Our perception of the world, and our imagination, which seems to magically cognate from nothing, as well as our conception to action, had throughout human history seemed separate from the material realm. Philosophical and religious interpretations of our conscious experience and cognition generally incorporated a supernatural, otherworldly or divine attribution. In Theravada Buddhist traditions the Pāli Canon considerers the mind in three components, the citta, the manas and the viññāṇa. Perhaps oversimplified here, the citta refers to thought, while manas is the non-verbal cognition of the sensory input. The viññāṇa is our consciousness, with six components, the five consciousness from the senses and the mind consciousness of ideas — it is supernatural within and outside our body across time and lives [14]. In Hinduism, although with some differences among the various schools, the analogous Sanskrit vijñāna is considered the way of attaining the knowledge of Brahman, or in the Bhagavad Gita, knowledge of Brahma or Supreme Spirit [15]. In western philosophy, this ethereal mind with corporeal body dualism of experience also prevailed, with one aspect our material body, and the other an immaterial supernatural psych or soul, as developed by Plato. Plato considered the soul and mind immaterial, and while Aristotle disagreed, and considered our body material intertwined with a material soul, he believed the intellect was immaterial and otherworldly [16]. Parts, or all of the workings of our “mind’s eye”, or cognitive self, have been described as a supernatural ‘soul’ or some form of divine influence or entity, in many religious interpretations of our experience that have evolved in human history. In the ‘Abrahamic religions’, many beliefs have the individual’s souls existing in some form in the afterlife. Where animism prevails, all living things possess it, along with our human entity.

During the scientific revolution, Descartes attempted to reconcile Christian interpretations of our existence in Europe at the time with technological advances in hydraulics, and provide an explanation for dualism in the form of the ‘mind-body problem’. His theory speculated that the mind is one with God’s unseen ether, which then manipulates the pineal gland like a pump, to contract fluid through our nerves to coordinate movement in the body [17, 18, 19]. Ingenious in its time, Descartes ‘balloonist’ theory of fluid filled nerves intricately considered hydraulics as well as his contemporary’s research on the pineal gland, even if it continued to ascribe a supernatural basis of our consciousness and cognition. Analogies on nervous system operation have traditionally drawn upon major technological advances, from hydraulics in Descartes time, to electricity of Galvani persisting into the 19th and early 20th centuries, to the late 20th and early 21st analogy of brain activity a computational code and our perception the manifestation of these like on a screen or 3D projection. By the 20th century, mind-body dualism was philosophically refuted by Gilbert Ryle in The Concept of Mind, where he states that despite appearances and feeling of the mind as a separate entity that lives outside and without the body, that it is just “the ghost in the machine”, or a philosopher’s myth [20]. However, our experience of this pervasive duality that inspired the mind-body problem may have at its biological foundation in the difference between neural and astrocyte communication and physiology, and could be revisited in relation to the philosophy of the mind with the new evidence from a completely biological perspective.

In Western philosophy, by the 18th century, the supernatural notion had begun to wane in some philosophical circles, and instead the immaterial world outside space and time was perceived by our inborn material. Kant had developed influential concepts of the mind as part of the individual, from perception to conception that he categorized into various schema to demonstrate how we perceive the immaterial world [21, 22]. However, perhaps a better analogy for our cognitive experience, and the difference between astrocyte/neuron physiology, as seen in the current experimental evidence, comes from Schopenhauer in the early 19th century. Schopenhauer’s ideas had a broad impact on the early formation of the psychological sciences. He placed the importance of the mind as the central entity within ourselves with the word Vorstellung [23]. The Vorstellung was inborn in our self, our interpretation of that information from our senses, the illusion of our existence, as our perception, our imagination, and conception of ideas to volition. Like Kant’s schema, it was our interpretation of that true reality we cannot know due to the limitations of our senses, the immaterial world which is outside space and time. For Schopenhauer, it was an individual’s limited material’s illusion of the immaterial world. Therefore, this situatedness of our consciousness in space and time is just a property of our inherent ability to make sense of the immaterial world from the input we receive from the senses. As Schopenhauer mentions: “if occasioned by the accession of certain sensations in my sense-organs, there comes about in my mind a perception of things which are extended in space, permanent in time, and casually active, that by no means justifies my assumption that such things exist in themselves… [24]”.

What biomatter is responsible for this illusory perception, this imagination, this conception to action? Until the advent of modern cognitive sciences, this had not been biologically addressed. In biopsychology, the dominance of behaviorism in the mid-20th century placed all study on behavioral outcomes in response to sensory stimulus, because they were concrete and measurable. What happened between, the Vorstellung, was the unstudied, indeterminate ‘black box’ of BF Skinner. Radical behaviorism proposed by Skinner thought that since only defined behaviors were measurable, higher thought processes within were not able to be adequately studied, and though the approach of cognitive science to be futile [25]. With advanced tools and understanding of molecular biology, these mysteries are under active pursuit by neuroscientists and neurophysiologists in the 21st century: mainly, from a cellular biology perspective, what is the basis of the Vorstellung?

