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\begin{document}

\title{Cortical synaptic basis of consciousness}



\author[1]{Min Zhuo}%
\affil[1]{Department of Physiology,}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
Consciousness is one of final questions for humans to tackle in
neuroscience. Due to the lack of understanding of the basic brain
network and mechanisms of functions, our knowledge of consciousness
remains at the theoretical level. Recent studies using brain imaging in
humans and modern neuroscience techniques in animal studies reveal a
basic brain network for consciousness. The projection from the thalamus
to different cortical regions form a network of activities to maintain
consciousness in human and animals. These feedback and feedforward
circuits maintain the consciousness even in certain brain injury
conditions. Proteins and ion channels that contribute to these circuit
neural activities are targets for drugs and manipulations that affect
consciousness, such as anesthetic agents. Synaptic plasticity that
trains synapses during learning and information recall, modify circuits
and contribute to a high level of consciousness in certain populations.%
\end{abstract}%



\sloppy


\textbf{Cortical synaptic basis of consciousness}

Min Zhuo

Department of Pharmacology, Qingdao University School of Pharmacy,
Qingdao, Shandong 266073, China

Department of Neurology, First Affiliated Hospital of Guangzhou Medical
University, Guangzhou, China

Department of Physiology, Faculty of Medicine, University of Toronto,
Toronto, ON, Canada

\textbf{Correspondence:} minzhuo10@gmail.com

\textbf{Running title:} \emph{Synaptic hypothesis of consciousness}

\textbf{Keywords:} \emph{consciousness; cortex; thalamus; synaptic
plasticity; LTP; pain, ACC}

\textbf{Word counts:}

\textbf{Abstract}

\textbf{Consciousness is one of final questions for humans to tackle in
neuroscience. Due to a lack of understanding of basic brain networks and
mechanisms of functions, our knowledge of consciousness mainly stays at
a theoretical level. Recent studies using brain imaging in humans and
modern neuroscience techniques in animal studies reveal the basic brain
network for consciousness. The projection from the thalamus to different
cortical regions forms a network of activities to maintain consciousness
in humans and animals. These feedback and feedforward circuits maintain
consciousness even in certain brain injury conditions. Pterions and ion
channels that contribute to these circuit neural activities are targets
for drugs and manipulations that affect consciousness such as anesthetic
agents. Synaptic plasticity that trains synapses during learning and
information recall modified the circuits and contributes to a high level
of consciousness in a certain population.}

\textbf{Introduction}

Consciousness is the status that humans and animals can feel and detect
the environment, and are capable to make appropriate responses to
changed stimuli. In recent years, neuroscientists have taken difficult
experimental approaches to investigate the consciousness, or neuronal
correlates of consciousness (NCC). This is the minimal neuronal
mechanism that supports any specific consciousness experience
(Koch\emph{et al.} , 2016; Koch, 2018; Seth \& Bayne, 2022). Different
experimental approaches have been used to investigate such neuronal
mechanisms, including brain imaging, and animal experiments with brain
injury or anesthesia. Pain and pleasure, are two major types of emotion
affecting the brain. Consciousness of pain is a key type of sensory
consciousness. It has been proposed to use to evaluate the level of
consciousness as well as the recovery of consciousness during
anesthesia.

The studies of consciousness have recently advanced by the use of modern
science and technology. Brain imaging has demonstrated that certain
central nervous system (CNS) areas that are activated or inactivated
during consciousness or during reappearance of consciousness. Animal
studies using optogenetic and selective brain stimulation revealed that
certain brain areas are critical for re-starting consciousness from
unconsciousness statues. It is believed that cortex and related
subcortical nuclei that form neuronal connections and feedback controls
with cortical neurons play important roles in consciousness
(Koch\emph{et al.} , 2016). It is no doubt that sensory sent through the
spinal cord, and motor-related neuronal activity contribute to
consciousness.

For our sensory experience, the more we learn, and more complex it
becomes. For many years, we treat all pain as one type of pain, or we
called it acute pain. Identification of capsaicin receptors and opioid
receptors has greatly helped us to understand pain. Recent progress in
synaptic plasticity leads to our understanding of chronic pain is
completely different from acute pain. How about consciousness? Are there
different forms of consciousness that are mediated by different chemical
proteins and receptors? Are there different types of consciousness, for
one, obedient consciousness that required minimal effort to brain
activity, and highly self-aware, and sustained consciousness? In this
review, I will first briefly review recent advances in the
thalamus-cortex investigation of consciousness, and discuss the possible
roles of the anterior cingulate cortex (ACC) in consciousness. Then,
from a pharmacological point of view, I will discuss several proteins,
receptors, and chemicals that interfere with consciousness, and their
possible synaptic functions that take place in the thalamus-cortex
network.

