The call for papers below was extended for one more month

Intra-neuronal (changes in protein conformation, concentration and synthesis) and extra-neuronal factors (extracellular proteolysis, substrate patterning, myelin plasticity, microbes, metabolic status) can have a profound effect on neuronal computations. This means molecular message passing may have cognitive connotations.

A review (including also glial factors):

https://www.researchgate.net/publication/273452923_Information_processing_in_the_CNS_a_supramolecular_chemistry

Article Information processing in the CNS: a supramolecular chemistry?

Dear Arturo, in your excellent paper you wrote: 

"In summary, based on recent data, we hypothesize that

although all neurons exhibit a common repertoire of

macromolecules, each neuron embodies a specific, non-covalent

and transitory supramolecular assembly. This

explains why each neuron is apparently similar to others,

but functionally different. An important question arises:

if macromolecules play a part in neuronal information

processing, why has this link has not been emphasised

by the current paradigms that focus on electric pulses?

One answer is that there are still many unexplored

aspects, because protein dynamics is more sensitive than

structure to environmental factors such as crowding,

solvent, temperature, pressure, confinement. While in

vitro experiments remain the only way to investigate the

intrinsic properties of molecules, this approach ignores

the fact that – in their natural milieu – proteins are

surrounded by other molecules of different chemical

nature, and this crowded environment considerably

modifies their behaviour "

Alfredo: One explored aspect in astrocyte physiology is the complex formed by ions-water-proteins. This is the substrate of calcium ion waveforms in the astroglial network.

Dear Alfredo, don't forget your idea about dewetting transitions...

Dear Arturo, I am not really sure if the ions in the brain are completely wet or dry. Recently I discovered another possibility: they may be trapped by a kind of crystalline state of water that allow them to vibrate and form the waves of energy that correspond (according to my hypothesis) to mental phenomena (more precisely to feelings, as in the case of chronic pain). Do you know Pollack´s hypothesis? Please see his conference in the link below.

https://www.youtube.com/watch?v=XVBEwn6iWOo

Dear Alfredo, you got involved in the classical theory of the solitons.  I have a very nice paper about neurons  & solitons, somewhere, when I'll find it I will send it (probably tonight).  This is a theory starting  to be deeply investigated.  If you like to talk about it in the context of brain, one of the most important scientists in the field is Girolamo Garreffa.  You can find him on RG.   

Dear Arturo, I am specially interested in how solitons could help me to understand the physical-chemical nature of the astroglial calcium wave. Another idea that I would like to discuss is if neuronal oscillations depend on water dipole oscillations at the fundamental level (""below"" the Hodkins-Huxley mechanism); would neuron oscillations be a result of an amplification of molecular phenomena?

I found a paper of him about such brain things which might be very helpful! see: 

https://www.researchgate.net/publication/277776535_The_Dark_Side_of_Brain_Function

Girolamo is much more skilled than me in the interesting field you are talking about: talk with him, and make my name!

Then, let me know about your discussion: I'm very interested!

Research The Dark Side of Brain Function

Before you sent this paper (Abstract only) I had already seen it in his RG page and commented without making your name...sorry! He really seems to be the right person to discuss what I am interested in. I will ask him to join this discussion.

New findings are reinforcing the hypothesis of participation of astrocytes in mental activities, as in the free access paper below (attached):

Physiol Rep. 2015 Oct;3(10). pii: e12454. doi: 10.14814/phy2.12454

Subtle modulation of ongoing calcium dynamics in astrocytic microdomains by sensory inputs.

Asada A, Ujita S, Nakayam, Oba S, Ishii S, Matsuki N, Ikegaya Y

Abstract

Astrocytes communicate with neurons through their processes. In vitro experiments have demonstrated that astrocytic processes exhibit calciumactivity both spontaneously and in response to external stimuli; however, it has not been fully determined whether and how astrocytic subcellular domains respond to sensory input in vivo. We visualized the calcium signals in astrocytes in the primary visual cortex of awake, head-fixed mice. Bias-free analyses of two-photon imaging data revealed that calcium activity prevailed in astrocytic subcellular domains, was coordinated with variable spot-like patterns, and was dominantly spontaneous. Indeed, visual stimuli did not affect the frequency of calcium domain activity, but it increased the domain size, whereas tetrodotoxin reduced the sizes of spontaneous calcium domains and abolished their visual responses. The "evoked" domain activity exhibited no apparent orientation tuning and was distributed unevenly within the cell, constituting multiple active hotspots that were often also recruited in spontaneous activity. The hotspots existed dominantly in the somata and endfeet of astrocytes. Thus, the patterns of astrocytic calcium dynamics are intrinsically constrained and are subject to minor but significant modulation by sensory input.

Ca2+ concentrations in astrocytes and neurons present "rich information content" - another free access paper (attached)

Neuron. 2015 Oct 21;88(2):277-88. doi: 10.1016/j.neuron.2015.09.043.

Time-Resolved Imaging Reveals Heterogeneous Landscapes of Nanomolar Ca(2+) in Neurons and Astroglia.

Zheng K, Bard L, Reynolds JP, King C, Jensen TP, Gourine AV, Rusakov DA.

Abstract

Maintaining low intracellular calcium is essential to the functioning of brain cells, yet the phenomenology and mechanisms involved remain an enigma. We have advanced a two-photon excitation time-resolved imaging technique, which exploits high sensitivity of the OGB-1 fluorescence lifetime to nanomolar Ca(2+) concentration ([Ca(2+)]) and enables a high data acquisition rate in situ. The [Ca(2+)] readout is not affected by dye concentration, light scattering, photobleaching, micro-viscosity, temperature, or the main known concomitants of cellular activity. In quiescent tissue, standard whole-cell configuration has little effect on resting [Ca(2+)] inside neuronal dendrites or inside astroglia dye-filled via gap junctions. Mapping basal [Ca(2+)] in neurons and astrocytes with submicron resolution unveils heterogeneous concentration landscapes that depend on age and preceding activity. The rich information content represented by such landscapes in acute slices and in vivo promises to unveil the hitherto unexplored, potentially fundamental aspects of brain cell physiology

This excellent 2013 review focus on connexin mechanisms of astrocyte information processing through gap junctions and hemichannels and has a section on the involvement of astrocytes in emotion processes. It is not free access - I paste only the Abstract and the link below.

Trends Neurosci. 2013 Jul; 36(7):405-17. doi: 10.1016/j.tins.2013.04.004. 

Emerging role for astroglial networks in information processing: from synapse to behavior.

Pannasch U, Rouach N.

Abstract

Astrocytes contribute to neurotransmission through a variety of mechanisms ranging from synapse isolation to active signaling. Astroglial involvement in neurophysiology has been mostly investigated at the single-cell level. However, a unique feature of astrocytes is their high level of intercellular connectivity mediated by connexins, the proteins forming gap junction (GJ) channels. These astroglial GJ circuits enable the rapid intercellular exchange of ions, metabolites, and neuroactive substances. Recent findings have suggested that, despite their extensity, astroglial networks are also selective, preferential as well as plastic, and can regulate synapses, neuronal circuits, and behavior. The present review critically discusses the impact of astroglial networks on normal and pathological neuronal information processing as well as the underlying mechanisms.

http://www.cell.com/trends/neurosciences/abstract/S0166-2236(13)00065-9?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0166223613000659%3Fshowall%3Dtrue

It's very interesting and I think also that we have to understand what consciousness means on the cell level. Time is also different and  everything happens as in a synchronicity system compared with the macro world which is more entropy. 

Dear Rita, I am working on the hypothesis that the large brain ionic waves that cross the astroglial network correspond to our conscious feelings (the form of each wave corresponds to the quality of the respective feeling). Waves in a single cell are the building blocks of the larger ones, but I would not say that a single cell wave is conscious. it seems that a holistic or holographic effect (the constructive interference of billions of small waves) is necessary to cross a critical threshold to generate conscious feelings. The waves that do not cross the threshold, I call them "unconscious emotions"...

A new frontier in Psychiatry is open: the investigation of the role of astrocytes in mental disease and illness, and the discovery of new therapies for them (possibly more effective than neuron-targeted drugs). There are several reviews in this regard (see below: ARNONE et al., 2015; GOLDMAN et al., 2015; MÉNARD et al., 2015; YAMAMURO et al., 2015). One of the most impressive results is the change in astrocyte physiology in suicidal depressive subjects (TORRES-PLATAS et al., 2015).

References:

ARNONE, D.; MUMUNI, A.N.; JAUHAR, S.; CONDON, B.; CAVANAGH, J. Indirect evidence of selective glial involvement in glutamate-based mechanisms of mood regulation in depression: Meta-analysis of absolute prefrontal neuro-metabolic concentrations. Eur Neuropsychopharmacol, S0924-977X(15)00121-2, 2015.

GOLDMAN, S.A.; NEDERGAARD, M.; WINDREM, M.S. Modeling cognition and disease using human glial chimeric mice. Glia, 2015. doi: 10.1002/glia.22862.

MÉNARD, C.; HODES, G. E.; RUSSO, S. J. Pathogenesis of depression: Insights from human and rodent studies. Neuroscience S0306-4522(15)00495-9, 2015.

YAMAMURO, K.; KIMOTO, S.; ROSEN, K. M.; KISHIMOTO, T.; MAKINODAN, M. Potential primary roles of glial cells in the mechanisms of psychiatric disorders. Front Cell Neurosci., v. 9, p. 154, 2015.

