IMR Press / JIN / Volume 21 / Issue 4 / DOI: 10.31083/j.jin2104112
Open Access Review
Astrocytes Imagined
Show Less
1 Biology Department, Neuroscience Program, University of Hartford, West Hartford, CT 06117, USA
*Correspondence: koob@hartford.edu (Andrew O. Koob)
Academic Editor: Rafael Franco
J. Integr. Neurosci. 2022 , 21(4), 112; https://doi.org/10.31083/j.jin2104112
Submitted: 31 December 2021 | Revised: 22 February 2022 | Accepted: 4 March 2022 | Published: 7 June 2022
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Abstract

The cellular, molecular and physiological basis of cognition has proved elusive until emerging studies on astrocytes. The appearance of a deliberate aggregating element in cellular neurophysiology was difficult to satisfy computationally with excitatory and inhibitory neuron physiology alone. Similarly, the complex behavioral outputs of cognition are challenging to test experimentally. Astrocytic reception and control of synaptic communication has provided the possibility for study of the missing element. The advancement of genetic and neurophysiological techniques have now demonstrated astrocytes respond to neural input and subsequently provide the ability for neural synchronization and assembly at multiple and single synaptic levels. Considering the most recent evidence, it is becoming clear that astrocytes contribute to cognition. Is it possible then that our cognitive experience is essentially the domain of astrocyte physiology, ruminating on neural input, and controlling neural output? Although the molecular and cellular complexities of cognition in the human nervous system cannot be overstated, in order to gain a better understanding of the current evidence, an astrocyte centric basis of cognition will be considered from a philosophical, biological and computational perspective.

Keywords
astrocyte
cognition
synapse
learning and memory
neural synchrony
computational neuroscience
philosophy of mind
neurophilosophy
1. Introduction

The discovery of the astrocytic control of synaptic communication has implications beyond molecular and cellular interactions. Initially, the clear evidence of astrocytic modulation of unconscious behaviors in neuroendocrine systems [1], as well as learning and memory in the hippocampus [2], led to further studies on astrocytic regulation of neuronal communication in the cortex. Gliotransmission from astrocytes has the ability to control and respond to many or single synapses, with interastrocyte communication on a separate time scale than neurons, allowing astrocytes to aggregate neural communication [3, 4], which seems to satisfy the spatial and temporal problem of a strictly neurophysiological interpretation of cognition [5, 6, 7]. Astrocytes connect 270,000–2 million synapses compared to 20,000–120,000 in rodents, and are 2.6 times larger with 27 times greater volume due to 10 times more processes, and can communicate 4 times faster than astrocytes in rodents [8, 9]. Therefore, working in concert with neurons, astrocytes contribute to cognition [10, 11, 12]. How much they contribute will become clearer as techniques continue to advance [13], and new ideas on experiments of cognitive outcomes are developed. However, based on the evidence to date, it is worth considering the possibility astrocyte physiology is cognition itself: the cell of perception, imagination, creativity, conception of ideas, and decisions to act. From a historical perspective, astrocyte physiology could be the biological basis of that aspect of human existence that until recently many religious and philosophical interpretations traditionally placed as supernatural, when contrasted with the material body in terms of sense and movement.

2. Early Philosophical and Religious Interpretations
2.1 Divine Attributions

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.

2.2 Schopenhauer’s Vorstellung

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?

3. Initial Experimental Considerations of Astrocytes in Cognition
3.1 Synaptic Position

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]”.

3.2 Emerging Physiological Evidence and Challenges
3.2.1 Calcium Physiology

As techniques advanced, emerging physiological evidence on neurons did indicate there was something else. Rapid fire neuronal signaling did not satisfy the slower assembly of neuronal units that occurred along with cognitive behaviors, and the persistent perception in cognition that another element needed to receive neural input, and coordinate and assemble the output—a cell type in the brain that was the matter of the Vorstellung.

It wasn’t until the 1990s, when experimental breakthroughs began to shed light on a possible regulatory element in the brain that could function on a different time course and coordinate neural assembles. Like all cells, astrocyte were discovered to regulate internal calcium levels, but in a manner that allowed them to signal to other astrocytes and respond to neurotransmitters [29]. This was subsequently observed in organotypically cultured slices of rat hippocampus, where ‘calcium waves’ were initiated from astrocyte to astrocyte via gap junctions in response to neuronal activity [30], which prompted the question ‘do astrocytes process neural information [31]?’ Afterwards, experiments further illuminated that this could occur in vivo, when glutamatergic Schaffer collaterals in the hippocampus were stimulated and caused increased intracellular calcium levels in astrocytes, suggesting it was occurring via metabotropic and ionotropic glutamate receptors [32]. Astrocytes are known to express glutamate receptors, and the phenomena was originally believed to occur via mGLUR5, a Gq pathway receptor capable of upregulating IP3, which can release calcium from internal organelles [33]. Soon afterwards, the discovery of ‘gliotransmitters’ such as glutamate, GABA, D-Serine and ATP that could be released from astrocytes in response to calcium increases in astrocytes, indicated that they could respond to and affect neuronal communication [34, 35, 36, 37, 38]. This exciting early evidence of astrocyte calcium physiology, and the astrocytic expression of receptors, transporters and transmitters, provided initial support of Galambos’ theory that astrocytes were an intimate player in neurocommunication. Because of their unique position, astrocytes were modulating the synapse, which was now ‘tripartite’, and consisting of pre- and post- synaptic elements, as well as the astrocyte [39]. After the initial evidence, many reviews and texts, with some publishing companies in this nascent field even hastily constructing grammatically incorrect subtitles [40], actively considered an astrocytic role in cognition.

