.salon.com/2015/02/14/love_is_like_cocaine_the_remarkable_terrifying_neuroscience_of_romance/, https://www.psychologytoday.com/blog/the-joint-adventures-well-educated-couples/201208/falling-in-love-is-smoking-crack-cocaine, http://www.medicaldaily.com/oxytocin-love-hormone-fuels-romance-how-your-brain-works-when-youre-love-269067). How very unromantic.

C-fos appears to be important in effectuating morphological changes in the brain (specifically, increased dendritic branching and dendritic spine density) as the process of addiction occurs, as well as in overcoming addiction after the object of the addiction has been removed (http://www.jneurosci.org/content/26/51/13287.full).

In a recent post, I cited a paper indicating that an accumulation of ΔFosB can be considered the molecular "on-switch" of addiction in the brain. A 2008 rat study found that ΔFosB represses c-fos (http://www.jneurosci.org/content/28/29/7344.full). Anhedonia--an inability to experience pleasure from positive life events--is more common in psychoactive substance-using populations, and it lessens as they get off drugs (https://www.ncbi.nlm.nih.gov/pubmed/24270310). It appears as though the brain could be homeostatically acting to remain "faithful" to the source of pleasure it became addicted to and so represses c-fos production that would allow formation of competing neural pathways associated with other pleasures. That would help explain the inability to find much pleasure outside of one's addiction and perhaps the occurrence of monogamy. Again, very unromantic.

I feel like I should repost this all on February 14th to be contrary. "Your mate might be faithful to you just because of an accumulation of ΔFosB that prevents him/her from finding the same pleasure with someone else." That won't show up on a Hallmark card anytime soon.... Still, you might as well face it if you are indeed addicted to love.

Ellagic acid apparently helps with withdrawal symptoms from morphine, too

Last time I posted about ellagic acid possibly being a help to overcome addiction. Afterwards, I came across this study from two years ago finding that it helped alleviate morphine withdrawal symptoms:

Abstract
According to our previous study, ellagic acid has both dose-related central and peripheral antinociceptive effect through the opioidergic and l-arginine-NO-cGMP-ATP sensitive K⁺channel pathways. In the present study, the systemic antinociceptive effects of ellagic acid in animal models of pain, and functional interactions between ellagic acid and morphine in terms of analgesia, tolerance and dependence were investigated. Ellagic acid (1–30 mg/kg; i.p.) showed significant and dose-dependent antinociceptive effects in the acetic acid-induced writhing test. Intraperitoneal ellagic acid acutely interacted with morphine analgesia in a synergistic manner in this assay. Ellagic acid (1–10 mg/kg; i.p.) also exerted analgesic activity in the hot-plate test. Pre-treatment with naloxone (1 mg/kg; i.p.) significantly reversed ellagic acid, morphine as well as ellagic acid-morphine combination-induced antinociceptin in these two tests. More importantly, when co-administered with morphine, ellagic acid (1–10 mg/kg) effectively blocked the development of tolerance to morphine analgesia in the hot-plate test. Likewise, ellagic acid dose-dependently prevented naloxone-precipitated withdrawal signs including jumping and weight loss. Ellagic acid treatment (1–30 mg/kg; i.p.) had no significant effect on the locomotion activity of animals using open-field task. Therefore, these results showed that ellagic acid has notable systemic antinociceptive activity for both tonic and phasic pain models. Altogether, ellagic acid might be used in pain relief alone or in combination with opioid drugs because of enhancing morphine analgesia and preventing morphine-induced tolerance to analgesia and dependence.

http://www.sciencedirect.com/science/article/pii/S0014299914006293

Naloxone (trade name Narcan) causes opioid-withdrawal symptoms in those who are dependent on opioids.

Opiate withdrawal symptoms can be extremely unpleasant:

Early symptoms of withdrawal include:

• Agitation

• Anxiety

• Muscle aches

• Increased tearing

• Insomnia

• Runny nose

• Sweating

• Yawning

Late symptoms of withdrawal include:

• Abdominal cramping

• Diarrhea

• Dilated pupils

• Goose bumps

• Nausea

• Vomiting

Opioid withdrawal reactions are very uncomfortable but are not life-threatening. Symptoms usually start within 12 hours of last heroin usage and within 30 hours of last methadone exposure.

http://www.nytimes.com/health/guides/disease/opiate-withdrawal/overview.html

If ellagic acid, a component of easily-obtainable berries and walnuts, can reduce opiate withdrawal symptoms, that seems like something that should become common knowledge, doesn't it? I hope someone tests ellagic acid in humans for relief from opiate addiction withdrawal symptoms.

