1
Meta-Potentiation: Neuro-Astroglial Interactions Supporting Perceptual
Consciousness
Alfredo Pereira Jr.* and Fábio Augusto Furlan**
*Adjunct Professor - Institute of Biosciences - São Paulo State University
(UNESP) - 18618-000 - Botucatu-SP - Brasil; e-mail: apj@ibb.unesp.br
** Assistant Professor - Faculty of Medicine and Nursing - University of
Marília - e-mail: fabioaugustofurlan@yahoo.com.br
Abstract
Conscious perceptual processing involves the sequential activation of cortical
networks at several brain locations, and the onset of oscillatory synchrony
affecting the same neuronal population. How do the earlier activated circuits
sustain their excitation to synchronize with the later ones? We call such a
sustaining process "meta-potentiation", and propose that it depends on neuro-
astroglial interactions. In our proposed model, attentional cholinergic and
stimulus-related glutamatergic inputs to astroglia elicit the release of astroglial
glutamate to bind with neuronal NMDA receptors containing the NR2B
subunit. Once calcium channels are open, slow inward currents activate the
CaM/CaMKII complex to phosphorylate AMPA receptors in a population of
neurons connected with the astrocyte, thus amplifying the local excitatory
pattern to participate in a larger synchronized assembly that supports
consciousness.
Key-words
Meta-potentiation, Consciousness, Oscillatory Synchrony, Astrocyte, Slow
Inward Currents.
1 - Introduction
Two fields of experimental research have contributed to the progress in
the scientific study of consciousness: a) neuroimaging combined with the
performance of cognitive tasks and linguistic report of conscious states by
human subjects (Lloyd, 2002; Kamitami and Tong, 2005; Rees, 2007), and b)
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single and multichannel records of brain activity during cognitive tasks (Coull,
1998, Rodriguez et al., 1999).
Several results indicate that the occurrence of conscious processing
correlates with the brain hemodynamic response and oscillatory synchrony.
This correlation is, of course, too vague to count as an explanation, as they
may also be related to unconscious processes (e.g. 3 Hz oscillations in Slow-
Wave Sleep).
In this paper, we attempt to move one step forward into the
identification of a closer correlate of consciousness, a kind of activity that is
present only when conscious processing occurs. Our strategy to find a
univocal correlate of consciousness is to search for a kind of brain activity that
underlies both hemodynamic responses and oscillatory synchrony, and then to
make an analysis of the components of this activity to identify those that
satisfy suitable temporal and populational criteria.
Based on the work of Logothetis et al. (2001) and Logothetis and
Pfeuffer (2004), we found that the hemodynamic response measured by
BOLD fMRI is closely related to Local Field Potentials (LFPs). LFPs are
complex phenomena reflecting simultaneous slow synaptic activities of
neuronal populations. These activities include excitatory and inhibitory
postsynaptic potentials, and several modalities of membrane afterpotentiation.
Some but not all mechanisms underlying the generation of LFPs probably
participate in the generation of the kinds of oscillatory synchrony related with
conscious processing. Which are the components of LFPs specifically related
to conscious processing?
In order to find an answer to the question, we use two criteria. First, the
consciousness-related component(s) should be able to sustain a continuous
sequence of excitatory postsynaptic potentials (EPSP) from around 200
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milliseconds to 2/3 seconds, to allow conscious processing to occur. Second,
the consciousness-related LFP component(s) cannot be restricted to the single
neuron, but should affect a large cellular population, in order to elicit
oscillatory synchrony (and also to have an impact on the hemodynamic
response).
We suggest that neuro-astroglial interactions (Antanitus, 1998) provide
the link between local and global excitatory patterns. These interactions occur
at the glutamatergic tripartite synapse, where the release of presynaptic
glutamate - and other mediators - induces calcium waves in astrocytes, leading
to the release of astroglial glutamate and the resulting activation of NMDA
receptors of the postsynaptic neurons and other neurons connected to the
astrocyte.
Such a conjoint activation elicits the formation of a local assembly that
propagates the excitation to other parts of the brain, triggering oscillatory
synchrony and then the formation of a large-scale functional assembly
putatively supporting perceptual consciousness. This phenomenon provides
broad afterpotentiation effects in neurons pertaining to the functional
assembly, providing the sustaining of excitation in lower-order (sensory)
cortical areas while the sequence of activations reach higher-order
(associative) cortical areas.
We call this afterpotentiation effect meta-potentiation, in order to
distinguish it from other modalities of membrane potentiation, as well as from
other kinds of afterpotentiation effects. Meta-potentiation is proposed to be a
necessary mechanism to make possible the phase-locking of membrane
electric oscillations in perceptually activated brain circuits, forming a
functional collective.