\textbf{Recent new approaches for studying consciousness}

Brain functional imaging provides a powerful tool to investigate
possible neuronal mechanisms for consciousness in healthy humans. By
designing different visual/sensory/auditory sensory stimulation cues,
one can compare brain imaging to detect which brain regions are
specially related to consciousness or self-recognition (Gu \emph{et al.}
, 2013; Scheinin \emph{et al.} , 2021; Mashour, 2022). In addition, it
is also possible to perform the same study in patients with disorders of
consciousness (DOC), and such studies with a comparison with human
subjects certainly reveal brain areas or brain connectivity that
contribute to consciousness (Qin\emph{et al.} , 2010).

Animal research using anesthesia combined with brain stimulation, recent
studies have revealed several key pathways that are able to wake animals
from anesthesia, an indirect way to approach consciousness
(Redinbaugh\emph{et al.} , 2020; Afrasiabi \emph{et al.} , 2021;
Redinbaugh \emph{et al.} , 2022). For example, in primates, Tasserie et
al (2022) reported that deep brain stimulation of the thalamus restored
consciousness during anesthesia (Tasserie \emph{et al.} , 2022).
Interestingly, Redinbaugh et al (2022) found that thalamic deep brain
stimulation using multi-microelectrode could reduce the level of
consciousness during anesthesia, indicating that thalamus-related
activity may be able to produce biphasic modulation of the
consciousness. These works provide clear evidence that animal
experiments during anesthesia may help us to understand the basic
mechanism of brain circuits to consciousness.

Cellular and synaptic studies in cortical and related circuits have
found that glutamate is the major transmitter in the circuits.
Optogenetic, whole-cell patch, and molecular approaches can provide
detailed synaptic mechanisms (Bliss \emph{et al.} , 2016; Zhuo, 2016b).
Thus, these projection systems are not grey boxes anymore. By using
optogenetic and virus approaches, one can investigate the neuronal
mechanism for transmission and modulation of consciousness.

\textbf{Key thalamus-cortical network}

The thalamus-cortex network is well known for transferring peripheral
sensory information to the cortex, including gentle touch, pain itching,
and visual and auditory signals. Cumulative evidence suggests that this
sensory information including nociceptive information is not diffusely
distributed in the cortex. For example, for painful information or
unpleasant information, it has been demonstrated that ACC and the
insular cortex (IC) play vital roles in the coding of unpleasantness or
pain (Zhuo, 2008; 2014; Bliss \emph{et al.} , 2016; Zhuo, 2016a). It has
been proposed that the thalamus-cortex networks play critical roles in
consciousness (Llinas \emph{et al.} , 1998; Roy \& Llinas, 2008).
Interestingly, in a key milestone article of neural science by Albright
et al (2000), both cortical regions have been suggested to contribute to
consciousness. It has to be pointed out that there are different aspects
of consciousness including awareness of the environment by sensory
stimuli, and volition, the voluntary control of thoughts and feelings
(Albright \emph{et al.} , 2000). To understand synaptic and molecular
mechanisms of consciousness, it is highly possible that the very first
component of consciousness can be tackled at the present time and
consciousness of different forms of pain is a key indicator for
consciousness (Ambron, 2023).

By using human brain imaging and non-human primate studies, it becomes
clear that the thalamus and its related cortical areas play important
roles in consciousness (Redinbaugh \emph{et al.} , 2020;
Afrasiabi\emph{et al.} , 2021; Scheinin \emph{et al.} , 2021; Mashour,
2022). It is generally accepted that the thalamus-cortex projections
play key roles in consciousness, and inhibition or disruption of such
projections will lead to loss of consciousness, and activation of this
system can facilitate the recovery from unconsciousness. Based on these
observations, I would like to propose a possible network for
consciousness, especially for the awareness component of consciousness.
As shown in Figure 1, the projection from the thalamus to the prefrontal
cortex including ACC serves as a core network circuit for consciousness.
Callosal projections link two sides of the cortical network together to
add the flexibility and complexity of these consciousness circuits. The
other indirect links with subcortical regions and cortical areas serve
as possible loops to maintain the excitability of these core circuits.
Thus, a lesion of one side of the brain or regions will only affect or
reduce the level of consciousness, and will not completely block the
consciousness (Figure 1).

