Sensory Transduction and Subjective Experience
Expression of eight genes in
three senses suggests a radical model of consciousness
Chris King, Mathematics
Department, University of Auckland
21st June 2007
Abstract: Recent research into whole genome mapping
of the mouse brain has made possible direct investigation of the brain
expression of unusual genes. A search of the Allen Brain Atlas database has
provided genetic and neuro-anatomical evidence for widespread specific
expression in the brain of eight genes specific to sensory transduction, in
vision, hearing and touch. A novel biophysical model is proposed for the
function of these proteins, in generating the internal model of experiential
reality.
Introduction
Recent research in whole genome
mapping of the mouse brain 1,2 has made it possible to investigate
the potential central nervous function of genes that might otherwise be
associated primarily with peripheral sensory transduction. At the same time,
the actual molecules involved in sense transduction, in vision, hearing and
touch are being characterized. The
first putative transduction molecule for mammalian touch, stomatin-like protein
3 (SLP3, or Stoml3) was reported
this year in Nature 3, and putative molecules in the auditory
transduction pathway, epsin 4,5, and cadherin 23 (otocadherin) 5
have only been reported in the last five years and otoferlin 6,7 in
2006. Research into the genetic
evolution of the visual system has also unearthed provocative new findings
about vision, which became the trigger for this hypothesis. In parallel with the usual cilia-based
photo-transducer molecule c-opsin are retinal ganglion cells, which use
melanopsin, or r-opsin related to insect opsins (based on organelles called
rhabdomeres), which depolarize rather than hyperpolarize 8. It has also been discovered that both
types of opsin work in opposition in the reptile parietal (pineal) eye 9.
Figure 1: Large scale mouse
brain expression profiles of encephalopsin (Opn3), otocadherin (Cdh23), espin
(Espnl), otoferlin (Otof) and Stom3 (Allen Brain Atlas1) illustrate
the wide and discretely specific expression of sensory transduction molecules
for three senses, vision, hearing and touch in the central nervous system. Does this mean that the 'internal model of reality' evokes subjective experience using similar molecules to the physical senses?
Investigation
Interest in such idiosyncratic
incidences of sensory genes became the stimulus for making a short
investigation of molecules associated with sensory transduction in brain
tissues, using the Allen Brain Atlas 1 of the mouse. This
immediately threw up a further opsin variant, encephalopsin 10,
discovered in 1999 and known to have a broad and selective distribution in the
brain, including, but not restricted to, areas involved in visual processing.
At the same time as making this search, Nature reported the discovery of Stoml3
in touch transduction 3 and a search revealed this also has a wide
brain distribution. Stoml3 was found to bind specifically to acid-sensitive ion
channels ASIC2 and 3 and a search likewise found a CNS-wide expression of these
genes. Finally a search was made for auditory molecules, which threw up epsin
and cadherin-23 4,5, which likewise show brain-wide specific
expression. Subsequently, the recent characterization of otoferlin 6,7,
claimed to be key to the sensitivity of auditory transduction led to
exploration of this auditory molecule as well, providing evidence of
wide-spread expression from five genes involving three senses.
Figure 2: Exploded view in the
lateral ventral cortex at the cellular level of expression of encephalopsin
(Opn3), otocadherin (Cdh23), espin (Espnl), otoferlin (Otof) and Stom3
demonstrate specific expression of a similar type in cortical tissue at the
cellular level.
In support of the central
nervous expression of genes believed to be associated primarily with sensory
transduction, an exploration of: (a)
rhodopsin, and encephalopsin, (b) otocadherin, espin, and otoferlin and
(c) acid-sensitive ion channels ASIC2 and 3 and stomatin-like protein 3 using the Allen Brain Atlas is included
in the figures. Figure 1 shows
lateral sagittal views of the whole mouse brain for five of these genes,
supporting their expression in the
brain. Figure 2 Figure 2 looks in
detail at an area of the ventral lateral cortex illustrating similar expression
of each of these genes at the cellular level. Figure 3 shows the specific expression of rhodopsin in the
cortex focused in areas consistent with visual function. Figure 4 exemplifies
more specialized activity of two of them in the olfactory bulbs and cerebellum.
Figure 5 shows varying expression for four of the genes in the parietal cortex.
Could the CNS contain
Transduction Cascades?
Opsins
are clearly transducers from photonic to electrochemical. Encephalopsin is also
expressed in other organs, and is also referred to as panopsin, so could have
another generalized cellular function. However there are several other opsins
of interest expressed in the CNS. Pinopsin is not confined to the pineal but
also occurs widely in the brain. In addition vertebrate ancient opsin is also
expressed in regions bordering the pineal. Rhodopsin has activity
concentrated in individual neurons across the cortex with a specific focus in
the occipital, consistent with a function in the primary visual cortex.