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2 On the Temporal Dynamics of Consciousness
Available data (Laureys, 2005; Buszáki, 2007) indicate that conscious
processing requires the co-activation of a large network of brain systems. In
perceptual processes, in order to achieve a global coherent pattern of
activation, the brain begins with the formation of distributed LFPs in primary
sensory areas. Each sensory neuron (or each small-scale functional assembly
in cortical tissue) responds to one aspect of the stimulus (the "receptive
field"). The local sum of activity - composing a LFP - is well correlated with
hemodynamic changes detected by BOLD fMRI.
As soon as local fields are generated, the brain uses another mechanism
to integrate local patterns into a global pattern of activity. This strategy
implies that each local field participating in the generation of a conscious
episode should be sustained for some time, even after the decay of stimulation.
During this period of sustained activity they possibly interact with other local
fields, spatially distributed in the brain, to generate the content of a conscious
perceptual episode.
The identification of the temporal dynamics of consciousness by means
of behavioral events is difficult, since in many cases conscious perception
emerges after the triggering of a behavioral response. Consciousness can
occur 500 ms after the beginning of a behavioral response, according to Libet
(1973, 2004).
Reaction times are also relative to the perceptual modalities involved,
and proportional to the inter-modal integrative and supplementary cognitive
processes necessary to generate the behavioral response to the presented
stimulus. They are typically shorter for single-modality signal detection, and
progressively longer for multimodal integration and for tasks that require
cognitive processing and/or selection of alternatives.
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Pöppel and Logothetis (1986) measured reaction times to visual stimuli,
and calculated that perceptual processing operates in units of 30 milliseconds.
This result is consistent with the role of gamma synchronous oscillations in
conscious perception (Poppel et al., 1990). It can also be applied to auditory
processing and inter-hemispheric integration required by a sensory-motor task
(Pöppel, Schill and von Steinbüchel, 1990).
Based on these results, Pöppel proposed a model of conscious
perceptual processing containing two temporal constraints. The basic unit is
estimated to be around 30 ms, while conscious episodes composing the
"conscious present" can be extended to periods of 2 or 3 seconds (Pöppel,
1994).
Progress in the estimative of the temporal dynamics of conscious
perceptual processing came from the measurement of brain events directly
correlated to the processing (not to the behavioral response). This strategy is
used in the Event-Related Potential (ERP) paradigm. Measurement of the
temporal location of brain events correlated with conscious processing evoked
by stimulus presentation can be found in ERP studies in human subjects, some
of them involving linguistic processing. This method is able to measure
electric phenomena temporally correlated with conscious processing. For
instance, the ERP P300 and N400 components are related to working memory
and/or attention functions that probably involve conscious processing (Knight,
1997; Coull, 1998). The corresponding brain events occur from 300 to 400 ms
after stimulus presentation.
There are also other ERP that take longer temporal intervals to occur,
but for the purpose of this study we assume 200 ms to be a good estimative
about the minimum temporal duration from stimuli presentation to the
formation of a conscious percept. This interval is consistent with data from
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Rodriguez et al (1999). In the process of image (face) recognition, gamma
synchronous oscillations occurred at 230 and 800 ms after external
stimulation. This second synchronous period refers to a motor response, while
the first period correlated well to perceptual conscious processing.
Subtracting from the 230 ms interval the time necessary for sensory
transduction to the CNS and generation of unconscious activity at several
brain locations, the minimum latency time for conscious processing would be
around 200 ms. Therefore, the sustaining of neuronal activity necessary to
support conscious processing would range from 200 ms to 2/3 seconds. How
does the brain achieve this result?
3 - Meta-Potentiation
Earlier attempts to identify a univocal correlate of consciousness
focused on axonal spikes. Crick and Koch (1990) proposed that the neuronal
correlate of visual consciousness was the phase-locked firing of neurons at 40
Hertz. Later they refined the hypothesis, stating that increased spiking activity
at some cortical locations (with emphasis on bursting cells located at cortical
layer 5) would be more crucial for visual consciousness (Crick and Koch,
1994).
An increase in firing rates of input neurons is surely important to
generate neuronal excitation underlying the hemodynamic response (related to
the formation of LFPs) and synchronized oscillations in neuronal populations.
It is well known that presynaptic axonal spikes contribute to generate EPSPs
by means of releasing excitatory neurotransmitters at the axon terminal to bind
with postsynaptic membrane ionotropic receptors. This is a usual pathway by
which an increase in presynaptic firing rates becomes the cause of increase in
postsynaptic excitation.
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Studies on subliminal perception (Murphy and Zajonc, 1993) reveal that
the time of presentation of a stimulus is important to determine if it is
conscious or unconsciously perceived. A visual stimulus presented for only 5
ms and followed by a mask is not consciously perceived, although it may have
unconscious priming effects. This requirement implies that input firing is
necessary for perceptual consciousness, although not sufficient. According to
our previous analysis, temporal sustaining of neuronal activity (from the scale
of hundreds of milliseconds to the scale of seconds) and population
synchronization elicited by the input signal are required for conscious
processing.