\textbf{Pain and consciousness}

Acute pain, which is a short-lasting stimulus, is known to increase the
level of consciousness. It has been proposed that sensory pain-related
consciousness may provide an excellent model for studying consciousness
itself (Tiengo, 2003; Gu \emph{et al.} , 2013; Ambron, 2023). In
patients with DOC, it has been reported that there is a strong
correlation between the responsiveness to nociceptive stimuli and the
level of consciousness (Thibaut \emph{et al.} , 2018). These findings
suggest that there is a certain overlap in neuronal circuits for pain
perception and consciousness such as ACC and IC. More interestingly, it
has been reported that repetitive transcranial magnetic stimulation
(rTMS) over ACC was able to increase pain perception in patients with
DOC (Naro \emph{et al.} , 2015). Consciousness can be a result of a
network within the brain that is capable of storing and retrieving key
self-information. A synaptic mechanism such as plasticity may play an
important role in maintaining the status of consciousness by activating
certain engram synapses that are previously learned. Disruption of such
network or general reduction of network activity will lead to minimal
consciousness statues or loss of consciousness. Two key components that
are likely important for consciousness are the storage of key
information about self; and sensory signaling that recalls the
consciousness. Some of this sensory information can serve as a
background activity that contributes to the maintenance of
consciousness; and loss of such background activity, which can be caused
by visual, auditory, somatosensory, motor position, etc., may lead to
sub-consciousness statues such as sleep. Therefore, it is very easy to
use such sensory information to recall consciousness back from sleep.
Loss of one of such sensory background activities may lead to
plasticity, and one may use other sensory information such as auditory
to compensate for the loss of visual information (such as deaf man). A
good dancer may use body position and muscle tones to gain a better
level of consciousness, and a musician may be more use auditory
signaling to do so. A thinker may use logical thinking to gain more
consciousness. It is thus possible to propose that for those people who
neither use a lot of sensory information nor inner brain activity, their
consciousness level may be lower than those they use them.

\textbf{Contribution of ACC to consciousness}

It has been proposed that ACC may play a key role in consciousness
(Albright \emph{et al.} , 2000), and such conclusions are mainly
generated from human imaging studies. It is believed that neurons in the
ACC may contribute to the conscious self. Dehaene et al (2003) reported
that conscious but not subliminal conflict affected ACC in normal human
subjects (Dehaene \emph{et al.} , 2003). Interestingly, in patients
suffering from schizophrenia, the activity in the ACC was reduced. In
patients with DOC, Qin et al (2010) reported that the degree of
consciousness in patients with DOC was correlated with neural activity
in the ACC triggered by auditory self-related stimuli, further
confirming possible roles of ACC in consciousness (Qin \emph{et al.} ,
2010). More interestingly, in healthy subjects, Stottinger et al (2015)
reported that ACC along with the anterior insula was activated at the
moment when conscious representations are updated (Stottinger \emph{et
al.} , 2015), indicating that ACC activity can contribute to conscious
self-recognition.

\textbf{Glutamatergic synapses in the consciousness network and ACC}

Using different experimental approaches, excitatory transmission in the
ACC has been well documented (Bliss \emph{et al.} , 2016). Glutamate
serves as a principal excitatory transmitter for fast transmission since
inhibition of glutamate AMPA and kainate (KA) receptors will abolish all
basic excitatory transmission. Excitatory synapses onto cortical
pyramidal cells are likely to be heterogeneous. In some synapses,
postsynaptic currents are purely mediated by AMPA receptors, while in
other synapses, both AMPA and KA receptors contribute to postsynaptic
responses. KA receptor-mediated currents are usually small, however, in
the case of the repetitive firing of action potentials, KA currents may
summate generate big responses in part due to their slow kinetics
(Wu\emph{et al.} , 2005). Recent studies reported that silent synapses
or pure NMDA receptor synapses exist in the adult cortex, including ACC
(Zhuo, 2023). These silent synapses may contribute to a postsynaptic
form of long-term potentiation (LTP) (post-LTP) (Figure 2).

