Potential Role of Astrocyte Glycogen Depletion and "Supercompensation" to the Putative Circadian Neurobiological Effects of UVB Exposure

In reference to my previous posting, it's interesting that, apart from the neuronal pathways by which neurons in the caudal trigeminal nucleus could directly or indirectly influence hypothalamic neurons (there's quite a bit of research on the interactions of hypothalamic neurons with the trigeminal system in the context of migraines), activity in sensory neurons causes localized glycogen depletion in parts of the brain [Dienel et al., 2002: (http://www.nature.com/jcbfm/journal/v22/n12/full/9591343a.html)(http://www.ncbi.nlm.nih.gov/pubmed/12468893); (http://scholar.google.com/scholar?q=sensory+glycogen+stimulation&hl=en&lr=)]. That article showed an adaptive increase in glycogen content during "recovery" from the sensory stimulation, much as noradrenaline-induced astrocyte glycogen depletion is followed by a "rebound" increase in glycogen content (like a miniature version of glycogen "supercompensation" that can occur after glycogen-depleting exercise, when a person eats a high-carbohydrate diet, etc.). That could be an additional mechanism by which UVB exposure of the face, in particular, could regulate circadian neurobiology. Astrocyte glycogen levels (which constitute most of the brain glycogen) generally decrease progressively, during prolonged wakefulness, and UVB could intensify that pattern of glycogen depletion and overcompensation, etc., intensifying the entrainment of circadian neurobiological rhythms (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=astrocyte+glycogen+sleep). The glycogen utilization, in the context of the asynchronous firing of trigeminal ganglion neurons, would produce depletion of astrocyte glycogen in various parts of the brain but could conceivably also participate in the subjective effects of UVB exposure. Maybe research on that type of mechanism would put all this business about "opioidergic" effects to rest.

Brief Summary of Mechanisms in UVB-Induced Neuroimmunomodulation via Trigeminal Ganglion and Dorsal Root Ganglion Neurons

My old paper is such a God-awful, rambling thing (http://hardcorephysiologyfun.blogspot.com/2009/05/another-old-paper-of-mine.html), that I thought I should attempt to summarize some of the mechanisms I reviewed in it. The overall concept is that UVB causes these "early mediators," such as prostaglandins and bradykinin, to be rapidly induced, within minutes of exposure. Some of these early responses are just mediated by superoxide production or by the activation of phospholipase enzymes, etc. These early-phase mediators, which cis-urocanic acid is also an example of, act on sensory nerve fibers innervating the epidermis and either directly induce axon reflex-mediated vasodilation or sensitize C-fibers and Adelta-fibers [the dorsal root ganglion (DRG) neurons] to the more potent actions of UVB-induced nerve growth factor and interleukin-6 and TNF-alpha, all of which are expressed in UVB-irradiated keratinocytes and cause the stronger, sustained effect of inducing "spontaneous" (but obviously not spontaneous) action potentials by acting directly on the peripheral terminals of DRG neurons innervating the epidermis. An axon reflex occurs when an action potential only travels to a branch point in a C-fiber, with the second "branch terminal" or arborization innervating the dermis and terminating at a blood vessel. The action potential "becomes" efferent at the branch point and then travels to the "second terminal" of the peripheral branch of the C-fiber, in the skin. Some of these apparent axon reflexes may, in fact, be dorsal root reflexes, however. There can also be weaker currents in C-fiber terminals that are not actual action potentials but that could cause neuropeptide release. But then, once DRG neurons begin to fire en masse, asynchronously, the action potentials traveling to the dorsal horn or, in response to UVB-irradiated facial skin, the caudal trigeminal nucleus and release CGRP and substance P and glutamate from their central terminals into the dorsal horn or caudal trigeminal nucleus. The CGRP and substance P then act on interneurons or spinothalamic tract neurons or spinoreticular tract or "trigeminothalamic tract" neurons, etc. As a result, the firing of these neurons can induce neurotransmitter release at segments rostral to the spinal segments at which the C-fibers releasing them entered the dorsal horn, and this type of polysynaptic transmission has been shown to occur in the spinal cord in response to UVB exposure of the skin.