TORRES-PLATAS, S.G.; NAGY, C.; WAKID, M.; TURECKI, G.; MECHAWAR, N. Glial fibrillary acidic protein is differentially expressed across cortical and subcortical regions in healthy brains and downregulated in the thalamus and caudate nucleus of depressed suicides. Mol Psychiatry, 2015. doi: 10.1038/mp.2015.65

It is a very beautiful way of thinking. I didn't mean that the cell is conscious but it is also more than unconscious.

First there is the problem what is understood by consciousness. I should say that we better make a shift from thinking and feeling to the action, what we really do, the rhythm we follow, the measure we take, the moment we choose, the place we visit.

Then we see that the action in a cell is more precise as we do. It can be, the more complex a system becomes the more information which can be lost.

Dear Rita, consciousness is related to feeling, knowing and doing. There are different definitions, some emphasizing feeling (as mine), some emphasizing knowing (classical approaches) and some emphasizing doing (enactivist views). Harnad (see link below) argued for the feeling view; I basically agree with him.

http://nationalhumanitiescenter.org/on-the-human/2011/04/doing-feeling-meaning-explaining/

Dear Alfredo,

let me to resume my previous reply.

In my idea blood flow is only a medium (considering also microvascular structures) of possible fine mechanical oscillations involving not only central (brain) but also peripheral activities.

Astrocytes play an important role and are, as you know, strictly coupled with vascular network and neurons, in this scenario a multiple coupling (mechanical to electrical and viceversa), according to the model I am building, can take place...

I  consider vascular ntw involved in propagation of fine and hyperfine ”mechanical" signals and I agree with the hypothesis that some where (and some time) there is an Hub (obviously multiple hubs..) where an electro-mechanical (and viceversa) coupling occurs but, probably, according to my hypothesis,  this coupling locally happens in this order:  [A] 1) vascular ntw => 2) Astroglial ntw => 3) Neuronal ntw ; in reverse mode [B]  and in a third mode [Ci] that could be any possible combination in the order. Then, if we consider a "single" Hub  (Hi) the single hub could be in a given (order) state. This kind of Coupling may also happens between only two ntw components. 

I am just writing a second "short paper" on RG which I hope to make available in few days...

Dear Girolamo,

Please write a "long" paper on this exciting issue! If possible and convenient (and if you have the money to pay for the publication), please submit it to the special issue I announced in my first message in this thread (the Call for Papers was extended for one month).

Earlier hypotheses about hemodynamic media for consciousness (e.g. Moore, C.M., Cao, R., 2008. The hemo-neural hypothesis: on the role of blood flow in information processing. J. Neurophysiol. 99, 2035–2047) rely mostly on "chemical" signaling. "Mechanical" (piezoelectric activity, solitons, Pollack's "liquid cristal" state of water in living systems) information processing capacities of blood flow is a new hypothesis. It surely can be combined with astroglial physiology and also with information processing in cerebrospinal and extracellular fluids, then providing a "continuum" of processes in brain tissue. In neurons, this kind of dynamics probably interacts with dendritic (graded) fields, but not so much with axonal "discrete" signaling (for physiological reasons, as the lipid insulation of many fibers).

Also muscles present calcium waves that could in principle participate in conscious processes; this may be the case specially for the heart nervous system. The problem known as "the binding problem" is about how all these dynamic patterns from several parts of the body get together to compose the conscious episodes that we experience. A conscious episode has an approximate duration of 2 or 3 seconds; inside this temporal window, there are several brief conscious events that acquire their meaning in relation to the whole episode. How to account for both spacial and temporal integration? 

The astrocyte network seems to be specially suited to perform both spacial and temporal integration, since it provides spatial connection between blood flow, cerebrospinal/extracellular fluid and neurons; and its temporal dynamics (calcium waves) occurs in the range of seconds. These properties were noted in a recent meeting by glial cell specialists.

In an interview to Nature News in 2013 Dr. R. Douglas Fields (NIH-USA) said (my italics): “When experts on neuronal plasticity and computational neuroscience came together with glial experts at a workshop in February entitled Glial Biology in Learning and Cognition, held at the US National Science Foundation in Arlington, Virginia, our unanimous conclusion was that neurons working alone provide only a partial explanation for complex cognitive processes, such as the formation of memories...The complex branching structure of glial cells and their relatively slow chemical (as opposed to electrical) signaling in fact make them better suited than neurons to certain cognitive processes. These include processes requiring the integration of information from spatially distinct parts of the brain, such as learning or the experiencing of emotions.”

The results of the meeting were published in: Fields RD, Araque A, Johansen-Berg H, Lim SS, Lynch G, Nave KA, Nedergaard M, Perez R, Sejnowski T, Wake H.(2014) Glial biology in learning and cognition. Neuroscientist 20(5):426-31. In the Abstract, the authors wrote (my italics): "Neurons are exquisitely specialized for rapid electrical transmission of signals, but some properties of glial cells, which do not communicate with electrical impulses, are well suited for participating in complex cognitive functions requiring broad spatial integration and long-term temporal regulation. Astrocytes, microglia, and oligodendrocytes all have biological properties that could influence learning and cognition. Myelination by oligodendrocytes increases conduction velocity, affecting spike timing and oscillations in neuronal activity. Astrocytes can modulate synaptic transmission and may couple multiple neurons and synapses into functional assemblies. Microglia can remove synapses in an activity-dependent manner altering neural networks. Incorporating glia into a bicellular mechanism of nervous system function may help answer long-standing questions concerning the cellular mechanisms of learning and cognition."

Considering the explanatory factors agreed by glial cells specialists, I conclude that your model of blood "mechanical" information patterns could be included in a broader model having glial cell networks (more specifically, the astrocyte network) as the "Master Hub" where feelings relative to conscious episodes with duration of 2 to 3 seconds are instantiated.

@Alfredo Pereira Junior  What if the the unconscious waves do reach threshold but are faster than conscious perception and at a different frequency? In this way the large brain ionic  brain waves could be a part of a symphony, A breakdown in this order might cause unconscious cognitive dissonance  over time, I wonder if this is part of the  compensatory time frame that keeps us sane?

Dear Amy, the unconscious waves are probably part of our cognitive and affective identity (the symphony). Every conscious state has an unconscious beginning, and is determined by the process that generates it; the beginning and the ending should not be dissonant. Only after we feel what it is like to be in a conscious state our brain feedback mechanisms influence the process that led to that state. However, I would say that if the waves are too fast or too slow they do not reach the threshold! It is easy to relate slow waves (delta rhythms) with unconsciousness, because they dominate the EEG power spectrum during dreamless sleep. High amplitude waves are known to cause the loss of consciousness, as in the case of absence epilepsy. Fast waves, if they happen (as the top range of gamma, around and above 100 Hz), could carry neuronal unconscious process influencing the 2-3-seconds (below 1 Hz) waves that correlate with conscious episodes. The compensation that you mention may be related to the Fourier harmonics of brain activity as a whole. Evidence about brain physiology suggests that gamma rhythm waves do not occur in the astrocyte network; however, if they are found, we already have a role for them!

Dear Alfredo, do you know what the top range of gamma looks like in high stress trauma that in some leads to PTSD and if this contributes to the brain not finding closure? Wondering because I am not yet satisfied with the why TETRIs or the rapid eye movement therapy works.

Dear All: The relation of brain rhythms with astroglial waves is complex. Amplitude modulated (AM) waves are in fact composed of two waves, the carrier (corresponding to synchronized activity in delta, theta, alpha, beta, gamma ranges) and the modulating waves. The modulating wave shapes the amplitude variations of the resulting complex waves (see the figure and link below). These waves that appear in the EEG are generated mostly by neuron graded (dendritic) potentials. According to the hypothesis of a "carousel effect" (Pereira Jr and Furlan, 2009; 2010 - see my RG page) the neuronal AM waves generated at the dendrites are electromagnetically and chemically (by means of transmitters) transferred to the astroglial network, generating small calcium waves that interfere to produce larger ones with frequencies below 1 Hz.

http://www.scholarpedia.org/article/Freeman's_mass_action

Dear Amy, I am sorry, but I am not an expert in the area you are interested. Maybe a search in PubMed could help; if not, making a new RG question, as a last attempt to find the answer!

C6 rat astrocytoma cells should be looked at re: serine racemase and D-amino acid oxidase given new understanding re: astrocytes' role in modulation of NMDARs

Article Mediation by cyclic AMP of hormone-stimulated glycogenolysis...

Dear Amy, some second thoughts on your ideas: if synchronous neural oscillations in the range of 7 to 40 Hz generate astroglial calcium waves in the range of 0,5 Hz (corresponding to conscious episodes in a temporal window of 2 seconds), then neural oscillations in the range of 100 Hz would lead to the compression of conscious episodes into 1 second! People in this condition would have their attention span shortened, and therefore this may be a physiological cause of anxiety and attention deficit disorders.

Wow, yes amazing, this is what I was wondering and it explains a lot and worth investigating Thanks you

In the FMA paper we could read that the wave packet carries the percept and expresses the content. A new assembly forms when a subject learns something new, so we get a new AM pattern. The AM pattern changes during consolidation and when it is given a different context. The AM pattern signals the contextual meaning and significance.

This is a fine thread but how we come to the quality of that meaning. We are blocked by the measure of patterns.

As consciousness has to do with gradation always changing. a higher state of consciousness does not give a better pattern. 

Very important is the order in the FMA concept. They put that the perception advances in a segment of frames. The binding of AM of ECoG reveals the degree they bind in synchony.

When AM goes to 0 it is written that the order disappears and that the neurons lose themselves in disorder and evaporates into noise.

