neurodudes

Fluoxetine targets early progenitor cells in the adult brain — Encinas et al. 103 (21): 8233 — Proceedings of the National Academy of Sciences

One of the first mechanistic attempt at explaining the effects of SSRIs. But how do new progenitors affect depression? Maybe this is an epiphenomenon. Maybe not.

Doctors Struggle to Treat Mysterious and Unbearable Pain – New York Times

Hadn’t heard about this before:

[...] she felt a sudden pop in her hamstring. “It felt like a guitar string had been plucked and it had broken,” said Ms. Toussaint, who is now 45.

An intense burning sensation followed; it felt as if her leg had been doused in gasoline and set on fire, she said. The next day, the college athletics trainer determined that she had pulled her hamstring. But even years later, the pain would not subside. It migrated to her other leg, leaving her bedridden for nearly a decade, and overtook her vocal cords, leaving her temporarily mute.

All the while, doctors puzzled over and even doubted her mysterious condition.

Ms. Toussaint now knows that she is among an estimated one million Americans living with complex regional pain syndrome, a nerve disorder formerly known as reflex sympathetic dystrophy syndrome. For patients with the disorder, a trauma as mild as a fractured wrist or a twisted ankle can cause the nerves to misfire, so much so that intense pain messages are constantly sent to the brain.

Interestingly, neural stimulation only provides a short-term benefit with eventual adaptation. In some cases, ketamine administration (enough to put the patients in a temporary coma) has completely stopped the pain. Ketamine is an anesthetic (although it has been known to actually stimulate circulation at certain doses) with well-known psychedelic properties. It is also a non-competitive NMDA antagonist that is often used in conjunction with traditional opiods for an analgesic effect.

I wonder if this effect is simply due to the interaction with the NMDA receptor or is something more complex. (For example, the analgesic effects of ketamine when combined with a opiods seem unrelated.)

Here’s a link to the original paper in the journal Pain, which suggests that CRPS patients have suffered damage to small-diameter PNS nociceptive fibers.

Neuron : Uncertainty, Neuromodulation, and Attention

Haven’t read this article from Peter Dayan’s lab yet but some interesting Bayesian modeling implicating acetylcholine as a signal of expected uncertainty and norepinephrine as a signal of unexpected uncertainty.

Abstract:

Uncertainty in various forms plagues our interactions with the environment. In a Bayesian statistical framework, optimal inference and prediction, based on unreliable observations in changing contexts, require the representation and manipulation of different forms of uncertainty. We propose that the neuromodulators acetylcholine and norepinephrine play a major role in the brain’s implementation of these uncertainty computations. Acetylcholine signals expected uncertainty, coming from known unreliability of predictive cues within a context. Norepinephrine signals unexpected uncertainty, as when unsignaled context switches produce strongly unexpected observations. These uncertainty signals interact to enable optimal inference and learning in noisy and changeable environments. This formulation is consistent with a wealth of physiological, pharmacological, and behavioral data implicating acetylcholine and norepinephrine in specific aspects of a range of cognitive processes. Moreover, the model suggests a class of attentional cueing tasks that involve both neuromodulators and shows how their interactions may be part-antagonistic, part-synergistic.

Cell : Astrocytes Put down the Broom and Pick up the Baton [N&V summary]

Some beautiful work [original article] by Oliet’s lab in a recent issue of Cell demonstrates the importance of glia in synaptic plasticity. The show a system where D-serine and not glycine controls the NMDA receptor in a coagonist role (or perhaps glutamate is really the coagonist…) and show how similar pairing protocols can have opposite effects (LTD vs. LTP) depending on D-serine modulation by astrocytes. Yet more hidden factors in plasticity are being revealed!

Here’s the key figure:

More details from the News & Views summary after the jump. (more…)

Intelligent Life 2006 | From A to Zzzzz

Introducing CX717, a drug being developed by Cortex Pharmaceuticals of Irvine, California. It’s the first of what promises to be many aimed at detaching people from the daily routine of eight hours each for work, rest and play.

Tests conducted on rhesus monkeys last year suggest that CX717 can wire users to remain awake for 36 hours without the jitters, euphoria and eventual crash that come after mega-doses of caffeine or amphetamines. Further down the line are even more radical compounds—stimulants that can wipe out sleep for several days at a stretch, and pills that deliver a whole night’s shut-eye in two hours.

More information about the ampakine CX717 can be found here. We previously mentioned the delay match-to-sample performance improvement of monkeys on CX717.