In addition to its postsynaptic expression, presynaptic KA and NMDA
receptors have also been reported in cortical synapses (Wu \emph{et al.}
, 2005; Koga \emph{et al.} , 2015; Chen \emph{et al.} , 2021).
Activation of these receptors may contribute to the regulation of
excitatory and inhibitory transmission. Furthermore, activation of KA
receptors in the ACC has been reported to contribute to a presynaptic
form of LTP (pre-LTP) (Koga \emph{et al.} , 2015).

\textbf{NMDA receptor and its dependent synaptic plasticity}

NMDA receptors are known to contribute to synaptic LTP (Bliss \&
Collingridge, 1993). In the ACC, there are two key forms of LTP: pre-LTP
and post-LTP. For post-LTP, NMDA receptors, including GluN1 and GluN2
(GluN2A-D) isoforms, have been reported to contribute to the induction
of LTP (Bliss \emph{et al.} , 2016; Li \emph{et al.} , 2019). LTP
induction protocols such as theta burst stimulation (TBS), pairing
training and spike-EPSPs can induce NMDA receptor-dependent LTP. The
expression of NMDA receptor-dependent LTP requires postsynaptic
modification or insertion of GluA1-containing AMPA receptors.
AC1-dependent, protein kinase A (PKA) phosphorylation of AMPA receptors
GluA1 contributes to LTP (Liauw \emph{et al.} , 2005; Yamanaka \emph{et
al.} , 2017; Miao \emph{et al.} , 2019). A recent study using selective
knock-in mice demonstrates that phosphorylation of AMPA receptor GluA1
plays an important role in synaptic potentiation. However, the same LTP
did not require CaMKII/PKC phosphorylation site serine 831 (Ser831).
These results demonstrate that ACC LTP employs a different mechanism
than hippocampal LTP (Song \emph{et al.} , 2017).

In addition to post-LTP, an NMDA receptor-independent form of LTP can
also be readily induced in the ACC by paired-pulse low-frequency
stimulation. This form of LTP is resistant to NMDA receptor blockade and
was inhibited in mice lacking the KA receptor GluK1 subunit
(Koga\emph{et al.} , 2015). Pharmacological experiments using a potent
GluK1-selective KA receptor antagonist, UBP310, further confirmed that
this form of LTP is KA receptor-dependent. Both genetic and
pharmacological evidence consistently indicates that this form of LTP is
pre-LTP. Pre-LTP in the ACC is sensitive to a
hyperpolarization-activated cyclic nucleotide-gated channel inhibitor,
ZD7288 (Koga \emph{et al.} , 2015). In addition, p42/p44
mitogen-activated protein kinase inhibitors PD98059 and U0126 suppressed
the induction of pre-LTP and did not affect the maintenance of pre-LTP.
The activation of presynaptic extracellular signal-regulated kinase was
required for the induction of pre-LTP (Yamanaka \emph{et al.} , 2016).

\textbf{Ketamine and consciousness}

NMDA receptors play multiple roles in cortical synapses. Its main role
is its contribution to synaptic plasticity, including LTP and long-term
depression (LTD) (Bliss \emph{et al.} , 2016). Depending on the
stimulation pattern and postsynaptic depolarisation, activation of the
NMDA receptor may lead to LTP and LTD in the cingulate cortex.
Postsynaptic AMPA receptors, including different subtypes of
receptors-mediate synaptic potentiation and depression (Bliss \emph{et
al.} , 2016). In addition, there are reports of silent or pure NMDA
receptors in the adult cortex (Zhuo, 2023). In physiological awake
conditions, these NMDA receptors may contribute to synaptic
transmission. Ketamine is an old anesthetic agent that acts as a
non-competitive NMDA receptor antagonist. It is reported that
ketamine-induced anesthesia is accompanied by the development of slow
oscillation across the cortex (Ballesteros \emph{et al.} , 2020).

In healthy human subjects, low-dose of ketamine can produce altered
states of consciousness (Vlisides \emph{et al.} , 2018), suggesting that
NMDA receptor functions play important roles in controlling
consciousness under physiological conditions. Considering that most of
NMDA receptors are inhibited at resting membrane potentials, these
results suggest that the ketamine effect may be mediated by
non-activity-dependent synaptic plasticity mechanisms, such as
functional NMDA receptors and/or presynaptic NMDA receptors.