I think that here pre-consciousness is coming in and that the order stays, it is this field that I feel must be of great interest. The order which is, but for the moment can't be measured. Probably it is this that make us different of animals. David Bohm explained this in a implicate and explicate order which is a good term for the flux of consciousness.

Ultimately the Ca(2+) waves could be interpret in a quantum frame. 

Thank you for the paper.

Yes, Rita, you got the message. The difference between Freeman's approach and mine is that I add astroglial calcium waves as another layer for dynamic patterns related to feeling experiences. These waves are slower than the EEG waves that correspond mostly to active synchronous neuronal assemblies.

New perspectives in the treatment of gliomas (from the link below):

"The treatment involves first dosing the patient with medication. Afterward, harmless microbubbles are injected into the bloodstream, and a high-intensity ultrasound beam is directed at the tumor, causing the microbubbles to vibrate. This gently tears the proteins around the capillary walls, allowing the medication to painlessly and harmlessly enter the brain tissue, something that has been impossible to achieve up to this point....Attempting to remove all of a glioma from a patient’s brain surgically is almost invariably fatal. Patients with glioblastomas (stage four gliomas) survive an average of one year, and almost never survive beyond three with conventional treatment. Doctors can use chemotherapy to treat the remaining parts of the tumor, but at best, 25 percent of the chemotherapy drugs reach the brain due to the blood-brain barrier. Chemotherapy has to be very carefully administered, as the drugs can be fatal themselves in greater doses; it’s not simply a matter of increasing the treatment."

http://www.inquisitr.com/2552192/canadian-doctor-first-to-break-blood-brain-barrier/

Yes, the more layers we have, the closer we come to The Consciousness.  There was a huge discussion between Bergson and Einstein about becoming, experience in time. Einstein could not find the time of feeling, if I understood well.

So I see it another way; what is bringing 2 lovers together. On the level of love, the mind is very attentful and in a higher range. This can be reflected in synchrony behaviour in a spacetime model. This happens also in actions done with passion. The same happens in research; at a certain moment the astrocytes start showing the way, because there is a kind of intuition. That intuition is the sum of every pre-consciousness, feeling, emotion, knowledge, memory. The point where all this come together is not a point in space. This can be a knot of waves but here we must shift to the quantum frame and take into account the non-locality, where the waves are everywhere in no-time. 

I take synchronicity because this  can be proved, as Pauli did and Jung. If we take the feeling, we can start with poetry and music and see what is happening there.

It may be very good to see the field of astrocytes and how the researcher is coming into contact with the matter.

For myself I see always, the particle, the cell and the person, 3 different levels where the consciousness of the researcher is the common ground.

Papaverine (a phosphodiesterase inhibitor) can abolish conditioned avoidance in rats.

Papaverine robustly inhibits phosphodiesterase in cultured rat glial cells.

Reversing condition avoidance in rats predicts that a substance will be an antipsychotic in people.

SO....extremely speculative, but above suggests that increasing cAMP by blocking phosphodiesterase in astrocytes may predict antipsychotic efficacy.

Dear Lewis, in my Progress in Neurobiology 2010 paper with Furlan (attached; see page  417) we used the example of Conditioned Taste Aversion to illustrate the proposed mechanism by which astrocytes modulate neuronal activity.

This is important work and as someone who does research RE:

schizophrenia resonates with my somewhatfarfetched

ideas RE:antipsychotics abolishing condition avoidance 

suggest that glia (Greek for glue....Virchow thought glia were glue holding neurons together) and astrocyte dysfunction may have something to do with etiology of

schizophrenia...THANK YOU/OBREGADO

Dear Lewis, your 1972 work is impressive and surely ahead of time! It opened the possibility of further research on astrocyte-targeted psychiatric drugs. Could you please tell us more about the effects of norepinephrine on astrocytes? I have an impression that the pathway of activation of the astrocyte network in the human brain corresponds to the diffusion of NE, but a colleague told me it is not causal. Do you know about the mechanism of action of lithium (as treatment of bipolar disorders) in astrocytes? How does this ion interact with calcium waves?

For my PhD (granted in 1975) I studied (among other things) C6 rat astrocytoma cells which I lovingly kept alive using Dulbecco's modification of Eagle's medium. The chairman of my department was Alfred Gilman Sr and Harry Eagle was chair of Cell Biology.  Gilman Sr's son (ALFRED GILMAN JR, WHO LATER BECAME A NOBEL LAUREATE) had just reported that when he added norepinephrine to the medium in which he was growing C6 rat astrocytoma cells there was a rapid and HUGE increase in cAMP. So I decided to look further and found that norepinephrine increased activity of adenylate cycles which turned on protein kinase which lead to glycogenolysis: it was clear that astrocytes were not just inert glue but were playing a vital role triggered by the neurotransmitter norepinephrine. I later showed that norepinephrine turned of phosphofructokinase and glycolysis (although not in the 1972 paper).   Forty-five years after I did the original work, it is exciting to see why astrocytes needed to turn up carbohydrate metabolism in response to norepinephrine (and I suspect other neurotransmitters).

Let me think about your question RE: lithium: if I come up with something, even wildly speculative, you will be the first person I tell.

Lew Opler

I PROMISED I WOULD THINK ABOUT LITHIUM SO HERE ARE THOUGHTS OF LAO (those are my initials):

I have been thinking about NMDA-glutamate receptors (NMDARs) which gate neuronal calcium channels. (I don't know if astrocytes have NMDARs but suspect they do.) So for calcium to enter, calcium channels need to open, which requires 3 things:

Glutamate needs to bind to glutamate receptors

Glutathione needs to occupy the allosteric REDOX allosteric site

Either glycine or D-serine needs to occupy the GLYCINE allosteric site.

BUT EVEN IF ALLTHOSE CONDITIONS ARE MET, CALCIUM ENTRANCE CAN BE BLOCKED IF PHENCYCLIDINE BINDS IN THE CHANNEL ITSELF....AND MAGNESIUM IS ALEWADY PRESENT IN THE CALCIUM CHANNEL AND BEING LIKE CALCIUM A DIVALENT CATION, CANNOT STOP BUT CAN SLOW DOWN CALCIUM INFLUX.

So how about lithium?My thoughts start to race (maybe I need lithium):

Either

1-monovalent cations, in this case lithium could interfere with the DIVALENT actions calcium and/or MAGNESIUM....maybe  at toxic levels lithium even promotes excitotoxicity like glutamate....or via glutamatergic mechanisms

And/or 

2-lithium is several systems has been thoyght to "stabilize receptors although precise mechanism is not understood...so could lithium stabilize NMDARs?

And that's as far as I have gotten.....if the above seems disjointed and thought disordered don't blame me: you did ask for "Lew's associations"....

Dear LAO, My two cents of speculation: astrocytes have NMDA receptors too; lithium can interfere with these receptors, but can also operate in the intra-cellular milieu (endoplasmatic reticulum and microdomains). It is a good guess that they interfere with Ca2+, since Coulomb's Law says cations repel each other. How do they stabilize mood? Well, if mood instability (bipolarity) is due to too much glutamate/too much calcium at some times and too less of both at other times, then lithium may take Ca2+ place and produce weaker (in terms of amplitude) BUT more stable waves. Lithium comes from the BBB (not from the extracellular matrix and of course not from neurons) and possibly competes with Ca2+ internally to the cell. Magnesium is (possibly) not relevant for lithium's mechanism of action because the astrocyte membrane is hyperpolarized, possibly keeping magnesium at a distance from the NMDA channel; only one Glu pulse may be sufficient to activate it. Metabotropic Glu receptors also do not need membrane excitation to produce Ca2+ waves mediated by IP3. These Ca2+ waves generated from the interaction with the outside is counterbalanced by the lithium that comes from the blood.

Good points!

Obregado!

Dear Lewis, I wished more experts could discuss with us the mecahanism of action of psychiatric drugs and substances on astrocyte physiology. This is a frontier in biological psychiatry that should attract scientific as well as commecial interests.

I agree....perhaps we should write something on this topic....but not today as I am driving to a meeting where I am presenting...

Dear Lewis, in 2013 I had an opportunity to discuss the findings below (see link for the free access paper) with some of the authors. They were surprised by the finding that after injecting several substances on astrocytes 'in vivo' and observe the resulting calcium waves with two-photon microscopy, only NE was sufficient to generate calcium waves!

Cell Calcium. 2013 Dec;54(6):387-94. doi: 10.1016/j.ceca.2013.09.001. 

α1-Adrenergic receptors mediate coordinated Ca2+ signaling of cortical astrocytes in awake, behaving mice.

Ding F1, O'Donnell J, Thrane AS, Zeppenfeld D, Kang H, Xie L, Wang F, Nedergaard M.

1Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, United States.

Abstract

Astrocyte Ca2+ signals in awake behaving mice are widespread, coordinated and differ fundamentally from the locally restricted Ca2+ transients observed ex vivo and in anesthetized animals. Here we show that the synchronized release of norepinephrine (NE) from locus coeruleus (LC) projections throughout the cerebral cortex mediate long-ranging Ca2+ signals by activation of astrocytic α1-adrenergic receptors. When LC output was triggered by either physiological sensory (whisker) stimulation or an air-puff startle response, astrocytes responded with fast Ca2+ transients that encompassed the entire imaged field (positioned over either frontal or parietal cortex). The application of adrenergic inhibitors, including α1-adrenergic antagonist prazosin, potently suppressed both evoked, as well as the frequently observed spontaneous astroglial Ca2+ signals. The LC-specific neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), which reduced cortical NE content by >90%, prevented nearly all astrocytic Ca2+ signals in awake mice. The observations indicate that in adult, unanesthetized mice, astrocytes do not respond directly to glutamatergic signaling evoked by sensory stimulation. Instead astrocytes appear to be the primary target for NE, with astrocytic Ca2+ signaling being triggered by the α1-adrenergic receptor. In turn, astrocytes may coordinate the broad effects of neuromodulators on neuronal activity.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858490/

Dear Lewis, this is a recent paper co-authored by glia expert Alexei Verkhratsky. It corroborates our especulations about lithium!