It has also been shown in response to UVB exposure of the eyes of rodents, but the anatomical pathways are obscure. The action potentials probably just go to the trigeminal nucleus, from the trigeminal ganglion neurons innervating the corneas, and then cause neurons projecting from the caudal trigeminal nucleus to the hypothalamus to fire and cause hypothalamic neurons to induce the release of alpha-MSH from the pituitary, etc. (the effect could be blocked by hypophysectomy or ciliary ganglionectomy). I'm saying that because the ciliary ganglionectomy procedure may have actually cut some trigeminal ganglion nerve fibers passing through the accessory ciliary ganglion, I think it's called. I looked into the anatomical possibilities in detail but was nonetheless not able to definitively narrow down the possibilities. The anatomy is surprisingly complex, and I think the peripheral branches (sometimes referred to as "postganglionic" fibers, even though they're sensory neurons) of some trigeminal ganglion neurons travel through the ciliary ganglia and on to the caudal trigeminal nucleus. I forget the details, but it's another example of polysynaptic neurotransmission induced in response to UVB exposure to the skin. I explained the way dorsal root reflexes work in a previous posting, and it's noteworthy that GABA produces depolarization, not hyperpolarization, of the central terminals of C-fibers and Adelta fibers, upon its release from interneurons in response to other C-fiber inputs [a dorsal root reflex requires two separate C-fibers (C-type DRG neuron) or one C-fiber and an Adelta fiber, etc., and the feature that distinguishes it from an axon reflex is that the efferent action potential begins in the dorsal horn, at the central terminal of the "second" C-fiber in response to GABA receptor activation on the C-fiber].

There are obviously many other parts of the brain that would be likely to be affected, but there hasn't been much research, since the 1990s, on the changes that occur in the spinal cord. To my knowledge, no one has examined the specific phenotypic changes that would be expected to occur in the trigeminal nucleus or other parts of the midbrain or brainstem, for example, in rats exposed to UVB. Presumably, someone is interested in doing basic research in photobiology/photoneuroimmunology and learning what the effects on the circadian rhythm are. It's very likely that there are effects on circadian neurobiology, etc., and that they occur via the sensory nerve fibers.

The general idea behind systemic immunosuppression induced by UVB is that Langerhans cells, which are immature dendritic cells in the skin, are induced to migrate to regional lymph nodes in large numbers, within 6 hours or so of UVB exposure. They can induce tolerance to skin-associated or skin-derived antigens because they never mature, essentially. I'm forgetting why their migration precludes their maturation, but immature dendritic cells are tolerogenic. The infiltration of monocytes and neutrophils into the skin, at various time points after exposure, is also required for UVB-induced systemic suppression of delayed-type hypersensitivity to protein antigens injected intradermally into the UVB-exposed site, right after exposure. Different types of cells are constantly infiltrating into and migrating from the skin in response to UVB exposure, and these cells are acted upon by cytokines released from mast cells in the skin and from keratinocytes, etc. The infiltrating monocytes and neutrophils also release cytokines that act on keratinocytes and sensory nerve fibers, etc.

These are not just effects that result from increases in skin temperature or from some other nonspecific effect, because the researchers controlled for that by using cold UV sources and controlling for skin temperature and also because the phenotypic changes in the spinal cord can last up to 7-9 days. It'll probably be another 20 years before anyone does the research, though, the way things are now. It's unfortunate, because it's an interesting set of mechanisms. Obviously, these are potentially very damaging effects, and I would strongly urge anyone to talk with his or her doctor, very seriously, before receiving any sun exposure.

I'm explaining this because it's interesting and because researchers have been bullied, over the years, into not discussing it or even looking at the research, seemingly. The research has been sitting around for almost 20 years, while all the (anti-)intellectual bullying has gone on and led nowhere.