Depending on their target, axonal spikes can also cause inhibitory
activity and membrane hyperpolarization. Logothetis (2001) showed that the
hemodynamic response overlaps with LFPs measured by extracellular
electrodes placed in the dendritic network, but not with the activity measured
by single-cell electrodes placed at the axon hillock of neurons, or by multiple-
unit activity. One of the reasons of such a non-correlation is that membrane
hyperpolarization can contribute to the magnitude of the fields and the
response, but not to an increase in firing rates of the same neurons. For the
sake of simplicity, in the following we will not consider the contribution of
hyperpolarization to the activity measured by fMRI.
The LFPs measured by Logothetis were elicited by sustained
stimulation (during intervals from 4 to 24 seconds). They depended on the
maintenance of high input spike rates at the measured regions. However, in
the study of consciousness we are mostly interested in what happens after
external stimulation ceases and the corresponding presynaptic spike rates
decay. What occurs after presynaptic stimulation ends?
There are four possibilities:
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a) postsynaptic excitation spontaneously decreases to the baseline;
b) postsynaptic excitation decreases to the baseline or below it, because of
an inhibitory action made by other neurons;
c) postsynaptic excitation is sustained, in the same neuronal population or
elsewhere, for a task that is independent of conscious processing; and
d) postsynaptic excitation is sustained, in the same neuronal population or
elsewhere, exclusively for conscious processing.
Considering that conscious processing requires an appropriate temporal
dynamics (from 200 ms to 2/3 secs), and considering that it does not always
depend on constant stimulation, we assume that the sustaining of postsynaptic
activity after the decay of presynaptic firing rates, leading to the onset of
oscillatory synchrony in a larger neuronal population, could be taken as a
reliable index of conscious processing.
With this assumption, the investigation should focus on postsynaptic
mechanisms that sustain neural excitation beyond 200 ms after the decay of
presynaptic stimulation. Since conscious processing is related to the activity of
LFPs and oscillatory synchrony, the mechanism implies the involvement of a
neuronal population to (putatively) integrate the activity of multiple LFPs
distributed along the brain into a unitary conscious episode.
The initially excited neuronal population has the role of triggering an
excitatory pattern in a larger population, being able to return to baseline or
become hyperpolarized soon after accomplishing this task. The dynamics of
excitatory activity that corresponds to conscious processing does not
necessarily affect the same neurons from the beginning to the end, but can be
temporally distributed in sequentially activated populations.
Therefore, the LFP component that is more closely related to conscious
processing is the one that leads to the generation of a global excitatory pattern
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affecting a large neuronal population. In order to identify this component, we
distinguish three postsynaptic phases:
a) excitatory postsynaptic response to presynaptic input: in the
glutamatergic synapse, the postsynaptic response lasts up to 150 ms
(Haydon and Carmignoto, 2006), and includes the sequential opening of
AMPA and NMDA channels, eliciting several processes that increase
the spiking activity of the postsynaptic neuron, and may also take part
in short-term and/or long-term potentiation (STP/LTP) processes;
b) afterpotentiation effects: following the beginning of the primary
postsynaptic response, a variety of excitatory processes occur,
generating several afterpotentiation effects. These processes include:
presynaptic reinforcement by means of retrograde messengers (nitric
oxide, arachidonic acid) promoted by activation of NMDARs;
backpropagation of potentials in each neuron; excitatory modulation of
ionotropic receptors by means of metabotropic receptor G-protein
pathways, and the opening of voltage-gated ion channels;
c) meta-potentiation: afterpotentiation effects trigger a continuous
sequence of events that reach a larger neuronal population exclusively
for the task of conscious processing. Considering that conscious
processing can extend to periods of 2/3 seconds, and involves sustained
excitation of large neuronal populations, the previously mentioned
neuronal mechanisms are not sufficient to generate it. We propose that
meta-potentiation can be explained by means of the participation of
astrocytes in tripartite synapses and extrasynaptic transmission.
An important note to the above definition is that the three proposed
postsynaptic phases can partially overlap, i.e., they compose a sequential
process in which the beginning of one phase necessarily precedes the
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beginning of another phase, but the ending of one phase does not have to
occur before the beginning of the next phase.
4 - Astroglial Contribution to Meta-Potentiation
Recent results on astroglia research indicate that these cells participate
in glutamatergic tripartite synapses (Haydon and Carmignoto, 2006),
contributing to the onset of synchrony (Fellin et al., 2004). Considering that
consciousness requires the coordination of local and global patterns of activity
in the brain (Buszáki, 2007), the above results qualify neuro-astroglial
mechanisms to be a link between local and global activity.