Amino Acids. 2015 May;47(5):1045-51. doi: 10.1007/s00726-015-1936-y. 

Chronic treatment with anti-bipolar drugs suppresses glutamate release from

astroglial cultures.

Liu Z(1), Song D, Yan E, Verkhratsky A, Peng L.

Author information:

(1)Laboratory of Brain Metabolic Diseases, Institute of Metabolic Disease

Research and Drug Development, China Medical University, No. 77 Puhe Road,

Shenyang North New Area, Shenyang, People's Republic of China.

Astroglial cells are fundamental elements of most neurological diseases,

including bipolar disorders in which astrocytes show morphological and functional

deficiency. Here we report the suppression of astroglial glutamate release by

chronic treatment with three anti-bipolar drugs, lithium salt (Li(+)),

carbamazepine (CBZ) and valproic acid (VPA). Release of glutamate was triggered

by transient exposure of astrocytes to ATP (which activated purinoceptors) and 45

mM K(+) (which depolarised cell membrane to ~-30 mV). In both types of

stimulation glutamate release was regulated by Ca(2+) entry through plasmalemmal

channels and by Ca(2+) release from the endoplasmic reticulum (ER) intracellular

stores. Exposure of astroglial cultures to Li(+), CBZ and VPA for 2 weeks led to

a significant (more than 2 times) inhibition of glutamate release, which may

alleviate the hyperactivity of the glutamatergic transmission in the brain of

patients with bipolar disorders and thus contribute the underlying mechanism of

drug action.

I found your wonderful discussion. The functions of glial cells are developed every year. It's no wonder. Glial cells 10 times higher than the nerve. Consequently, a priori it could be assumed that the role of glia diverse than trophic, support, Immune Protective. My graduate student studying the role of glial cells in the mechanisms of brain plasticity in modeling apnea. Soon join the discussion.

The idea that nature made us like that, brings me already in a good mood.

If people would read more about molecular biology, there would be less terror in the world and more surprise and humility.

Dear Rita! Everything you said is something that belongs to the Human. But many people are werewolves. Through brain person can become worse than an animal. Due to the brain the person can hypocritically promised benefits and, at the same time to kill. You're all by yourself can continue the analogy.

All the tragedies that occur in the world today, resonate in the Human Heart. But the origins of these tragedies in our minds and actions.

PS. So, we are all responsible for what has happened recently with the plane crash and the terrorist attacks in Paris.

...and we all have a responsibility to transcend individualism and collectively work to create a world that does not resort to guns/bombs/scapegoating/racism

Aujoudhui je suis Parisien. (I already was Belarusian, since my maternal grandmother was born there in the late 1800s.)

Yes, Lewis! You're right. Only together can resist evil. I am glad that you have kept a good memory of Belarus. Thank you. Vladimir

Today we are all Parisiens AND Russians: the bombing of the plane was an act of BARBARISM.

Lew/Lvov/Louis

No Vladimir, I’m not responsible for it, please! My father was for 4 years at the Resistance. We had our war here in Belgium too but my parents never told me about it and let us grow without the terror in love. It is only through poetry, movie and my father's songs that I came across the horror. I read about politics as less as possible and all the sensation of the media I negate.

My heart is clear, if people would turn to music and self-study, if women would get a better place and if the science of love on the quantum level could be cleared out, we could have a better society. I love the cell, the molecules and all the particles that find their way in that order, what sometimes is called chaos. 

Order out of order is the paradigm.

But we cannot be totally uninvolved: in the 1960s my family was involved in the civil rights moment (specifically voter registration in Mississippi) when Cheney/Goodman/Schwerner were killed by the KKK and I was active in the late 1960s/early 1970s in protesting US involvement in Vietnam--and my father (an anthropologist trained by Ruth Benedict and Franz Boas) made me aware of Boas' work showing that race is NOT a valid BIOLOGICAL CONSTRUCT although it is a SOCIAL CONSTRUCT used to justify discrimination, sterilization, and even genocide.

 Eldridge Cleaver in SOUL ON ICE writes: "either you are part of the solution or you are part of the problem."

Vladimir would agree that Rachel was not an ISIS terrorist: but Nazi genocide to the events in Paris 2 days ago require that scientists like everyone else must do more to save the world from fascism/BARBARISM/annihilation.

Spacebo, Vladimir, for raising this important topic.

Lew/Leonid/Louis

Obregado, Alfredo, for bringing attention to astrocytes: much more numerous than neurons and structurally and medically complex, they are clearly not just "glue" holding neurons together as Virchow hypothesized.

And yet most theories of psychology and psychopathology speak of neurons and rarely even mention astrocytes.

Why?

Dear Lewis, the blame is on Ramon y Cajal and his "Neuron Doctrine" that dominated the neuroscientist's mind for a century. Neurophysiology textbooks are based on the Hodkin-Huxley equation that applies only to neurons. Astroglial physiology is a topic in the frontier of neuroscience, and many colleagues do not investigate it because it still does not afford good jobs and promising careers. Some places like Rochester have a conjunction of positive factors, as being close to an Optics department that provides the technology for imaging astroglial calcium waves, and a Medical department that provides human astroglial cells and tissues for scientific study.

The first published explicit statement of the relation between astrocytes and conscious activity is (to my knowledge):

J Physiol Paris. 2002 Apr-Jun;96(3-4):251-5. The Astrocentric Hypothesis: proposed role of astrocytes in consciousness and memory formation. Author: Robertson JM. From the Abstract: "(...) It is proposed that protoplasmic astrocytes bind attended sensory information into consciousness and store encoded memories. This conclusion is supported by research conducted by gliobiologist over the past 15 years."

The author of the hypothesis, MD. James Robertson, has helped my investigation on the topic for many years.

There is a book on the relation of glial cells and mental functions that is likely to become a classic in the near future (see link below)

A presentation of the book from the site below:

"About the book

Despite everything that has been written about the brain, a very important part of this vital organ has been overlooked in most books – until now. The Other Brain is the story of glia, which make up approximately 85% of the cells in the brain. Long neglected as little more than cerebral packing material (“glia” means glue), glia are sparking a revolution in brain science.

Glia are completely different from neurons, the brain cells that we are familiar with. Scientists are discovering that glia have their own communication network, which operates in parallel to the more familiar communication among neurons. Glia provide the electrical insulation for neurons, and glia even regulate the flow of information between neurons.

But it is the potential breakthroughs for medical science that are the most exciting frontier in glia research today. Diseases such as brain cancer and multiple sclerosis are caused by diseased glia. Glia are now believed to play an important role in such psychiatric illnesses as schizophrenia and depression, and in neurodegenerative diseases such as Parkinson’s and Alzheimer’s. They are linked to infectious diseases such as HIV and prion disease (mad cow disease, for example) and to chronic pain. Scientists have discovered that glia repair the brain and spinal cord after injury and stroke. The more we learn about these cells that make up the “other” brain, the more important they seem to be.

Written by a neuroscientist who is a leader in the research to reveal the secrets of these brain cells, The Other Brain offers a first-hand account of science in action. It takes us into the laboratories where important discoveries are being made, and it explains how scientists are learning that glia cells come in different types, with different capabilities. It tells the story of glia research from its origins to the most recent discoveries and gives readers a much more complete understanding of how the brain works and where the next breakthroughs in brain science and medicine are likely to come."

http://theotherbrainbook.com/about.php

Two giants of astrocyte research think that the main function of the astroglial network is brain homeostasis (see Abstract below). My position in the debate is that besides the homeostatic function the astroglial network also has the (mental) function of instantiating conscious feelings.

The list of publications of Dr. Verkhratsky (see link below) is really impressive. He is the author of the most used textbooks about astroglial physiology.

Dr. Nedergaard's Lab has produced the main results that fuel my investigations.

Neurochem Res. 2015 Feb;40(2):389-401. doi: 10.1007/s11064-014-1403-2.

Why are astrocytes important?

Verkhratsky A, Nedergaard M, Hertz L.

Abstract

Astrocytes, which populate the grey and white mater of the brain and the spinal cord are highly heterogeneous in their morphology and function. These cells are primarily responsible for homeostasis of the central nervous system (CNS). Most central synapses are surrounded by exceedingly thin astroglial perisynaptic processes, which act as "astroglial cradle" critical for genesis, maturation and maintenance of synaptic connectivity. The perisynaptic glial processes are densely packed with numerous transporters, which provide for homeostasis of ions and neurotransmitters in the synaptic cleft, for local metabolic support and for release of astroglial derived scavengers of reactive oxygen species. Through perivascular processes astrocytes contribute to blood-brain barrier and form "glymphatic" drainage system of the CNS. Furthermore astrocytes are indispensible for glutamatergic and γ-aminobutyrate-ergic synaptic transmission being the supplier of neurotransmitters precursor glutamine via an astrocytic/neuronal cycle. Pathogenesis of many neurological disorders, including neuropsychiatric and neurodegenerative diseases is defined by loss of homeostatic function (astroglial asthenia) or remodelling of astroglial homoeostatic capabilities. Astroglial cells further contribute to neuropathologies through mounting complex defensive programme generally known as reactive astrogliosis.

http://www.manchester.ac.uk/research/alexej.verkhratsky/publications

Dear Rita! Dear all! What we have in mind at the mention of responsibility for something evil world scale. There was the death of innocent citizens in the heart of Europe. And many are thinking. Exactly what everyone did, that did not happen. How many volunteers are in the terrorists from developed countries? How many volunteers there is one of those people who sometimes live in our neighborhood? That's what I was referring to the responsibility of everyone. The responsibility of each of the living in this world for what is happening in this world. Even in the aspect of sympathy to the victims.