A way to lessen withdrawal anxiety?

In a land of plenty where many cases of cancer and other physical illness have become curable due to medical advances, the problem of intractable mental illness is beginning to be far more apparent. One form of mental disorder that seems to be very prevalent is addictive disorders. One study estimated that approximately half the US population suffers from addictive disorder symptoms in the course of a year:

An increasing number of research studies over the last three decades suggest that a wide range of substance and process addictions may serve similar functions. The current article considers 11 such potential addictions (tobacco, alcohol, illicit drugs, eating, gambling, Internet, love, sex, exercise, work, and shopping), their prevalence, and co-occurrence, based on a systematic review of the literature. Data from 83 studies (each study n = at least 500 subjects) were presented and supplemented with small-scale data. Depending on which assumptions are made, overall 12-month prevalence of an addiction among U.S. adults varies from 15% to 61%. The authors assert that it is most plausible that 47% of the U.S. adult population suffers from maladaptive signs of an addictive disorder over a 12-month period and that it may be useful to think of addictions as due to problems of lifestyle as well as to person-level factors.

http://ehp.sagepub.com/content/34/1/3.short

If nearly half of adults are "addicted" in any given year, then addiction by definition would seem to be a fairly normal process of the brain. When the addiction is to something that helps increase our ability to enjoy and function in life, we call it things like "enthusiasm" or "dedication," but when it robs us of our ability to function productively and healthily, we consider it a disease. (http://www.iflscience.com/health-and-medicine/theres-no-such-thing-as-an-addictive-personality-heres-why/all/) One element of an addictive disorder is that the addicted person suffers from withdrawal symptoms when deprived of the substance or behavior to which he/she is addicted.

What chemically happens in the brain during withdrawal? We know that ΔFosB (delta-FosB), a gene transcription factor is a chemical on-switch for both substance and behavior addictions:

The longevity of some of the behavioral abnormalities that characterize drug addiction has suggested that regulation of neural gene expression may be involved in the process by which drugs of abuse cause a state of addiction. Increasing evidence suggests that the transcription factor ΔFosB represents one mechanism by which drugs of abuse produce relatively stable changes in the brain that contribute to the addiction phenotype. ΔFosB, a member of the Fos family of transcription factors, accumulates within a subset of neurons of the nucleus accumbens and dorsal striatum (brain regions important for addiction) after repeated administration of many kinds of drugs of abuse. Similar accumulation of ΔFosB occurs after compulsive running, which suggests that ΔFosB may accumulate in response to many types of compulsive behaviors. Importantly, ΔFosB persists in neurons for relatively long periods of time because of its extraordinary stability. Therefore, ΔFosB represents a molecular mechanism that could initiate and then sustain changes in gene expression that persist long after drug exposure ceases. Studies in inducible transgenic mice that overexpress either ΔFosB or a dominant negative inhibitor of the protein provide direct evidence that ΔFosB causes increased sensitivity to the behavioral effects of drugs of abuse and, possibly, increased drug seeking behavior. This work supports the view that ΔFosB functions as a type of sustained “molecular switch” that gradually converts acute drug responses into relatively stable adaptations that contribute to the long-term neural and behavioral plasticity that underlies addiction.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC58680/

When mice are given the opportunity to become addicted to ethanol (alcohol) and then deprived of it, the level of ΔFosB in their brain dramatically rises during the withdrawal period. (http://www.sciencedirect.com/science/article/pii/S0091305713003419) If ΔFosB levels can be kept from rising during the withdrawal period, perhaps that will weaken the power of the addiction and make it easier to get past.

Why does ΔFosB hang around for so long in the brain? Is there a way we can keep it from hanging around for so long so that levels of ΔFosB don't rise as much during withdrawal periods?

The transcription factor ΔFosB (also referred to as FosB2 or FosB[short form]) is an important mediator of the long-term plasticity induced in brain by chronic exposure to several types of psychoactive stimuli, including drugs of abuse, stress, and electroconvulsive seizures. A distinct feature of ΔFosB is that, once induced, it persists in brain for relatively long periods of time in the absence of further stimulation. The mechanisms underlying this apparent stability, however, have remained unknown. Here, we demonstrate that ΔFosB is a relatively stable transcription factor, with a half-life of ∼10 h in cell culture. Furthermore, we show that ΔFosB is a phosphoprotein in brain and that phosphorylation of a highly conserved serine residue (Ser27) in ΔFosB protects it from proteasomal degradation. We provide several lines of evidence suggesting that this phosphorylation is mediated by casein kinase 2. These findings constitute the first evidence that ΔFosB is phosphorylated and demonstrate that phosphorylation contributes to its stability, which is at the core of its ability to mediate long-lasting adaptations in brain.