In our proposed model (Fig. 1), the excitatory period supporting
consciousness begins with presynaptic neuronal Glutamate (Glu) release and
binding with postsynaptic AMPA. The opening of this ionotropic receptor
triggers several excitatory activities, producing postsynaptic membrane
excitation that lasts up to 150 ms after presynaptic stimulation extinction.
While this excitation lasts, the presynaptic Glu also binds with NMDA
receptors belonging to neighbor astrocytes. Astrocytic NMDA receptors, upon
binding with presynaptically released Glu, induce calcium waves that promote
the release of astrocytic Glu, which binds with neuronal NMDA containing
the NR2B-type subunit.
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Fig. 1 Neuro-Astroglial Mechanism Promoting Meta-Potentiation of the
Postsynaptic Neuron in a Tripartite Synapse System.
In the awake state, calcium waves in the astrocytic syncytium are
previously activated by cholinergic input from neurons, generating high
calcium concentrations at the interface with the postsynaptic neuron. In this
condition, Glu release from the presynaptic neuron can prompt the release of
astroglial glutamate to bind with neuronal NMDA receptors containing the
NR2B subunit. The opening of these receptors elicits slow inward currents of
calcium ions. The ions enter the cell and bind to calmodulin (CaM) and
calmodulin-dependent kinase II (CaMKII) that completes the activating cycle
by phosphorylating AMPA. The same action of the astroglial cell on a
Glu
Ca
++
waves
AMPA
NR2A
NR2B
Dendritic
Spíne
Astrocyte
Axon
Ca
++
Ca
++
Na+
Glu
CaM/CaMKII
Ach
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neuronal population generates a larger excitatory pattern. By means of this
mechanism, the star-shaped astroglial network promotes the coordinated
excitation of a large neuronal population, triggering the phenomenon of
oscillatory synchrony.
The above model solves a theoretical problem originally identified by
Koch (2003, p. 17). The reciprocal activation of neuronal and astroglial
NMDA receptors requires the presence of high Ca++ concentrations in the
astrocytic terminal that releases Glu to the postsynaptic neuron. How to get
high Ca++ concentrations there 150 ms after presynaptic stimulation,
considering that Ca++ waves in the astrocytic syncytium are relatively slow
(in the scale of seconds)?
One solution is to consider that calcium waves are previously activated
during wakefulness. Their readiness for postsynaptic meta-potentiation
requires a previous activation of calcium waves in the astrocytic syncytium,
regularly made by cholinergic (Seigneur et al., 2006) and other mechanisms
(e.g., purinergic; see Di Garbo et al., 2006) during the awake state. One
possible signal-transduction pathway involved with cholinergic activation is
the increase of extracellular potassium caused by the spiking activity of the
postsynaptic neuron, leading to calcium influx to the astrocyte at the site of
interaction with the neuron (see Postnov et al., 2007). An implication of the
above solution is that during the awakening process the conscious brain would
take around 40 seconds to work properly (as discussed by Hobson, 1994).
Slow inward calcium currents through NMDARs can take several
seconds to occur, in the case of an exclusive presynaptic Glu activation, but
they can become "fast" relatively to the presynaptic excitatory signal, by
means of a previous cholinergic activation of calcium waves in astrocytes,
raising Ca++ concentrations at the interacting regions. Once Ca++
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concentration is high in these regions, the release of astrocytic Glu following a
presynaptic activation is relatively "fast" (beginning around 150 ms after the
initial phase of the EPSP).
In this condition, calcium currents that flow through NMDARs are able
to activate CaM and CaMKII, and then sustain the excitatory pattern elicited
in AMPA channels by the external stimulus. Such an extension of the EPSP
makes possible for the postsynaptic neuron to participate in a larger neuronal
assembly, together with neurons from other brain areas which were
sequentially activated by the same stimulation.
5 - Concluding Remarks
In summary, we propose that:
a) meta-potentiation of neuronal populations around tripartite synapses
sustains LFPs to participate in a larger collective response;
b) astrocytes are adequate to this task, since these cells, being star-shaped,
simultaneously interact with a population of neurons, and
c) astrocytic networks are adequate to coordinate neuronal assemblies,
triggering oscillatory synchrony and possibly participating in the
process of `binding' informational patterns distributed along the brain.
Each LFP possibly embodies a potential conscious content. In
perceptual processes, LFPs that do not sustain activity to participate in the
larger collective response possibly do not have their excitatory pattern
included in the content of perceptual consciousness. Once the spread of
excitation is (meta-)potentiated by astrocytes, other mechanisms contribute to
the onset of synchrony and its maintenance: a thalamic pacemaker and electric
synapses. An identification of the function of each mechanism may provide a
deeper understanding of the mechanisms underlying oscillatory synchrony, the
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role of astrocytes in the generation of this phenomenon, and its relation with
consciousness.
Acknowledgments: FAPESP, CNPQ (Alfredo P. Jr)
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