This 2011 review (published in 2012)  is very interesting:

Pharmacol Biochem Behav. 2012 Feb;100(4):712-25.

doi: 10.1016/j.pbb.2011.03.021.

Does conventional anti-bipolar and antidepressant drug therapy reduce

NMDA-mediated neuronal excitation by downregulating astrocytic GluK2 function?

Peng L(1), Li B, Du T, Wang F, Hertz L.

Author information:

(1)Department of Clinical Pharmacology, China Medical University, Shenyang, PR

China. [email protected]

Chronic treatment with anti-bipolar drugs (lithium, carbamazepine, and valproic

acid) down-regulates mRNA and protein expression of kainate receptor GluK2 in

mouse brain and cultured astrocytes. It also abolishes glutamate-mediated,

Ca(2+)-dependent ERK(1/2) phosphorylation in the astrocytes. Chronic treatment

with the SSRI fluoxetine enhances astrocytic GluK2 expression, but increases mRNA editing, abolishing glutamate-mediated ERK(1/2) phosphorylation and [Ca(2+)](i)

increase, which are shown to be GluK2-mediated. Neither drug group affects

Glu4/Glu5 expression necessary for GluK2's ionotropic effect. Consistent with a

metabotropic effect, the PKC inhibitor GF 109203X and the IP(3) inhibitor

xestospongin C abolish glutamate stimulation in cultured astrocytes. In CA1/CA3

pyramidal cells in hippocampal slices, activation of extrasynaptic GluK2

receptors, presumably including astrocytic, metabotropic GluK2 receptors, causes

long-lasting inhibition of slow neuronal afterhyperpolarization mediated by

Ca(2+)-dependent K(+) flux. This may be secondary to the induced astrocytic

[Ca(2+)](i) increase, causing release of 'gliotransmitter' glutamate. Neuronal

NMDA receptors respond to astrocytic glutamate release with enhancement of

excitatory glutamatergic activity. Since reduction of NMDA receptor activity is

known to have antidepressant effect in bipolar depression and major depression,

these observations suggest that the inactivation of astrocytic GluK2 activity by

antidepressant/anti-bipolar therapy ameliorates depression by inhibiting

astrocytic glutamate release. A resultant strengthening of neuronal

afterhyperpolarization may cause reduced NMDA-mediated activity.

Copyright © 2011 Elsevier Inc. All rights reserved.

Dear Alfredo, as a hands-on clinician I always seek to understand what is happening underneath my hands when I work with people and underneath my own skin as I continuously glean information from my inner and outer environments. I very much appreciate the increase in understanding of the astroglial functions you are doing so much to help to bring about. Personally I consider the coherent order of water hydrating the astroglial network of particular importance in view of the protonic and electronic flow of information it makes possible as well as the high degree of sensitivity and responsiveness to resonance itbrings about. 

Recently in an article by James Oschman, which I am trying to find and will post as soon as I do, I read about research that revealed the structure of certain "connective tissue" fibrils in the eye that are right-turning on both sides... the only structures in the head that  are not symmetrical as in a mirror. I have to go, but will try to find this research and post it here.

Found it! Vortical Structure of Light and Space: Biological Implications

http://www.omicsonline.com/open-access/vortical-structure-of-light-and-space-biological-implications-2090-8369-1000112.php?aid=41736

Someone came to pick me up before and, although I had the general idea in my head, at that time I couldn't think of the right words: the reason why I think this article might be of interest in this context is because James Oschman writes about the spacing of collagen fribrils building a "crystal-like lattice which has the same right-handedness in both eyes and is thus bilaterally asymmetrical." (p.2 of the article). ...enabling both eyes to "accomodate to light moving vortically in the same right-handed path".

Another of his articles in the same magazine is The Heart as a Bi-directional Scalar Field Antenna - http://www.omicsonline.com/open-access/the-heart-as-a-bidirectional-scalar-field-antenna-2090-8369-1000121.php?aid=60866

I believe that astrocytes are made up to a large degreee of collagen-like fibrils, aren't they? Therefore one of the main characteristics that would relate astrocyte functions with conscious activity must be the semiconducting structure of collagen with its hydration shell.

To Vladimir, Lewis and Rita, in response to your latest answers in this question, may I invite you as well as all others to visit this report: Zero in on a Blind Spot: The Gun Powder Factory in Düneberg - Tracking history at http://dfa-spr.blogspot.com.es/2015/10/zero-in-on-blind-spot-gun-powder.html . It is about a practical approach to the question posed here. Thanks Alfredo for posting it!

Dear Brigitte, many thanks for your constructive comments! 

You wrote: 

"James Oschman writes about the spacing of collagen fribrils building a "crystal-like lattice which has the same right-handedness in both eyes and is thus bilaterally asymmetrical." (p.2 of the article). ...enabling both eyes to "accomodate to light moving vortically in the same right-handed path".... I believe that astrocytes are made up to a large degreee of collagen-like fibrils, aren't they? Therefore one of the main characteristics that would relate astrocyte functions with conscious activity must be the semiconducting structure of collagen with its hydration shell."

Alfredo: I tend to agree with you. My friend Vera Maura Fernandes de Lima is an expert on the retina; we recently wrote a paper together (submitted). Please take a look at her RG page to find some of her publications. She is the person who told me about Pollack's theories of structured water. I am trying to figure out how the relation between polarized water (resulting in a kind of collagen, gel or crystalline arrangement - I am not sure what is the best term), calcium ions and proteins could be. For instance, Pollack's "exclusion zone" must have an effect on calcium concentrations in astrocytes. Hydrophilic and hydrophobic sites of proteins too. The complex interactions of ions, water and proteins is probably the central mechanism that makes life and consciousness possible. 

This is an interesting discussion and I am glad to participate in it. Please note that astrocytes are not "made up to a large degree of collagen-like fibrils." With a few exceptions, collagen is an extracellular material. The fibrillar systems within astrocytes are parts of the cytoskeleton, i.e.  microtubules and neurotubules. Stuart Hameroff A tiny neuron, a thousandth of an inch in diameter, has about 9 feet of cytoskeleton. Hence there are close to a billion miles of semiconducting fibers in the brain. They form a sophisticated semiconducting electronic communication network. Messages can be conveyed by action potentials and neurotransmitters, and also by the movement of charges and conformational waves through the cytoskeletons. Hameroff and Penrose developed a model of memory and consciousness in which hydrated molecular arrays of microtubules in brain neurons store information and regulate neuronal activities. They suggested a connection between brain biomolecular processes and the fine-scale structure of the universe (Penrose & Hameroff, 2011), a fascinating concept.

Dear James, many thanks for your comments! As far as I know, Hameroff's theory is about conformational changes of microtubule proteins in neurons. The connection of ions with water and proteins in astrocytes is very different. Astrocyte have calcium ion waves in the endoplasmatic reticulum (ER) and in cytoplasm microdomains (not microtubules). I am not sure if the release of calcium ions from the ER is through microtubules. I am also not sure about the structure of these microdomains. I thought they were structured by glial fibrillary acidic proteins, but an expert recently told me that these proteins are not so frequent in all types of astrocyte. 

Dear James, thank you for that clarification. Since glia cells have their name because of their glue-like function and collagen is a glue-like substance, my mind led me to put those two together... one of the pitfalls of being a linguist and practitioner of pattern recognition. 

Thanks Alfredo. I briefly looked into Vera Maura's page, and will read the article you refer to when I find the time. As you can see by the delay in my response, I was busy elsewhere... Gotta go.

To be fair, I should also post some results that seem to indicate that astrocyte activities are not involved in signaling processes directly related to conscious activities. The main "negative" result was obtained with genetically modified mice (see link to the free access paper below).  

From the Abstract of the paper: "Assuming that astrocytic Ca2+ fluxes play a critical role in synaptic physiology, it would be predicted that elimination of astrocytic Ca2+ fluxes would lead to marked changes in behavioral tests. Here, we tested this hypothesis by conducting a broad series of behavioral tests that recruited multiple brain regions, on an IP3R2 conditional knockout mouse model. We present the novel finding that behavioral processes are unaffected by lack of astrocyte IP3R-mediated Ca2+ signals. IP3R2 cKO animals display no change in anxiety or depressive behaviors, and no alteration to motor and sensory function. Morris water maze testing, a behavioral correlate of learning and memory, was unaffected by lack of astrocyte IP3R2-mediated Ca2+-signaling. Therefore, in contrast to the prevailing literature, we find that neither receptor-driven astrocyte Ca2+ fluxes nor, by extension, gliotransmission is likely to be a major modulating force on the physiological processes underlying behavior."