Low Solubility and Kinetics of Spontaneous Degradation of L-Glutamine in Aqueous Solution

The authors of this article [Arii et al., 1999a: (http://www.ncbi.nlm.nih.gov/pubmed/10493999)] cite research showing that L-glutamine degrades spontaneously to 5-pyrrolidone-2-carboxylic acid, at a rate of between 0.7 and 5 percent per day, in aqueous solution at pH values near 7 (neutral, as in the pH of tap water, etc.). The authors' own experiments show that, at 70 degrees C (158 degrees F), about 50 percent of the glutamine is gone in about 12 hours, at pH 7.39. That's a high temperature and would presumably accelerate the reaction rate, but it's still much slower than the degradation of the pyruvate anion in aqueous solution. Arii et al. (1999a) mention old research showing that glutamine can degrade to glutamic acid and ammonia in aqueous solution, and I remember reading some statements, by relatively unreliable sources, implying that this degradation was really rapid. It's not rapid, and the information in this article is consistent with information in other, reliable articles I've seen. The main reason free glutamine isn't commonly used in solutions for parenteral administration is that its solubility is quite low, but it's not as low as one might think. It just can't be used in "highly concentrated" solutions. I have an article that discusses this. Researchers primarily administer glutamine in the form of L-alanyl-L-glutamine, a dipeptide. In terms of its long-term "shelf life," that dipeptide is obviously much more stable than glutamine [Arii et al., 1999b: (http://www.ncbi.nlm.nih.gov/pubmed/9845788)]. I don't think that would substantially confound attempts to make subjective interpretations of data collected in people receiving intravenous glutamine, in the form of that dipeptide. The export of alanine from the skeletal muscles tends to coincide with the output of glutamine from the skeletal muscles (in vivo) [Cersosimo et al., 1986: (http://www.ncbi.nlm.nih.gov/pubmed/3513612)], and the metabolism of orally-administered glutamine by intestinal epithelial cells sometimes produces an elevation of plasma alanine, etc.

Problems With Glutamine Research

A lot of these cell culture experiments showing the effects of exogenous glutamine, in the presence or absence of other substrates, are using these "luxuriant," as some authors describe "abundance" as being, concentrations of extracellular glutamine, such as 5 mM (http://scholar.google.com/scholar?q=glutamine+%225+mM%22&hl=en&lr=) or, more commonly, 2 mM (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=glutamine+%222+mM%22). Those are very high concentrations, and the extracellular fluid glutamine concentration in the brain is 400-1300 uM or so, which is 0.4-1.3 mM. I think there can be a tendency to do cell culture research and assume that cells in vivo are getting these abundant supplies of substrates, but it's not necessarily the case. I've seen that in research on magnesium, in which researchers explicitly assume that all of the ATP in vivo is going to be MgATP(2-). It's not the case, in my opinion. Also, most of the research on glutamine in humans has been done in people who have not been receiving any source of exogenous glutamine, and this is a major issue. Part of this has to do with the assumption that glutamine does not enter the brain, but there's considerable evidence that it does. The rate of efflux from the brain is almost always higher than the rate of uptake into the brain, but that says nothing about the extent to which glutamine can enter the brain. Neither does the absence of a discernable "spike" or increase in the ECF glutamine concentration, in response to the infusion of intravenous glutamine, provide any information about the extent to which glutamine has entered the brain. The glutamine-glutamate cycle is very dynamic and flexible and tends to adapt to sources of exogenous glutamine. This means that, for example, the glutamine is converted into glutamate and then either directly into 2-oxoglutarate, by glutamate dehydrogenase, or transaminated, with oxaloacetate, into 2-oxoglutarate (2-OG) and aspartate. The 2-OG can then be oxidized in the tricarboxylic acid (TCA) cycle, and its carbons can appear in all TCA cycle intermediates and in acetyl-CoA also, etc. Yudkoff et al. (1988) [Yudkoff et al., 1988: (http://www.ncbi.nlm.nih.gov/pubmed/2900878)] found that a physiological concentraion of extracellular glutamine (500 uM) caused cultured astrocytes to demonstrate no net utilization or synthesis of glutamine, and a supraphysiological concentration of 5 mM (5000 uM) was required to show a net utilization of glutamine by astrocytes. They had to remove all glutamine from the culture medium to cause the astrocytes to show a net synthesis of glutamine. The rate of synthesis is not the same thing as the rate of export, but I'm not going to get into all of that. This seems strange, but they're talking about utilization of labeled glutamine. Similarly, exogenous glutamine can spare the utilization of the existing glutamate pool for glutamine synthesis and not even elevate the total intracellular glutamate concentration [Qu et al., 2001: (http://www.ncbi.nlm.nih.gov/pubmed/11746415)]. These and other articles tend to suggest that, following ischemia, for example, the drastic increases in the oxidation of 2-OG are likely to cause exogenous glutamine to appear to exert no effect on the brain. I've discussed other mechanisms that suggest this, in recent postings. In other articles, researchers have noted that very few sites in the body demonstrate a *net* formation of glutamine, meaning that the rate of export from the tissue or cell group at large is higher than the rate of utilization of glutamine. A lot of research portrays the glutamine-glutamate-GABA cycle as if it's constantly generating all this glutamine and that there's endless glutamine being supplied and that cells can't oxidize more than 5 percent and can't even use all of it, because there's so much of it, or whatever. But large amounts of ATP are constantly being used up to maintain the cycle, and the amount of superfluous glutamine is likely to be quite small in many tissues, especially in trauma patients, etc.