\textbf{Genetic autoantibodies and consciousness}

Additional evidence for the contribution of glutamatergic NMDA receptors
to consciousness comes from patients with anti-NMDA encephalitis
(Panzer\emph{et al.} , 2014; Lynch \emph{et al.} , 2018). In these
cases, patients' antibodies bind to the NMDA receptors and cause loss or
reduction of NMDA receptor functions (Panzer \emph{et al.} , 2014).
Consequently, these patients suffer from impaired consciousness,
movement disorders, other psychiatric symptoms, and even death. The
positive allosteric modulators of NMDA receptors may be used in the
future for the treatment of such patients (Warikoo \emph{et al.} , 2018;
Mannara \emph{et al.} , 2020). It has been reported that positive
allosteric modulation of NMDA receptors can enhance synaptic LTP
(France\emph{et al.} , 2022). It may be possible that these new
chemicals may be used to modulate the level of consciousness in the
future.

\textbf{Modulators of consciousness: caffeine and alcohol}

It is known that the modulation of synaptic transmission may affect the
level of consciousness. Effects produced by caffeine, a common
ingredient of tea and coffee are a good example. Using animal anesthesia
as a model, Fox et al (2020) reported that caffeine is able to reverse
the unconsciousness induced by light anesthesia in adult rats
(Fox\emph{et al.} , 2020). Subsequently, Fong et al (2018) showed that
caffeine injected intravenously accelerate human emergence from
isoflurane anesthesia (Fong \emph{et al.} , 2018). These results provide
strong evidence that brain excitatory indeed play an important role in
the loss of consciousness during anesthesia, and it is possible to
explore the basic mechanisms of consciousness using pharmacological
approaches in both human and animals. Interestingly, they also found
that alteration of anesthesia and consciousness levels are correlated
well with brain electroencephalogram (EEG) activity, a common parameter
obtained in humans. At the cellular level, it is believed that caffeine
produced this effect by increasing intracellular cAMP level, triggering
immediate early genes, and regulation of the dopamine- and
cAMP-regulated phosphoprotein, M(r) 32 kDa (Lindskog \emph{et al.} ,
2002; Fisone \emph{et al.} , 2004) and inhibit neuronal adenosine A
receptors in the brain.

Alcohol is well known to cause unconsciousness or death when it is
consumed at higher dosages. At a low dose range, alcohol can cause
disinhibition and anxiolytic effects (Harrison \emph{et al.} , 2017).
Cumulative evidence indicates that alcohol affects both excitatory and
inhibitory transmission in the brain (Zorumski \emph{et al.} , 2014).
One of the key actions is that alcohol enhances the actions of
\selectlanguage{greek}γ-\selectlanguage{english}aminobutyric acid (GABA) at certain GABA\textsubscript{A} receptors
and inhibits the function of NMDA receptors. Effects of alcohol on AMPA
as well as KA receptors have also been reported. It is thus predictable
that alcohol also affects central synaptic plasticity such as LTP. These
actions provide a basic mechanism of CNS dysfunction caused by alcohol
such as memory impairment, blackouts, and loss of consciousness.

\textbf{Inhibitory transmission and anesthetic agents}

GABA is the major inhibitory transmitter throughout the CNS (Figure 3).
Most of inhibitory effects are mediated by postsynaptic
GABA\textsubscript{A} subtype receptors, including its role in
anesthesia and inhibition of consciousness. With the key cortical and
subcortical regions that contribute to consciousness,
GABA\textsubscript{A} receptor-mediated major inhibitory action.
Inhibition of excitatory transmission by activating
GABA\textsubscript{A} receptors likely led to widespread inhibition of
neural transmission. Most commonly used anesthetic agents such as
propofol, etomidate, thiopental, and isoflurane act through
GABA\textsubscript{A} receptors (Brohan \& Goudra, 2017;
Hemmings\emph{et al.} , 2019). The proposed targets include endogenous
sleep circuits, and ascending arousal pathways (Hemmings, 2017). With
the ACC, it has been reported that ACC pyramidal neurons receive local
inhibitory modulation (Cao \emph{et al.} , 2010; Bliss \emph{et al.} ,
2016).

\textbf{The synaptic hypothesis of consciousness}

Based on brain imaging and network studies, I would like to propose that
the thalamus-cortex serves as a key component in consciousness. Among
cortical areas, ACC may be one of the key harbors for it, although
alternative cortical areas may be able to compensate for the loss of
such function when ACC activity is lost. Recent network studies reveal
that ACC forms multiple connections with other cortical areas, and
ACC-ACC connections may well serve as an alternative center to maintain
consciousness. For example, in case of loss of one side of the ACC
function, the other ACC may take over. It is also likely that this
network is complex, and has multiple feedback systems. Thus, a lesion of
any component will not lead to a loss of consciousness completely.
Figure 1 proposes some initial models for such loops.