http://www.jneurosci.org/content/26/19/5131.long

This suggests that inhibiting casein kinase 2 could diminish the amount by which ΔFosB increases in the brain during withdrawal periods. What inhibits casein kinase 2? Two commonly consumed inhibitors of casein kinase 2 are apigenin (highest in chamomile, parsley, and celery) and ellagic acid (highest in berries and walnuts). Chamomile extract containing apigenin has been observed to reduce anxiety (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600408/), and ellagic acid has been observed to lessen withdrawal symptoms in nicotine-addicted mice (https://www.uaeh.edu.mx/investigacion/producto.php?producto=5628).

Therefore, if trying to overcome a behavior that has started to drift into "addiction" territory, I would be sure to include high levels of foods containing ellagic acid and apigenin if I felt anxiety at suspending the behavior to which I'd become addicted. Wild strawberries appear to be one of the very best sources of ellagic acid (http://pub.jki.bund.de/index.php/JABFQ/article/viewFile/3114/3485), which tidbit would no doubt please Ingmar Bergman--a Swedish film producer whose film Wild Strawberries is about a very old man overcoming a lifetime of habitual aloofness--were he still alive.

High altitude link to depression

I live nearly 2000 m above sea level, so I'm especially interested in a finding last year that female mice put in conditions simulating high altitudes are more prone to developing symptoms of depression:

Hypobaric Hypoxia Induces Depression-like Behavior in Female Sprague-Dawley Rats, but not in Males

The researchers housed rats for a week at simulated altitudes of sea level, 10,000 feet and 20,000 feet using altitude chambers, and at local conditions of 4,500 feet, the elevation of Salt Lake City where the research took place. They then used a widely accepted behavioral test in which depression is gauged by how much persistence rodents demonstrate in a swim test. “In female rats, increasing altitude of housing from sea level to 20,000 feet caused a parallel increase in depression-like behavior,” Kanekar says.
The correlation between altitude and high rates of depression and suicide is strikingly obvious in the Intermountain West region of the United States where elevations are considerably higher than in the rest of the country. In 2012, the eight states that comprise the Intermountain West–Utah, Colorado, Wyoming, Montana, Idaho, Nevada, Arizona and New Mexico–had suicide rates exceeding 18 per 100,000 people compared with the national average of 12.5 per 100,000, according to the American Foundation for Suicide Prevention. The high rates of self-inflicted death in the West have earned the region a gloomy moniker: the Suicide Belt.
....
“The fact that both depression and suicide rates increase with altitude implies that current antidepressant treatments are not adequate for those suffering from depression at altitude, leading to high levels of unresolved depression that can contribute to higher levels of suicidal ideation and suicide attempts,” says Kanekar.

http://healthcare.utah.edu/publicaffairs/news/2015/03/03-25-15_KankekarRats.php; full text of study online at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376288/.

I know of a couple of people--both of whom are female, which fits the finding of this mice study--dealing with difficult-to-treat depression here in Colorado. (Although most of my regular contacts are LDS, neither of these two people is LDS, which doesn't seem to fit with occasional claims that LDS people are more prone to depression than non-LDS people.) Could their depression be in part due to the lower barometric pressure and oxygen content of Colorado air?

Despite my adoring the mountains, if my daughters were to suffer from chronic depression, I would consider moving to a lower elevation if I couldn't somehow up the amount of oxygen they inhale.

Learning to conduct

I was asked to be a church choir director a month ago. In my church, we have a lay ministry where we give our time freely in positions as we are called upon to fill them. The choir rehearses most Sundays for about 45 minutes and includes everyone from beginners and children up to very talented instrumental and vocal musicians. And yet, it doesn't actually have many people.

My mother taught me how to wave my hand around in a 4/4 pattern when I was around 11 years old, but she never taught me about ictus, how to bring in singers, or how to cut off a note. She put me in voice lessons with a professional opera singer back when I was in grade school and singing Shirley Temple songs, so I can produce notes well enough. Unfortunately, I am now expected to NOT sing and instead focus on teaching others to sing and directing them appropriately. Thankfully, there are YouTube videos available to help. Here is a good one on ictus, in case you're wondering what that is:

https://www.youtube.com/watch?v=6GmrlY0pA_Q

Wish me luck at this directing gig! (I'm going to need it.)