Note on Terminology of Trigeminal Reflexes

I guess the term "trigeminal root reflex" isn't commonly used, but I think I'll call it that anyway. I forget what the different terms are, for the reflexes I'm thinking of. Assuming one buys into all of the "strict rules" about different processes and reflexes, there are 50 names for every other aspect of the trigeminal system.

Regulation of Cerebral Blood Flow By Trigeminal Root Reflexes or Other Causes of Efferent Action Potentials in Trigeminal Ganglion Neurons

This article [Arbab et al., 1992: (http://www.ncbi.nlm.nih.gov/pubmed/1481736)] describes the anatomical pathways that could allow ultraviolet B (some of the articles describing the use of "UVA" to induce sunburn pain are likely to be really showing effects mainly mediated by UVB; if even 1 percent of the irradiance of a source of UV radiation is in the UVB wavelengths, this small amount of UVB can be responsible for something like 95 percent of the biological effects) to influence cerebral blood flow or the degranulation of perivascular mast cells, etc. (this is in reference to a paper of mine that I posted a couple of days ago). The authors cite research showing that severing the peripheral branches of some trigeminal ganglion nerve fibers of the maxillary and ophthalmic divisions of the trigeminal nerve can reduce the diameter of the ipsilateral cerebral arteries by 25 percent, meaning that CGRP and substance P and other mediators are released, in response to efferent action potentials that are probably originating in the caudal trigeminal nucleus, from the peripheral terminals of trigeminal ganglion neurons and contribute, under baseline conditions, to the dilation of the middle cerebral artery, etc. There's also quite a bit of research on the role of neuropeptides released from C-type trigeminal ganglion neurons (the nomenclature is slightly different for different classes of trigeminal ganglion neurons, but they can still be called C-fibers, etc.) and the trigeminal nucleus in vasospasm, following subarachnoid hemorrhage (http://scholar.google.com/scholar?q=trigeminal+vasospasm+subarachnoid&hl=en&lr=). And electrical stimulation of the trigeminal ganglion can influence cerebral blood flow (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22cerebral+blood+flow%22+trigeminal+ganglia+OR+ganglion). There are different types of trigeminal root reflexes, and they're not the same as dorsal root reflexes. But the underlying concept is similar. The concept is that two trigeminal ganglion neurons are required. An afferent action potential in a trigeminal ganglion neuron, originating from the skin of the face or the corneal epithelial cells on the surface of the eye, which is innervated by trigeminal ganglion neurons of the ophthalmic branch of the trigeminal nerve, travels to the caudal trigeminal nucleus and activates an interneuron, for example. GABA or glutamate released from the interneuron depolarizes the central terminal of a second trigeminal ganglion neuron (part of the reason this could occur relates to the anatomical relationships between some interneurons and the central branches of trigeminal ganglion neurons whose peripheral branches terminate at a wide variety of locations) and produces an efferent action potential. This can induce CGRP or substance P release at sites adjacent to the middle cerebral artery, etc., thereby causing headaches or just vasodilation or thromboses or remodeling of the smooth muscle cells, because of the release of mast cell proteases by degranulating mast cells, or any number of other effects. Dorsal root reflexes have been suggested to be a mechanism whereby sensory inputs can be "refined," so that more efferent action potentials are being induced or suppressed in some C-fibers in response to specific nociceptive or inflammatory activity in some location that is innervated by other C-fibers or Adelta fibers, etc. A similar type of "refining" effect could occur in the trigeminal nucleus, but the result could also be just inflammatory hyperalgesia and ongoing damage and inflammation, etc.