Based on this hypothesis, it is well predicted that external stimulation
can recall consciousness from unconsciousness. Furthermore, due to the
rich expression of plastic excitatory synapses among these circuits, it
is like that consciousness can be trained and enriched. I would suggest
that consciousness can be categorized into three basic levels, basic,
normal, and high level. Learning will lead to a high consciousness
level, at least to the related environment or sensory inputs. Humans and
animals are highly sensitive to contextual information and novel
subjects. This environment information will process through the
hippocampus and hippocampus-related structures.

For consciousness, it maybe it is the status of electrical flow to keep
the circuits to be active. It is thus not precisely located in several
nuclei or neurons. It is consistent with networks that have multiple
layers in order to be constantly or not easily affected by lesions or
interruption. However, it is sensitive enough to synaptic activity with
circuits that can have a range of levels to be operated. Inhibition or
overexcitation can lead to loss of consciousness, if appropriate
information can not be recalled, such as names, visual identification
sensory, etc. Since ACC neurons are likely activated and contribute to
many key brain functions, it is likely that consciousness can not be
stored or carried out by the soma of pyramidal cells; instead, I propose
that consciousness is processed by certain synapses that form specific
connections with other cortical and subcortical areas. In order to
effectively recall updated consciousness information, these synapses are
likely to be trained and learned. Thus, the same groups of neurons may
carry out different tasks through these highly diversified synapses.
Consciousness is a result of neuronal activities of a subset of the
brain network. It is unlikely processed by selective regions or nuclei.
Selectivity is not coded by action potentials but by the firing of
certain groups of neuronal networks.

\textbf{Disorder of consciousness and brain injury}

The research of consciousness can benefit from the investigation of
disorder of consciousness, or impaired consciousness. Loss of
consciousness occurs when there is damage to the brain. There are three
major forms of DOC, including coma, vegetative state, and minimally
conscious states. In these situations, loss of consciousness is
prolonged or even permanent. Several clinical studies indicate that the
impairment of the thalamus-cortex and thalamus/basal ganglia contribute
to the DOC (Lutkenhoff \emph{et al.} , 2015; Yu \emph{et al.} , 2021),
providing clinical human evidence for the important roles of the
thalamus-cortex network in consciousness. No doubt, the prolonged loss
of consciousness may trigger subsequent plastic changes within the
brain. As compared with the DOC, the use of anesthesia has also
facilitated the search for a mechanism for acute loss of consciousness.
Future studies of these mechanisms using animal models will help us to
better understand the mechanism for reversible loss and permanent loss
of consciousness.

\textbf{Aging and natural death: loss of consciousness?}

It is well known that old animals and humans tend to be less aware or
conscious (Cheng \emph{et al.} , 2020). The ability to learn, and form
new memory are significantly reduced. At the synaptic level, it has been
reported that hippocampal late-phase LTP is impaired in old animals that
performed poorly in memory tests. In those animals that show normal
memory performance, late-phase LTP is normal (Bach \emph{et al.} ,
1999). This finding suggests the importance of synaptic LTP in
age-related memory loss. Recently, it has also been reported that
synaptic tagging in the ACC is reduced in middle-aged animals (Zhou
\emph{et al.} , 2023). Similarly, synaptic plasticity is less robust in
the aged animals' cortex. It is quite possible that these reduced
synaptic LTP and tagging will contribute to altered consciousness levels
in orders. It will be very important to investigate the last moments of
natural death by aging if the loss of consciousness is due to the
failure of synaptic transmission and plasticity in the brain. Natural
death due to aging may be related to changes in consciousness or
shutdown of the consciousness network. It remains to be explored if deep
brain stimulation and/or novel chemicals that increase synaptic
activity/plasticity may prolong life before natural death.