Otoferlin,
which was only characterized in Oct 2006, is as close as research can establish
to the transduction step. Otoferlin functions right in the critical steps
of the signaling cascade stimulating the fast kinetics of the most mature Ca
dependent neurotransmitter vesicles, thus triggering the receptor cell
response, and it's also transmembrane and possibly a Ca channel so it is right
on the transduction interface. In particular Parsons 6 notes
that the hair cell has evolved a unique calcium-sensing
molecule, otoferlin, for controlling neurotransmitter release. The
action of otoferlin allows a hair cell?s specialized synapses —
ribbon synapses, a specific class of afferent synapse common
to sensory systems — to meet the requirements of
hearing. Roux et. al. 7 describes otoferlin as a novel protein
and transmembrane cochlear-expressed gene. So its function looks like a Ca++
ion channel or channel modulator that excites mature kinetically unstable vesicles.
This could be the direct result of a phononic or solitonic event in the
membrane.
The
presence of no less than three molecules from the auditory transduction pathway
- otoferlin, otocadherin and espin in the CNS suggests functional linkage in
the CNS and a possible signaling cascade. All three don't have to be directly
involved in transduction, but all may be essential to it, as is evidenced by
deafness studies.
SLP3
is a transduction modulator, which binds specifically to acid-sensitive ion
channels ASIC 2&3. The atlas found very similar cortical
distributions of all three molecules, again setting up a putative model for a
transduction cascade here as well. However ASIC may have more
general ion-channel functions in the CNS which makes the role of SLP3
interesting. Wetzal et. al. 3 show mechano-sensitive
ion channels found in many sensory neurons do not function
without SLP3 including touch mechanoreceptors as a whole and cites their
coupling to ASIC 2&3.
Figure 3: Expression of
rhodopsin in the CNS shows both strong selective neuronal expression and a
focal expression in the occipital cortex consistent with expression in the
primary visual areas.
Subjective Consciousness and
Biophysical Transduction
Interest in the biophysical
basis of subjective consciousness has become central to the emerging area of
consciousness research. A variety
of models have been put forward for the involvement of CNS proteins in, quantum
computation by orchestrated objective reduction in microtubules12,13,14,
and others involving coherent quantum excitations including a protein/water/EM field model15,16,17,18. A variety of functional proteins
in the CNS are under investigation to test for their possible role in the
biophysical underpinning of subjective consciousness. It has also been proposed
that conscious anticipation might be made possible through quantum excitations
both emitted and absorbed by the CNS 27,28.
Although subjective
consciousness has many attributes, from the sense of self-awareness
(self-consciousness) through semantic and rational processes (rational mind)
and working memory, some of which involve subliminal processing on the fringes
of consciousness or unconsciously, there is a major central arena of conscious
experience, sometimes referred to as the Cartesian theatre 19,20,
which gives the subjective expression of an envelope of sensory experience,
whether it involves experiences of the external world or purely internal states
such as dreaming. This in turn
gives rise to the notorious binding problem – how a distributed parallel
processing organ like the cortex with disparate sensory areas can bring in all
back together. However the primacy
of internal ?sensory experience? in subjective consciousness suggests a
biophysical support based on the same principles as are involved in sensory
transduction.
Figure 4: Specialized
expression of encephalopsin (Opn3) in the cerebellum, and of otocadherin
(Cdh23) in the olfactory lobes illustrate divergent specialized function of
these genes in specific brain areas contrasting with their similar expression
in figure 2.
The occurrence of putative
sensory transduction genes in the central nervous system is consistent with a
novel biophysical model supporting subjective consciousness – that the
distributed functioning of the central nervous system provides an ?internal
sensory system? which can generate abstracted sensory experiences of reality
forming an ?internal model of reality? using the same physical principles as
are involved in sensory transduction in a bi-directional manner, enabling
coherent generation and reception of biophysical excitations, particularly
those associated with vision and audition. Olfaction has a fundamentally
different basis, both in brain architecture and in the fact that it involves
specific molecular receptors, which cannot regenerate their stimuli by reverse
transduction, although there is evidence for olfactory synesthesia 21,22.
Some forms of synesthesia, such as responding with feeling to seeing another
person?s finger touched 23, may also involve specific interactive
circuitry, including mirror neurons 24.
The model gives a succinct
explanation of why subjective experience such, as dream, memory and reflection,
as Carl Jung 25 put it, so successfully evokes the deep qualitative
differences between the senses, when a purely electrochemical model has no
qualitative differences between the senses, except in terms of differential
developmental and stimulus-induced processing connectivities. The wide
distribution of each of these molecules, not confined to one sensory area,
suggests that the evolution of the cortex as an adaptable system, has resulted
in a flexible design, in which widespread areas of the brain may be capable of
generating dynamics simulating more than one sensory process biophysically,
consistent with descriptions of kaleidoscopic synesthesia 21 in the
medical literature, in psychedelic folklore, and manifest in ancient cave art
running far back into our human origins 26.