These mechanisms could, therefore, easily produce or account for pathological changes in the cerebral blood vessels, and much of this research has been done in the context of migraines and other pathological disease states that involve the trigeminal system. But basic research has become devalued to an absurd extent in some of these areas, and it seems as if these types of mechanisms are of no interest whatsoever to anyone. Of course, if one buys into some of the dogma, there is no regulation of cerebral blood flow by neuronal activity. That's obviously not true, in my opinion, although the extent to which neuronal regulation ("nervous regulation") influences cerebral blood flow is likely to be less in a person who is in perfect health than in a person who is not. And UV exposure would obviously be more likely to produce pathological effects in a person in a disease state, in my opinion, than in a person who is not in a disease state. But my main point is just that all of the crazed dogma, in some of these areas, can ultimately confound all attempts to view biological processes in an objective and "scientifically-curious" manner. There's a disturbing kind of arrogance in trying to put a value-laden spin on some of these fundamental processes in biology.

Sympathetic Activation During Resistance vs. Endurance Exercise: Relationship to Exercise-Induced Increases in Noradrenergic Transmission in the Brain

This article [Iellamo et al., 2002: (http://circ.ahajournals.org/cgi/reprint/105/23/2719)(http://www.ncbi.nlm.nih.gov/pubmed/12057984?dopt=Abstract)] is interesting, and it gives the reader at least some sense of the capacity of high-intensity exercise to produce quite different cardiovascular effects than low-intensity, aerobic exercise produces. There's a popular notion that aerobic exercise is the "heart-healthy" form of exercise and that weight training/resistance exercise is just about "muscle-building" or who knows what. The article by Iellamo et al. (2002) shows that high-intensity exercise tends to increase beta-adrenoreceptor responsiveness more than lower-intensity exercise, but the authors seem to evidently still be under the impression that this is "bad." There are just lots of problems with research in exercise. I know it's apparently impossible to research the effects of weight training in rodents, because they can only run on wheels, etc. But researchers keep doing studies on people who are in really pretty decent shape to begin with and then finding no changes or minimal changes in variables related to adrenergic functioning. In general, in my opinion, based on the information from many articles, resistance exercise produces more of an enhancement of beta-adrenoreceptor sensitivity but does not cause some kind of "pressor" effect, and endurance exercise is well-known to produce more of a pronounced increase in vagal (vagus nerve), or parasympathetic, tone, and this is not always purely beneficial to people. Sigal et al. (2004) [Sigal et al., 2004: (http://care.diabetesjournals.org/cgi/content/full/27/10/2518)(http://www.ncbi.nlm.nih.gov/pubmed/15451933)] discuss the fact that, during aerobic (endurance, lower-intensity) exercise, the regulation of glucose availability is primarily driven by these sort of subtle changes in neuroendocrine activity, and endurance exercise tends to decrease insulin levels and cause either unchanged or, actually, decreased plasma glucose levels, during exercise. In contrast, the increases in free fatty acids and plasma glucose that occur during resistance exercise are driven primarily by strong, sympathetic activation and can elevate adrenaline (epinephrine) levels by 15-fold, significantly elevate plasma growth hormone (GH) levels, and increase cortisol meaningfully, etc. So resistance exercise has a very different effect, and, in my opinion, "high-intensity" endurance exercise is not going to mimic those effects very effectively, if at all, in the long term. Reading various articles, one would think that no one has any problem with diminished sympathetic (I'm referring to adrenergic) tone, in terms of the vasoconstriction that is required for venous return to the heart, but this article discusses the high degree of prevalence of postural tachycardia (syncope can result from severe postural tachycardia/postural hypotension, and they're really talking about postural tachycardia and orthostatic intolerance in this article) [Van Lieshout et al., 2003: (http://jap.physiology.org/cgi/reprint/94/3/833)(http://www.ncbi.nlm.nih.gov/pubmed/12571122?dopt=Abstract)]. The authors discuss the fact that improving the strength of leg muscles can improve these symptoms significantly (postural tachycardia manifests itself as dizziness or as an inappropriate and prolonged increase in heart rate upon standing, etc.) and that the venous return to the heart plays a role in maintaining cerebral blood flow, etc.