The current belief is that cellular learning and memory at the base of cognition likely results from ‘neuroplasticity’, or experiential changes in the synaptic connections between neurons over time, which had been theoretically proposed by Donald O. Hebb in Organization of Behavior in 1949 [26]. Robert Galambos, who conducted pioneering work on the physiology of echolocation in the bat nervous system, considered astrocytes intimate position at the synapse in a published a review in 1961 [27]. This seminal work was prescient, with his concepts now realized experimentally. In the review, he uses the word glia, as all other non-neuronal cell types in the nervous system were blanketed with the term ‘glia’, even though now it is understood the different main types are in some cases as different from each other as they are from neurons, and like neurons, have innumerable subtypes within each classification. Galambos lamented that the conventional consideration from Santiago Ramón y Cajal’s Neuron Doctrine that glia are passive insulators in the nervous system prevented researchers from seeing the brain as an independent observer would, unpolluted by the doctrine, as “a huge collection of glia cells through which a nerve process occasionally wanders”. Furthermore, Galambos stated that “perhaps glia…‘tell’ the neuronal masses what they are supposed to do — in the same sense, I suppose, that the computer program ‘tells’ its digital units what order and sequence of processes they must execute.” He then concludes the essay stating: “Neurophysiology, dominated by the neuron theory of Cajal, has generated over the past 50 years a mountain of data without being able to formulate a convincing explanation for even such a commonplace behavioral event as remembering a name. It’s data, furthermore, repeatedly imply that something else besides mere neuronal activity is at work. Could the ‘something else’ …..be the physiological properties of that other cell population of the brain, the glia?” Galambos was referring to astrocytes based on the synaptic position and type of glia cell he considered. Even Cajal himself, perpetually acute ad infinitum, seemed to foretell the death knell of a strictly Neuron Doctrine of cognition in 1899, and realized how the focus on neurons with his theory might sideline glia. He said that to consider them passive was “the main obstacle that the research needs to remove to get a rational concept about the activity of neuroglia [28]”.

The processing and subsequent control of neuronal communication at the synapse by astrocytes is responsible for many unconscious processes. In these experiments, defined measurable behavioral outputs are able to be tested in conjunction with cell physiology. Initial studies of the astrocytic effect of unconscious behaviors can provide a window into how the astrocyte might influence cellular communication in cognition. For example, astrocytes are the initial cell in the brain stem detecting pH increases due to elevated CO${}_2$ in the blood, the astrocyte signal neuronal firing, which stimulates the lungs to take a breath [58]. Astrocytes have also been shown to control oxytocin neurons in response to sensory stimuli that drives lactation and other behaviors in the hypothalamus [59]. Likewise, in the suprachiasmatic nucleus, astrocyte signaling controls neuronal communication to drive our circadian rhythms [60, 61, 62]. In feeding behaviors, it was initially observed that leptin receptors on astrocytes were essential for leptin-regulated feeding [63]. Astrocytes are also required for osmoregulation in the supraoptic nucleus [64, 65]. In the amygdala, fear processing to stressful stimuli is determined through an astrocyte intermediary before the neuronal communicatory stress response, and astrocyte activation decreases the firing rate of central amygdala neurons, which reduces fear expression [66]. Most recently, it has been discovered that astrocytes also play a role in modulating reward through dopaminergic pathways and expression of opioid receptors in the nucleus accumbens [67, 68]. This list is by no means exhaustive, but astrocyte regulation of neuronal processes on measureable behaviors, indicates that their control of neuronal activity in cognition in seems likely.

Brainbow techniques confirmed the previous research that protoplasmic astrocytes in the cortex and hippocampus occupy distinct non-overlapping territories called tiling domains [88, 89, 90]. In these positions, in areas of the brain responsible for cognition, astrocytes can influence and respond to a single synapse, or hundreds/thousands of synapses, and are responsible for synchronous neuronal activity thought the be the basis of our unitary consciousness [91, 92]. In addition to the influence on synaptic plasticity [93], there is emerging evidence of the complexities of astrocyte heterogeneity throughout and within brain regions, which could provide further nuance to their physiological role [94]. Additionally, two astrocyte subtypes are unique to the primate cortex, the interlaminar astrocyte in the molecular layer, and the varicose projection astrocyte, which is only found in the human cortex in layers V and VI, and can extend a long process into other cortical layers [9]. Therefore, astrocytes are uniquely positioned to contribute the spatial integration and temporal regulation that is unsatisfactorily explained from a neural centric view alone [10]. Likewise, in all transmitter systems, astrocytes are positioned to provide intimate involvement in assembly and circuitry [95].

Systems and computational neuroscience has now begun to appreciate the burgeoning experimental evidence of the astrocyte regulatory element and the implications for cognition. Although until recently, this field has been conventionally the study of neurons, neuronal circuits and units, the incorporation of astrocytes in computational models and systems has proven to be particularly fruitful [124, 125]. The unsatisfactory explanation of computational self-tuning synapses [126] and self-regulating synaptic model attempt to design learning [127], with the model creator inserting a nuance that could now be achieved by a third element, the astrocyte [128]. The astrocyte is now the element that can synchronize, organize and bind neural input and output [129]. Initially, the computational power of astrocyte mediated synaptic plasticity was explored [130], especially in excitatory synapses, and how glutamate uptake by astrocytes can influence transmission and neural spiking [131]. The astrocyte has been shown to be the element to satisfy the computational quest to understand regulation of neuroplasticity [132]. Astrocytes in silico cell models have also now emerged as a player in neural networks [133]. Likewise, in a computational system, the tripartite synapse adds another dimension to the development and understanding of aggregation of neuronal units into synchronization observed in consciousness [134, 135, 136, 137]. These models provide a window into how astrocytes contribute to the neuron in a single unit level, and consider the implication it might have in complex circuits, networks and re-entrant signaling [138, 139].

The initial models have proven to be a spring board to further development to show how astrocytes improve such things as pattern recognition performance [140]. Similarly, models have been built and extended to incorporate astrocytes in the whole network level [141]. Including a model that considers the essential role of astrocytes in neural synchrony [142]. Researchers have also created a neural-neuroglia network builder interface, where novice computational biologists can now create models taking into account the two elements [143]. And more recently, artificial intelligence hardware containing a controlling astrocyte-like element have been constructed [5]. All of these studies are concluding something known in the experimental evidence: in order to replicate human intelligence, imagination, perception, the astrocyte is the keystone regulatory cell responsible for orchestrating neuronal communication.