Some questions to be made to the authors are:

a) Is it correct to conclude that the lack of behavioral sings implies that these animals do not experience anxiety or depressive conscious feelings?

b) Did you make optical registers to prove the absence of astroglial calcium waves in the genetically modified animals?

c) Would you expect that these animals do not have calcium waves generated by the action of the Ryanodyne receptor in Ca2+ ions trapped in the endoplasmatic reticulum? It is well known that these waves can be generated by both RyR and IP3Rs. Blocking IP3 would not impair RyR action.

http://journal.frontiersin.org/article/10.3389/fnbeh.2014.00384/abstract

On the "positive" side, here (see link below) is an article about the continuation of MIT's Mriganka Sur Lab line of research that began with Schummers (2008 - see above in the question's main text). Thanks to Brian Flanagan for sending this link to me!

The key word in the title is "critically"!

http://scitechdaily.com/study-suggests-that-astrocytes-are-critically-important-for-processing-sensory-information/

A "neutral" result showing that one subtype of metabotropic glutamate receptor is more active during development, and another type is more active in adults (link to free access paper below).

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3569008/

Some years ago I saw a videoclip of an astrocyte laying down a pathway along which a dentrite -or an axon, I can't remember- was growing. I have tried to find this video and have not been able to do so. Has anybody in this forum seen it and can give me the link to it?

Are you sure it was not and oligoglia?

During development, it may have been the astrocyte too...but I do not have the video

I do not now nor have ever had the video

I am not sure it was an astrocyte, it may very well have been an oligoglia.

Great method, but looking for the right kind of event (astroglial calcium waves modulating mental functions) in the wrong place (the cerebellum):

Glia. 2015 Dec 9. doi: 10.1002/glia.22947. [Epub ahead of print]

Probabilistic encoding of stimulus strength in astrocyte global calcium signals.

Croft W, Reusch K, Tilunaite A, Russell NA, Thul R, Bellamy TC.

Abstract

Astrocyte calcium signals can range in size from subcellular microdomains to waves that spread through the whole cell (and into connected cells). The differential roles of such local or global calcium signaling are under intense investigation, but the mechanisms by which local signals evolve into global signals in astrocytes are not well understood, nor are the computational rules by which physiological stimuli are transduced into a global signal. To investigate these questions, we transiently applied receptor agonists linked to calcium signaling to primary cultures of cerebellarastrocytes. Astrocytes repetitively tested with the same stimulus responded with global signals intermittently, indicating that each stimulus had a defined probability for triggering a response. The response probability varied between agonists, increased with agonist concentration, and could be positively and negatively modulated by crosstalk with other signaling pathways. To better understand the processes determining the evolution of a global signal, we recorded subcellular calcium "puffs" throughout the whole cell during stimulation. The key requirement for puffs to trigger a global calcium wave following receptor activation appeared to be the synchronous release of calcium from three or more sites, rather than an increasing calcium load accumulating in the cytosol due to increased puff size, amplitude, or frequency. These results suggest that the concentration of transient stimuli will be encoded into a probability of generating a global calcium response, determined by the likelihood of synchronous release from multiple subcellular sites. GLIA 2015.

It was a max. 2 minute video of some kind of glia cell sending out a ramification and an axon growing along that process.I'd love to see it again.

In trying to find out more about the different types of glial cells, in response to Lewis's answer, I came across the site below. I have not seen it in the list of studies you name. Maybe you find something of interest to you.

Diversity of synaptic astrocyte–neuron signaling is an article in the e-Neuroforum of Network Glia http://www.networkglia.eu/en/networks  This is the direct link to the forum: http://networkglia.eu/sites/networkglia.eu/files/pdf/neuroforum/engl/2015-3.pdf

Dear All, I ask for comments on this finding. The abstract (below) is a commentary on another paper by Habbas et al. (2015) - see link to the DOI.

My wishes of Happy Christmas to all participants in this thread!

Cell. 2015 Dec 17;163(7):1574-6. doi: 10.1016/j.cell.2015.12.001.

Astrocytes Underlie Neuroinflammatory Memory Impairment.

Osso LA, Chan JR.

Neuroinflammation is being increasingly recognized as a potential mediator of

cognitive impairments in various neurological conditions. Habbas et al.

demonstrate that the pro-inflammatory cytokine tumor necrosis factor alpha

signals through astrocytes to alter synaptic transmission and impair cognition in

a mouse model of multiple sclerosis.

http://dx.doi.org/10.1016/j.cell.2015.11.023

Astrocytes, gastrointestinal and somatic and pain in a free access new paper:

Front Cell Neurosci. 2015 Oct 13;9:412. doi: 10.3389/fncel.2015.00412.

eCollection 2015.

Role of satellite glial cells in gastrointestinal pain.

Hanani M.

Gastrointestinal (GI) pain is a common clinical problem, for which effective

therapy is quite limited. Sensations from the GI tract, including pain, are

mediated largely by neurons in the dorsal root ganglia (DRG), and to a smaller

extent by vagal afferents emerging from neurons in the nodose/jugular ganglia.

Neurons in rodent DRG become hyperexcitable in models of GI pain (e.g., gastric

or colonic inflammation), and can serve as a source for chronic pain. Glial cells

are another element in the pain signaling pathways, and there is evidence that

spinal glial cells (microglia and astrocytes) undergo activation (gliosis) in

various pain models and contribute to pain. Recently it was found that satellite

glial cells (SGCs), the main type of glial cells in sensory ganglia, might also

contribute to chronic pain in rodent models. Most of that work focused on somatic

pain, but in several studies GI pain was also investigated, and these are

discussed in the present review. We have shown that colonic inflammation induced

by dinitrobenzene sulfonic acid (DNBS) in mice leads to the activation of SGCs in

DRG and increases gap junction-mediated coupling among these cells. This coupling

appears to contribute to the hyperexcitability of DRG neurons that innervate the

colon. Blocking gap junctions (GJ) in vitro reduced neuronal hyperexcitability

induced by inflammation, suggesting that glial GJ participate in SGC-neuron

interactions. Moreover, blocking GJ by carbenoxolone and other agents reduces

pain behavior. Similar changes in SGCs were also found in the mouse nodose

ganglia (NG), which provide sensory innervation to most of the GI tract.

Following systemic inflammation, SGCs in these ganglia were activated, and

displayed augmented coupling and greater sensitivity to the pain mediator ATP.

The contribution of these changes to visceral pain remains to be determined.

These results indicate that although visceral pain is unique, it shares basic

mechanisms with somatic pain, suggesting that therapeutic approaches to both pain

types may be similar. Future research in this field should include additional

types of GI injury and also other types of visceral pain.

A great new paper here in RG (link below)

Article A New Outlook on Mental Illnesses: Glial Involvement Beyond the Glue

I agree

Article Mediation by cyclic AMP of hormone-stimulated glycogenolysis...

Another great review by Magistretti's Lausanne University group - here in RG.

Article Astrocytes: New Targets for the Treatment of Neurodegenerati...

The rise and fall and rise of Glutamate as an effector on astrocytes: "In contrast to existing observations in mice, we found that mature human astrocytes respond robustly to glutamate." (see link below)

http://www.cell.com/neuron/abstract/S0896-6273(15)01019-3

Dear Alfredo! Thank you for promising ideas in the articles. Glial cells in the order of magnitude greater than the nerve in the brain. This glial army not only in the baggage hold. The function of glial diverse than we thought before.

Astrocytes are active and respond robustly to norepinephrine

Article Mediation by cyclic AMP of hormone-stimulated glycogenolysis...

More on astrocytes and major depressive disorder:

Neuroscience. 2015 Dec 30. pii: S0306-4522(15)01137-9. doi:

10.1016/j.neuroscience.2015.12.044. [Epub ahead of print]

Density of GFAP-immunoreactive astrocytes is decreased in left hippocampi in

major depressive disorder.

Cobb JA(1), O'Neill K(1), Milner J(1), Mahajan GJ(1), Lawrence TJ(1), May WL(2),

Miguel-Hidalgo J(1), Rajkowska G(1), Stockmeier CA(3).

Author information:

(1)Department of Psychiatry and Human Behavior, University of Mississippi Medical

Center, Jackson, MS 39216, USA. (2)School of Health Related Professions,

University of Mississippi Medical Center, Jackson, MS 39216, USA. (3)Department

of Psychiatry and Human Behavior, University of Mississippi Medical Center,

Jackson, MS 39216, USA; Department of Psychiatry, Case Western Reserve

University, Cleveland, OH 44106, USA. Electronic address: [email protected].

Neuroimaging and postmortem studies of subjects with major depressive disorder

(MDD) reveal smaller hippocampal volume with lengthening duration of illness.

Pathology in astrocytes may contribute significantly to this reduced volume and

to the involvement of the hippocampus in MDD. Postmortem hippocampal tissues were

collected from 17 subjects with MDD and 17 psychiatrically-normal control

subjects. Sections from the body of the hippocampus were immunostained for glial

fibrillary acidic protein (GFAP), a marker of intermediate filament protein

expressed in astrocytes. The density of GFAP-immunoreactive astrocytes was

measured in the hippocampus using 3-dimensional cell counting. Hippocampal

subfields were also assessed for GFAP-immunoreactive area fraction. In CA1, there

was a significant positive correlation between age and either density or area

fraction in MDD. The density of astrocytes in the hilus, but not CA1 or CA2/3,

was significantly decreased only in depressed subjects not taking an

antidepressant drug, but not for depressed subjects taking an antidepressant

drug. The area fraction of GFAP-immunoreactivity was significantly decreased in

the dentate gyrus in women but not men with depression. In CA2/3, the area

fraction of GFAP-immunoreactivity was inversely correlated with the duration of

depression in suicide victims. Astrocyte contributions to neuronal function in

the hilus may be compromised in depressed subjects not taking antidepressant

medication. Due to the cross-sectional nature of the present study of postmortem

brain tissue, it remains to be determined whether antidepressant drug treatment

prevented a decrease in GFAP-immunoreactive astrocyte density or restored cell

density to normal levels.