It's well-known that pilots who fly some types of aircraft experience high G-forces can experience blackouts or "grayouts" tunnel vision, because of transiently diminished cerebral blood flow, and it's well known that resistance training, much more than endurance training, can reduce these symptoms by improving venous return, and Van Lieshout et al. (2003) mention some of that. The baroreflex that normally prevents orthostatic tachycardia or hypotension has multiple components and is really complex, but it's discussed, in much of the literature, as if everyone will benefit from an increase in vagal tone and that the vagal component of the baroreflex is the only relevant one. It's not, and the adrenergic activation that occurs in the brain is likely to be substantially more pronounced, in my opinion, during resistance exercise than during aerobic exercise.

The firing of muscle spindle afferent neurons increases during exercise and contributes to the activation of sympathetic neurons in the medulla, in the brainstem, and higher plasma adrenaline levels (which are obviously much higher during resistance exercise, in general, than during endurance exercise) correlate positively with larger amounts of noradrenaline release in the prefrontal cortex, in exercising rats [Pagliari et al., 1995: (http://www.ncbi.nlm.nih.gov/pubmed/7665408)]. The increases in plasma epinephrine result primarily from increases in the sympathetic outflow from the brain. The direct sympathetic innervation of the adrenal medulla allows epinephrine to be rapidly released during high-intensity exercise. ACTH is also released from the anterior pituitary gland during exercise and stimulates the release of cortisol from the adrenal cortex, during high-intensity exercise. Resistance exercise can induce prolonged elevations in plasma cortisol, at essentially all times during the increases and decreases in plasma cortisol that normally occur throughout the day. This can gradually contribute, over days, to an upregulation of beta-adrenoreceptor density and responsiveness and lead to changes in the magnitude and effects of the acute, exercise-induced increases in plasma epinephrine. Increases in plasma pCO2, during exercise, may also contribute to the activation of noradrenergic neurons in the A1/A2 adrenergic cell groups and the locus ceruleus, in the brain, during exercise [Bailey et al., 2003: (http://www.ncbi.nlm.nih.gov/pubmed/14513913)].

The release of noradrenaline in the prefrontal cortex is almost certainly a result, mainly, of increases in the firing rates of noradrenergic neurons whose cell bodies are in the locus ceruleus, although the other noradrenergic cell groups probably contribute more indirectly to that effect. The central noradrenergic activity, during exercise, is also required for brain-derived neurotrophic factor production in response to exercise, in the brain [Ivy et al., 2003 : (http://www.ncbi.nlm.nih.gov/pubmed/12759116), cited and discussed here: (http://hardcorephysiologyfun.blogspot.com/2008/12/noradrenergic-regulation-of-bdnf.html)], etc. There's a popular belief that increases in plasma beta-endorphin levels, which can occur during exercise, produce an opioidergic or morphine-like effect on the brain, etc., but an increase in plasma beta-endorphin levels is really an indication of a generalized stress response [Farrell et al., 1982: (http://www.ncbi.nlm.nih.gov/pubmed/7096149)]. To produce some kind of opioidergic reward, opioid peptides released into the blood would have to cross the blood-brain barrier, back into the brain, and somehow act selectively on opioidergic pathways that are involved in the mesolimbic reward system, and this isn't really likely to occur. There's a great deal of evidence that the increase in noradrenergic transmission, in the brain, during exercise is more likely to be a major factor regulating the subjective effects or mood elevation in response to exercise. Exercise can also increase dopamine release in the striatum (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=exercise+dopamine+release), and the catecholaminergic effects of exercise are likely to be crucially important for many of its effects.