\textbf{Conclusion and future directions}

Recent studies from human brain imaging and animal experiments have
provided new insights into consciousness. Among several possible
mechanisms, the thalamus projection to the brain is thought to be the
core mechanism. Excitatory transmission and plasticity may play
important roles in consciousness. Inhibitory transmission contributes to
excitatory/inhibitory balance, thus, also controls consciousness.
Studies using different experimental approaches reveal possible
selective circuits (by optogenetic) and proteins (by gene manipulation
and chemicals). From a basic research point of view, the future needs to
reveal molecular and cellular mechanisms for the neuronal mechanism of
consciousness. Animal experiments during anesthesia at least provide a
good animal model for such studies. For clinical application, deep brain
stimulation will only help to understand consciousness in humans, but
also help patients with DOC. More importantly, how learning may affect
the level of consciousness of human beings will be a vital question for
neurons as well as society. Maybe that is an evolutionary force for
human beings as well. High levels of consciousness due to constant brain
learning may lead to prolonged life of the brain. Many brains decide to
give up hope for life, at least in part, due to poor levels of
consciousness during aging.



\textbf{ACKNOWLEDGMENTS}

The authors would like to thank Emily England for the English edit. MZ
was supported in part by the Canadian Institute for Health Research
project grants PJT-148648 and PJT-419286.

\textbf{ABBREVIATIONS}

NCC: neuronal correlates of consciousness

DOC: disorders of consciousness

ACC: anterior cingulate cortex

IC: insular cortex

rTMS: repetitive transcranial magnetic stimulation

LTP: long-term potentiation

Pre-LTP: the presynaptic form of LTP

Post-LTP: the postsynaptic form of LTP

TBS: theta burst stimulation

EPSCs: excitatory postsynaptic currents

CaMKII: calcium/calmodulin-dependent protein kinase type II

LTD: long-term depression

GABA\textsubscript{A,B}: GABA subtype A (GABA\textsubscript{A}) and
subtype B (GABA\textsubscript{B})

L-VGCCs: L-type voltage-gated calcium channels

AC1: adenylyl cyclase 1

PKA: cAMP-dependent protein kinase



\textbf{References}

Afrasiabi, M., Redinbaugh, M.J., Phillips, J.M., Kambi, N.A., Mohanta,
S., Raz, A., Haun, A.M. \& Saalmann, Y.B. (2021) Consciousness depends
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\textbf{Figure legends}

\textbf{Figure 1. A prosed thalamus-cortex (ACC) network for
consciousness}

The direct projection from the thalamus to ACC serves as a key (if not
the only one) core circuits for consciousness. The projection to PFC
directly or indirectly may also contribute to this core. In addition,
different subnuclei of thalamus project to somatosensory, visual and
auditory cortices to convey sensory information from the outside world.
Pyramidal cells in these cortical areas form connections with ACC/PFC
neurons directly and indirectly. Through callosal projections, each side
of ACC may also affect other side of ACC by excitatory connections,
these positive feedback circuits provide a dual circuits for maintain
consciousness. Furthermore, in case of one side of brain injury, the
other side of circuits may take over to maintain minimal level of
consciousness. In addition, the pyramidal cells of ACC may also project
to subcortical and spinal cord neurons. These long distance positive
feedback circuits may also contribute to the consciousness.

\textbf{Figure 2. Different forms of LTPs in cortical excitatory
synapses}

Two major forms of LTPs have been reported in the ACC excitatory
synapses: presynaptic form of LTP (pre-LTP) and postsynaptic form of LTP
(post-LTP). In pre-LTP, the induction requires activation of glutamate
KA receptors at presynaptic side. Postsynaptic activation of NMDA
receptor is not required. The expression of pre-LTP is due to more
release of glutamate from presynaptic terminals. For post-LTP,
activation of NMDA receptors is required. The expression is mainly
mediated by the phosphorylation of AMPA receptors by cAMP PKA signalling
pathways. In addition, some synapses may be silent before the LTP
induction, the expression of functional AMPA receptors in these synapses
may also contribute to post-LTP. For long-lasting form of LTP, gene
regulation and protein synthesis are required.

\textbf{Figure 3. Excitatory and inhibitory synapses in the cortex}

Cortical pyramidal neurons receive excitatory and inhibitory innervation
from projection and local neurons. In most cases, long-distance
projections are excitatory, and local innervation si inhibitory.
Cortical neurons also form excitatory connections within the same
regions. Glutamate is the principle excitatory transmitter for
excitation, and GABA is the key inhibitory transmitter. At postsynaptic
sites, both AMPA and KA receptors may contribute to excitatory
transmission, although these excitatory synapses are not homogenous.
Some synapses only express functional AMPA receptors, and some synapses
contain both of them. At presynaptic sites, there are KA receptors as
well. For inhibitory transmission, GABA\textsubscript{A} receptor
mediate most of inhibitory transmission. GABA\textsubscript{B} subtype
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