A PubMed search on 'astrocyte" today (selection from the first page):

1. Front Integr Neurosci. 2016 Jan 11;9:63. doi: 10.3389/fnint.2015.00063.

eCollection 2015.

Role of Glia in Stress-Induced Enhancement and Impairment of Memory.

Pearson-Leary J(1), Osborne DM(2), McNay EC(3).

Author information:

(1)Department of Anesthesiology and Critical Care Medicine, Children's Hospital

of Philadelphia Philadelphia, PA, USA. (2)R.S. Dow Neurobiology Department,

Legacy Research Institute Portland, OR, USA. (3)Behavioral Neuroscience and

Biology, University at Albany Albany, NY, USA.

Both acute and chronic stress profoundly affect hippocampally-dependent learning

and memory: moderate stress generally enhances, while chronic or extreme stress

can impair, neural and cognitive processes. Within the brain, stress elevates

both norepinephrine and glucocorticoids, and both affect several genomic and

signaling cascades responsible for modulating memory strength. Memories formed at

times of stress can be extremely strong, yet stress can also impair memory to the

point of amnesia. Often overlooked in consideration of the impact of stress on

cognitive processes, and specifically memory, is the important contribution of

glia as a target for stress-induced changes. Astrocytes, microglia, and

oligodendrocytes all have unique contributions to learning and memory.

Furthermore, these three types of glia express receptors for both norepinephrine

and glucocorticoids and are hence immediate targets of stress hormone actions. It

is becoming increasingly clear that inflammatory cytokines and immunomodulatory

molecules released by glia during stress may promote many of the behavioral

effects of acute and chronic stress. In this review, the role of traditional

genomic and rapid hormonal mechanisms working in concert with glia to affect

stress-induced learning and memory will be emphasized.

PMID: 26793072 [PubMed]

2. Front Cell Neurosci. 2016 Jan 12;9:509. doi: 10.3389/fncel.2015.00509.

eCollection 2015.

The Role of Astroglia in the Antidepressant Action of Deep Brain Stimulation.

Etiévant A(1), Lucas G(2), Dkhissi-Benyahya O(3), Haddjeri N(3).

Author information:

(1)Integrative and Clinical Neurosciences EA481, University of Bourgogne

Franche-ComtéBesançon, France; CHRU BesançonBesançon, France. (2)Institut

François Magendie, Institut National de la Santé et de la Recherche Médicale

U862, University of Bordeaux Bordeaux, France. (3)Stem Cell and Brain Research

Institute, Institut National de la Santé et de la Recherche Médicale U1208Bron,

France; University of Lyon, University of Lyon ILyon, France.

PMID: 26793061 [PubMed]

3. Front Integr Neurosci. 2016 Jan 11;9:69. doi: 10.3389/fnint.2015.00069.

eCollection 2015.

Astrocytes Modulate Local Field Potential Rhythm.

Tewari SG(1), Parpura V(2).

Author information:

(1)Molecular and Integrative Physiology, University of Michigan Ann Arbor, MI,

USA. (2)Department of Neurobiology, University of Alabama at Birmingham

Birmingham, AL, USA.

PMID: 26793075 [PubMed]

4. Prog Neurobiol. 2016 Jan 12. pii: S0301-0082(15)30021-6. doi:

10.1016/j.pneurobio.2016.01.001. [Epub ahead of print]

Astrogliosis: an integral player in the pathogenesis of Alzheimer's Disease.

Osborn LM(1), Kamphuis W(2), Wadman WJ(1), Hol EM(3).

Author information:

(1)Swammerdam Institute for Life Sciences, Center for Neuroscience, University of

Amsterdam, Amsterdam, 1098 XH, The Netherlands. (2)Netherlands Institute for

Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences,

Amsterdam, 1105 BA, The Netherlands. (3)Swammerdam Institute for Life Sciences,

Center for Neuroscience, University of Amsterdam, Amsterdam, 1098 XH, The

Netherlands; Netherlands Institute for Neuroscience, An Institute of the Royal

Netherlands Academy of Arts and Sciences, Amsterdam, 1105 BA, The Netherlands;

Department of Translational Neuroscience, Brain Center Rudolf Magnus, University

Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. Electronic address:

[email protected].

Alzheimer's disease is the main cause of dementia in the elderly and begins with

a subtle decline in episodic memory followed by a more general decline in overall

cognitive abilities. Though the exact trigger for this cascade of events remains

unknown the presence of the misfolded amyloid-beta protein triggers reactive

gliosis, a prominent neuropathological feature in the brains of Alzheimer's

patients. The cytoskeletal and morphological changes of astrogliosis are its

evident features, while changes in oxidative stress defense, cholesterol

metabolism, and gene transcription programs are less manifest. However, these

latter molecular changes may underlie a disruption in homeostatic regulation that

keeps the brain environment balanced. Astrocytes in Alzheimer's disease show

changes in glutamate and GABA signaling and recycling, potassium buffering, and

in cholinergic, purinergic, and calcium signaling. Ultimately the dysregulation

of homeostasis maintained by astrocytes can have grave consequences for the

stability of microcircuits within key brain regions. Specifically, altered

inhibition influenced by astrocytes can lead to local circuit imbalance with

farther reaching consequences for the functioning of larger neuronal networks.

Healthy astrocytes have a role in maintaining and modulating normal neuronal

communication, synaptic physiology and energy metabolism, astrogliosis interferes

with these functions. This review considers the molecular and functional changes

occurring during astrogliosis in Alzheimer's disease, and proposes that

astrocytes are key players in the development of dementia.

Copyright © 2016. Published by Elsevier Ltd.

PMID: 26797041 [PubMed - as supplied by publisher]

5. Front Cell Neurosci. 2016 Jan 12;9:508. doi: 10.3389/fncel.2015.00508.

eCollection 2015.

Editorial: Cytokines as Players of Neuronal Plasticity and Sensitivity to

Environment in Healthy and Pathological Brain.

Alboni S(1), Maggi L(2).

Author information:

(1)Department of Life Sciences, University of Modena and Reggio Emilia Modena,

Italy. (2)Department of Physiology and Pharmacology, Sapienza University Rome,

Italy.

PMID: 26793060 [PubMed]

Dear Alfredo! Dear all! Glial cell is almost 10 times more than neurons in the brain. Glia diverse functions that need to be considered in modern models of neural networks. Otherwise, these models will be constantly weaker performance real neural networks.

Dear Vladimir, the proportion of glia and neurons is different in different brain regions. In the brain stem, limbic system and neocortex (all these regions important for conscious activity) there are more glia than neurons; in the cerebellum (less important for conscious activity) there are more neurons than glia.

There is a controversy about the proportion in the whole brain. Brazilian researchers have argued that the proportion is close to 1 to 1 in the total system. However, it is clear that in regions more important for conscious activity there are far more glia than neurons!

The scientific revolution moves forward (see link):

Astrocyte calcium signaling: the third wave

Narges Bazargani & David Attwell

Abstract: The discovery that transient elevations of calcium concentration occur in astrocytes, and release 'gliotransmitters' which act on neurons and vascular smooth muscle, led to the idea that astrocytes are powerful regulators of neuronal spiking, synaptic plasticity and brain blood flow. These findings were challenged by a second wave of reports that astrocyte calcium transients did not mediate functions attributed to gliotransmitters and were too slow to generate blood flow increases. Remarkably, the tide has now turned again: the most important calcium transients occur in fine astrocyte processes not resolved in earlier studies, and new mechanisms have been discovered by which astrocyte [Ca2+]i is raised and exerts its effects. Here we review how this third wave of discoveries has changed our understanding of astrocyte calcium signaling and its consequences for neuronal function.

http://www.nature.com/neuro/journal/v19/n2/full/nn.4201.html

The full size figures and legends of the Bazargani and Attwell paper can be seen by non-subscribers of Nature Neuroscience (link below)

http://www.nature.com/neuro/journal/v19/n2/fig_tab/nn.4201_ft.html

Feeling of pain related to astrocyte calcium waves (Bold marks by APJ):

J Neurosci. 2016 Jan 20;36(3):1008-18. doi: 10.1523/JNEUROSCI.2768-15.2016.

Chronic Neuropathic Pain: It's about the Rhythm.

Alshelh Z(1), Di Pietro F(1), Youssef AM(1), Reeves JM(1), Macey PM(2), Vickers

ER(1), Peck CC(3), Murray GM(3), Henderson LA(4).

Author information:

(1)Department of Anatomy and Histology and. (2)School of Nursing and Brain

Research Institute, University of California, Los Angeles, Los Angeles,

California 90095. (3)Faculty of Dentistry, University of Sydney, Sydney, New

South Wales 2006, Australia, and. (4)Department of Anatomy and Histology and

[email protected].

The neural mechanisms underlying the development and maintenance of chronic

neuropathic pain remain unclear. Evidence from human investigations suggests that

neuropathic pain is associated with altered thalamic burst firing and

thalamocortical dysrhythmia. Additionally, experimental animal investigations

show that neuropathic pain is associated with altered infra-slow (

One more review of recent results: 

Trends Cell Biol. 2016 Feb 16.

doi: 10.1016/j.tcb.2016.01.003. [Epub ahead of print]

Probing the Complexities of Astrocyte Calcium Signaling.