Synaptic tuning : Nature Reviews Neuroscience

For those interested in neuromodulators:

Treatment of striatal neurons with a D1 receptor agonist led to an increase in the dendritic staining intensity of NMDA receptor NR2B subunits. There was also an increase in the association of NR2B subunits with PSD-95 — a scaffold protein required for the assembly of NMDA receptors — and in the surface localization of NR2B-containing receptors.

Original article in J. Neurosci. from Dunah and colleagues. An excerpt from the original aricle of a neat application of FRET continues after the jump.
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Social isolation delays the positive effects of running on adult neurogenesis – Nature Neuroscience

From the Apr 9, Nature Neurosci:

Social isolation delays the positive effects of running on adult neurogenesis
Alexis M Stranahan, David Khalil & Elizabeth Gould

Social isolation can exacerbate the negative consequences of stress and increase the risk of developing psychopathology. However, the influence of living alone on experiences generally considered to be beneficial to the brain, such as physical exercise, remains unknown. We report here that individual housing precludes the positive influence of short-term running on adult neurogenesis in the hippocampus of rats and, in the presence of additional stress, suppresses the generation of new neurons. Individual housing also influenced corticosterone levels—runners in both housing conditions had elevated corticosterone during the active phase, but individually housed runners had higher levels of this hormone in response to stress. Moreover, lowering corticosterone levels converted the influence of short-term running on neurogenesis in individually housed rats from negative to positive. These results suggest that, in the absence of social interaction, a normally beneficial experience can exert a potentially deleterious influence on the brain.

Platelet-Derived Serotonin Mediates Liver Regeneration — Lesurtel et al. 312 (5770): 104 — Science

Although it is not suggested by this paper (which was brought to my attention by F1000 biology), I’d like to suggest this as a very, very naive hypothesis: That some part of the anti-depressant effect of SSRIs could be mediated by their ability to promote liver regeneration, as the above Science article suggests. The paper itself details how 5HT-2A and 2B receptors are upregulated during regeneration and how 2A & 2B antagonists slow regeneration.

There is some evidence for a connection between liver disease and depression. (Also, traditional chinese medicine views depression as a disease of the liver.) Without a doubt, the liver plays a well-established role in general detoxification.

Although I have no evidence to suspect it, I think it would be interesting to see if the SSRIs were leading to increased liver serotonin, resulting in liver regeneration and hence less depression.

Does Eating Salmon Lower the Murder Rate? – New York Times

Neat stuff on the role nutrition can play in brain function… it surprises me that the effect can be so large.

Most prisons are notorious for the quality of their cuisine (pretty poor) and the behavior of their residents (pretty violent). They are therefore ideal locations to test a novel hypothesis: that violent aggression is largely a product of poor nutrition. Toward that end, researchers are studying whether inmates become less violent when put on a diet rich in vitamins and in the fatty acids found in seafood.

Neonatal Antidepressant Exposure has Lasting Effects on Behavior and Serotonin Circuitry [Neuropsychopharmacology]

Since we’ve had some articles on SSRIs before, I thought I’d add this one.

Here’s the central result:

In neonatal rodents, chronic administration of serotonin reuptake inhibitors (clomipramine, fluoxetine, zimeldine, LU-10-134C) as well as some other tricyclic antidepressants but not the atypical antidepressants iprindole or nomifensine during the early life period from postnatal day 8 (PN8) to PN21 results in a pattern of maladaptive behaviors that are evident long after drug discontinuation and persist into adulthood (Mirmiran et al, 1981; Hilakivi et al, 1984; Hilakivi and Hilakivi, 1987; Hansen et al, 1997; Ansorge et al, 2004). These behavioral changes, described here as the ‘neonatal antidepressant exposure syndrome (NADES)’, in rats include alterations in locomotor activity, reduced male sexual activity and competence, increased ethanol consumption, dysregulation of the hypothalamic-pituitary-adrenal axis, increased rapid eye movement (REM) sleep time and reduced latency to enter the REM sleep phase, and increased immobility in the forced swim test (Mirmiran et al, 1981; Hilakivi et al, 1984; Hilakivi and Hilakivi, 1987; Hartley et al, 1990; Hansen et al, 1997). In contrast, adults exposed to similar doses and durations of antidepressants exhibit no persistent behavioral effects after drug discontinuation, indicating that the neurobiological response to long-term antidepressant administration differs markedly between early life and adulthood.

These findings indicate that there is some early (in development) regulation of the 5HT system. Without “proper” development, the organism suffers long-lasting deficits, but if the 5HT system is exposed to modulatory SSRIs later in life, there are no long-term changes. Interesting. I wonder what developmental switches (genes, etc.) are responsible for this difference.