By contrast with all other areas
of scientific discovery, from the human genome to cosmological grand
unification, the nature and basis of conscious experience remains the principal
scientific area in the third millennium for which there is yet no realizable
candidate theory, nor even a qualitative understanding in principle, of how our
?internal model of reality? is generated. While consciousness research has come
in from the cold as an accepted scientific research area 12,27,
there are still major stumbling blocks to a realizable theory of consciousness,
including the ?hard problem? 30 – whether subjective
consciousness is in any way qualitatively identifiable with an objective
description of reality, to the ?binding problem? - how multifarious processes come together to convey the impression
of a ?Cartesian theatre? 19,20
of the mind.
Figure 5: Expression of
encephalopsin (Opn3), stoml3, otocadherin (Cdh23) and otoferlin (Otof) in the
parietal cortex illustrate differing modes of cortical expression.
Research into the biophysical
basis of consciousness remains obscure, invoking a variety of speculative
theories, few of which have convincing experimental support at the cellular
level. Nevertheless subjective conscious states, from dreaming, through
psychedelic states, to memory and imagination, each possess a veridical
reality, which is of the same broad sensory nature as an external experience.
Indeed dreaming can become all too real, by any sensory measure, despite
attempts at lucidity checks!
Although we conceive of the
nominal five senses - vision, touch, hearing taste and smell - as biological
adaptions, they are actually manifestations of the principal quantum modes by
which an organism can interact with the physical world. Vision is
photon-orbital interaction, hearing comes somewhere between phonon-orbital and
the mechano-receptor dynamics of touch, taste and smell are traditionally
defined as an orbital-orbital shape-fitting, although some research 29
suggests smell involves quantum vibration modes as well. Sensory transduction is also capable of
working at the quantum limit. Frog rod cells are capable of responding to
single photons 26, pheromones likewise can elicit a response from a
single molecule (especially in insects) and the limits of audition involve
movements of the cochlear membrane of the order of a hydrogen atom radius 26,27.
CNS Gene Expression and REST
One line of caution about interpreting actual function of genes expressed in the brain is that neuronal cells have relatively open transcription, due to the very low levels of REST, the zinc finger protein RE-1 silencing transcription factor in neuronal cells. The transcriptional repressor REST 31 controls neuron-specific gene transcription via recruitment of histone deacetylases. "In neurons, only very low levels of REST can be detected. In fact, a decrease in the REST concentration during neuronal differentiation is most probably the essential prerequisite for transcription of neuronal genes. The chromatin configuration of neuronal genes is open, due to an extensive acetylation of the core histones. Transcriptional activators, as well as the RNA polymerase II complex, can gain access to the DNA and trigger gene transcription. In non-neuronal cells, however, REST is present and binds in a sequence-specific manner to several neuronal genes."
The relatively open transcription of neuronal cells has led some researchers to suggest that transcription in neurons is not a reliable indicator of gene expression since the relaxation of REST allows for wholesale expression of neuronal-related genes, which may not be actually translated due to RNA processing after transcription. This however runs counter to the fact that neurons, participating in the most complex finely tuned organ of all - the brain - need to have corresponding acuity of gene transcription. The idea that neurons are simply an open Pandora's box of randomly transcribed genes is not an accurate assessment.
However other evidence suggests that the influence of RNA may occur at a pre-transcriptional level and in a highly elegant manner that would permit just the sort of very specific gene expression required in the brain. Kuwabara et. al. 32 describe a small dsRNA that activates the expression of neuron-specific genes at a transcriptional level and that alone is capable of inducing the differentiation of neuronal progenitor cells into neurons. This RNA may represent the first member of a group of small RNAs that directly modulate gene expression at the transcriptional level. Intriguingly, this RNA, which is expressed in the nucleus, rather than the cytoplasm where most miRNAs and siRNAs are found, neither inhibits expression of REST (not having sequence correspondence with REST mRNA), nor does it inhibit REST's binding to DNA transcription sites, but rather alters REST's activity, from binding to other repressors, such as CoREST 31 to binding with activators of gene expression.
The purpose of the current paper is not to establish beyond doubt that sensory transduction molecules are functionally expressed in the brain, but simply to show that gene expression at the level of anatomical investigation is consistent with this idea. Several of the genes cited, particularly rhodopsin, appear to be functionally transcribed as their pattern of occurrence is anatomically specific and in the latter case, correlated with the visual cortex, suggesting that at least some of these candidates do have functional expression in the CNS.
Conclusion
While the evidence presented is from distributed gene expression and thus in no way confirms these molecules are performing a sensory transduction function in the central nervous system, the theory does present an innovative and scientifically provocative biophysical hypothesis about the genesis of the 'internal model', which could also have significant implications for cognitive science. Physically transduced quantum excitations phase correlated with the electrodynamics underlying the electroencephalogram could provide a realizable means for the brain to generate quantum entangled states, permitting forms of quantum computing using our massively parallel, phase coupled brain dynamics. Some models 27,28 also suggest such processes could also have an anticipatory function which might help explain free-will.
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