Shigetomi E, Patel S, Khakh BS.

 Abstract

Astrocytes are abundant glial cells that tile the entire central nervous system and mediate well-established functions for neurons, blood vessels, and other glia. These ubiquitous cells display intracellular Ca2+ signals, which have been intensely studied for 25 years. Recently, the use of improved methods has unearthed the panoply of astrocyte Ca2+ signals and a variable landscape of basal Ca2+ levels. In vivo studies have started to reveal the settings under which astrocytes display behaviorally relevant Ca2+ signaling. Studies in mice have emphasized how astrocyte Ca2+ signaling is altered in distinct neurodegenerative diseases. Progress in the past few years, fueled by methodological advances, has thus reignited interest inastrocyte Ca2+ signaling for brain function and dysfunction.

Dear All:

Do not miss Video 1 (link below) of the paper:

Nat Protoc. 2016 Mar;11(3):566-97.

doi: 10.1038/nprot.2016.021.

Visualization of cortical, subcortical and deep brain neural circuit dynamics during naturalistic mammalian behavior with head-mounted microscopes and chronically implanted lenses.

Resendez SL, Jennings JH, Ung RL, Namboodiri VM, Zhou ZC, Otis JM, Nomura H, McHenry JA, Kosyk O, Stuber GD.

Abstract

Genetically encoded calcium indicators for visualizing dynamic cellular activity have greatly expanded our understanding of the brain. However, owing to the light-scattering properties of the brain, as well as the size and rigidity of traditional imaging technology, in vivo calcium imaging has been limited to superficial brain structures during head-fixed behavioral tasks. These limitations can now be circumvented by using miniature, integrated microscopes in conjunction with an implantable microendoscopic lens to guide light into and out of the brain, thus permitting optical access to deepbrain (or superficial) neural ensembles during naturalistic behaviors. Here we describe steps to conduct such imaging studies using mice. However, we anticipate that the protocol can be easily adapted for use in other small vertebrates. Successful completion of this protocol will permit cellular imaging of neuronal activity and the generation of data sets with sufficient statistical power to correlate neural activity with stimulus presentation, physiological state and other aspects of complex behavioral tasks. This protocol takes 6-11 weeks to complete.

http://www.nature.com/nprot/journal/v11/n3/full/nprot.2016.021.html#videos

G R E A T! (As I have predicted) Open access! (PDF below)

NATURE COMMUNICATIONS | ARTICLE OPEN

Calcium imaging reveals glial involvement in transcranial direct current stimulation-induced plasticity in mouse brain

Hiromu Monai, Masamichi Ohkura, Mika Tanaka, Yuki Oe, Ayumu Konno, Hirokazu Hirai, Katsuhiko Mikoshiba, Shigeyoshi Itohara, Junichi Nakai, Youichi Iwai & Hajime Hirase

Nature Communications 7, Article number: 11100

doi:10.1038/ncomms11100

Received 20 January 2016

Accepted 19 February 2016

Published 22 March 2016

Abstract

Transcranical direct current stimulation (tDCS) is a treatment known to ameliorate various neurological conditions and enhance memory and cognition in humans. tDCS has gained traction for its potential therapeutic value; however, little is known about its mechanism of action. Using a transgenic mouse expressing G-CaMP7 in astrocytes and a subpopulation of excitatory neurons, we find that tDCS induces large-amplitude astrocytic Ca2+ surges across the entire cortex with no obvious changes in the local field potential. Moreover, sensory evoked cortical responses are enhanced after tDCS. These enhancements are dependent on the alpha-1 adrenergic receptor and are not observed in IP3R2 (inositol trisphosphate receptor type 2) knockout mice, in which astrocytic Ca2+ surges are absent. Together, we propose that tDCS changes the metaplasticity of the cortex through astrocytic Ca2+/IP3 signalling.

Subject terms:

Biological sciences

Neuroscience

Reduced Glu uptake in astrocytes related to anxiety

Front Cell Neurosci. 2015 Jun 3;9:219. doi: 10.3389/fncel.2015.00219. eCollection

2015.

Long-term NMDAR antagonism correlates reduced astrocytic glutamate uptake with

anxiety-like phenotype.

Zimmer ER(1), Torrez VR(1), Kalinine E(2), Augustin MC(1), Zenki KC(1), Almeida

RF(1), Hansel G(1), Muller AP(3), Souza DO(1), Machado-Vieira R(4), Portela

LV(1).

Author information:

(1)Department of Biochemistry, Universidade Federal do Rio Grande do Sul Porto

Alegre, Brazil. (2)Department of Biochemistry, Universidade Federal do Rio Grande

do Sul Porto Alegre, Brazil ; Department of Physiology, Universidade Federal de

Sergipe São Cristovão, Brazil. (3)Department of Biochemistry, Universidade

Federal do Rio Grande do Sul Porto Alegre, Brazil ; Laboratory of Exercise,

Biochemistry and Physiology, Universidade do Extremo Sul Catarinense Criciúma,

Brazil. (4)Laboratory of Neuroscience, LIM-27, Institute and Department of

Psychiatry, Universidade de São Paulo São Paulo, Brazil ; Center for

Interdisciplinary Research on Applied Neurosciences (NAPNA), Universidade de São

Paulo São Paulo, Brazil ; Experimental Therapeutics and Pathophysiology Branch,

National Institute of Mental Health, National Institutes of Health Bethesda, MD,

USA.

Erratum in

Front Cell Neurosci. 2016;10:93.

The role of glutamate N-methyl-D-aspartate receptor (NMDAR) hypofunction has been

extensively studied in schizophrenia; however, less is known about its role in

anxiety disorders. Recently, it was demonstrated that astrocytic GLT-1 blockade

leads to an anxiety-like phenotype. Although astrocytes are capable of modulating

NMDAR activity through glutamate uptake transporters, the relationship between

astrocytic glutamate uptake and the development of an anxiety phenotype remains

poorly explored. Here, we aimed to investigative whether long-term antagonism of

NMDAR impacts anxiety-related behaviors and astrocytic glutamate uptake.

Memantine, an NMDAR antagonist, was administered daily for 24 days to healthy

adult CF-1 mice by oral gavage at doses of 5, 10, or 20 mg/kg. The mice were

submitted to a sequential battery of behavioral tests (open field, light-dark box

and elevated plus-maze tests). We then evaluated glutamate uptake activity and

the immunocontents of glutamate transporters in the frontoparietal cortex and

hippocampus. Our results demonstrated that long-term administration of memantine

induces anxiety-like behavior in mice in the light-dark box and elevated

plus-maze paradigms. Additionally, the administration of memantine decreased

glutamate uptake activity in both the frontoparietal cortex and hippocampus

without altering the immunocontent of either GLT-1 or GLAST. Remarkably, the

memantine-induced reduction in glutamate uptake was correlated with enhancement

of an anxiety-like phenotype. In conclusion, long-term NMDAR antagonism with

memantine induces anxiety-like behavior that is associated with reduced glutamate

uptake activity but that is not dependent on GLT-1 or GLAST protein expression.

Our study suggests that NMDAR and glutamate uptake hypofunction may contribute to

the development of conditions that fall within the category of anxiety disorders.

PMCID: PMC4452887

PMID: 26089779 [PubMed]

The free access paper below (see link) does not have an Abstract, then I pasted the Intro and the Conclusion

J Pharmacol Pharmacother. 2016 Jan-Mar; 7(1): 22–24.

doi:  10.4103/0976-500X.179357

PMCID: PMC4831484

Inhibition of astrocyte activation is involved in the prevention of postoperative latent pain sensitization by ketamine and gabapentin in mice

Elizabeth Romero-Alejo, Margarita M. Puig, and Asunción Romero

"The pharmacologic management of postoperative pain has currently a double purpose: On one hand to reduce the intensity of the acute pain after surgery, and, on the other hand, to prevent the development of chronic postsurgical pain. Previous studies have shown that an inhibition of the glial activation is involved in the prevention of postoperative hyperalgesia (POH) by ketamine (KET) and gabapentin (GBP).[1,2] However, only a few data exist on the involvement of the glial activation in the prevention of the postoperative latent pain sensitization (PS) mediated by KET or GBP.

... ...

Our findings indicate that the antihyperalgesic effects of KET and GBP, two of the most important adjuvants currently employed in clinical practice to prevent chronic pain after surgery, could be partially mediated by an inhibition of microglia and astrocyte activation. It is known that N-methyl-D-aspartate -nitric oxide (NMDA-NO) pathways are involved in the development of hypersensitivity, and NO promotes glial fibrillary acidic protein expression in astrocytes.[4] Thus, the blockade of NMDA by KET could suppress NO liberation by NMDA neuronal receptors through the reduction of astrocyte immunoreactivity. The decrease of spinal glial activation by GBP could be due to an indirect modulation of the neuronal voltage-gated calcium channels α2/δ-1 subunits,[5] concurrent with Ca2+-dependent glutamate release from astrocytes.[6]

To the best of our knowledge, this is the first time that a delayed astrocytic activation, concomitant with a PS partial inhibition, has been shown to be partially prevented by KET and GBP in a model of post incisional pain. Further studies are warranted."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831484/

Things are changing, dear Alfredo. Hillary might not be running...

Best regards, Lilliana

Dear Lilliana, things are changing both in politics and neuroscience! I hope the changes are not for worse...I am confident on the astrocyte research to help us understanding how consciousness is generated in the brain, and on Sanders for a fresh new air into the binary system of USA politics!