3.2.2 Crux of Synaptic Communication

However, could astrocytes experimentally cogitate rapid fire neuronal input? Subsequent experiments have importantly shown astrocytes control synaptogenesis in learning through the release of thrombospondins [41] neuroligins [42], the glypicans [43] and release of TNFα [44]. Glutamate, GABA and glycine homeostasis is known now to be a function of astrocytes, and dysregulation through astrocyte dysfunction can be neurotoxic [45]. It appears that long term potentiation (LTP), can be achieved via the astrocyte [37]. Astrocytes communicate with microglia at the synapse to control synaptic pruning and synaptic communication in what has been coined the quadripartite or tetrapartite synapse [46, 47]. Also, neurovascular coupling is controlled by the astrocyte to provide nourishment to the parenchyma, due to their ability to monitor neurons simultaneous to their endfeet sensing of the microvasculature [48].

Some technical issues have persisted, however, as many of the initial studies to drive protein expression to observe effects in astrocytes were via the GFAP promoter, which is typically expressed in reactive states, and expressed by few cells in the normal healthy brain [13]. Likewise, the effects of gliotransmission needed to be revisited, because experiments studying astrocytic transmitter release by overexpressing a dominant-negative domain of vesicular SNARE (dnSNARE), was subsequently shown to also have low neuronal expression that could confound some early results [49]. Additionally, mGLUR5, the Gq pathway through IP3 signaling to release endoplasmic reticulum internal calcium in glutamatergic synapses, is essential for tripartite synapse formation in development, but the astrocytic expression may diminish in the adult, except in certain conditions [50, 51]. Astrocytes express many other metabotropic transmitter receptors, including adrenergic, purinergic, serotonergic, muscarinic and peptidergic receptors, in additional to glutamatergic and GABAergic, depending on the temporal expression and astrocytic subtype [52]. One explanation for the effects in the adult brain in response to glutamate would be through the mGLUR2/3 receptors which are Gi/o metabotropic receptors that do not directly activate IP3 but could indirectly effect calcium levels [53]. And lastly, some initial studies with IP3R2 –/– mice, which would abolish astrocytic IP3 signaling, did not display neuronal or neurovascular deficits [54]. However, further analysis in response to startle responses that considered different astrocytic compartments and cell anatomy, observed astrocytic calcium transmission at endfeet and fine processes via extracellular calcium, which contribute to 30–40% of the internal calcium elevations, enough to effect rapid neuronal and neurovascular communication [55]. Calcium can enter extracellularly through ionotropic receptors, as well as TRPA1 channels, which was demonstrated to cause inhibition of GAT-3 GABA uptake to increase extracellular GABA and inhibit adjacent neurons [56]. In order to better understand the relation of this discovery of calcium microdomain transients in endfeet and fine processes compared to IP3 induced somatic calcium release from endoplasmic reticulum stores, astrocytes and neurons in barrel cortices were observed after whisker deflection in mice. Calcium responses rapidly followed neuronal events and were independent of neuromodulatory activity from IP3R2 mediated signaling via acetylcholine, serotonin or norepinephrine receptors, which indicated astrocytes were quick enough to play a role in synaptic modulation and neurovascular coupling, while also capable of slower responses via IP3 [57].

3.3 Regulation of Unconscious Behaviors

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 CO2 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.

4. Astrocytes in Aging and Dementia

Synapse loss and cognitive decline is a byproduct of aging, and synapse loss is observed early in dementias such as Alzheimer’s disease [69, 70]. Astrocytes and microglia work in concert to react to injury, disease and aging by changing their morphology and genetic expression profile in the hopes of rescuing apoptotic neurons, phagocytosing necrotic neurons and degrading protein accumulation [71, 72, 73]. Astrocytes in this state of neuroinflammation are ‘reactive’, and devote their activities to the disrupted parenchyma [74]. Increased astrocyte reactivity correlates with cognitive decline [75, 76]. Because astrocytes are responsible for maintaining synaptic integrity, and synapse loss is the prevalent hallmark of dementia and aging, recent studies have begun to consider neurodegeneration and cognitive decline from the perspective of early astrocyte dysfunction or atrophy [71]. Astrocyte atrophy has been observed early in the entorhinal cortex in mouse models of Alzheimer’s disease [77, 78]. In mice, it has also been recently shown that astrocyte gene expression changes as a function of age, increasing synaptic pruning biomarkers that may accelerate disease [79]. Astrocyte senescence can cause vascular dysfunction, glutamate excitotoxicity and neural stem cell loss [80]. In a study on 766 individuals from publicly available whole-brain transcriptomes in human Alzheimer’s disease compared with control or mild cognitive impairment, the main difference found was in endolysosomal organelle loss early in disease in astrocytes followed by mitochondrial dysfunction, which suggests astrocyte dysfunction is the driver of the onset of dementia [81]. Likewise, monoclonal antibody treatments to target amyloid-β from the brain have been effective at removing plaques thought to be responsible for neuronal cell death, but cognitive decline persists [82, 83, 84]. Using a reactive astrocyte PET tracer 11C-BU99008, it was discovered that in late Alzheimer’s decreased astrocyte ability for tracer uptake corresponded to increased amyloid-β load in the region, indicating a loss of astrocyte function may correlate or precede amyloid-β deposition [85]. The astrocyte endolysosomal system is also responsible for the removal and degradation of proteins such as amyloid precursor protein, α-synuclein, tau, and huntingtin which accumulate in aging and dementia [86]. The proteins now appear to be ancillary byproducts of disease instead of the cause of cognitive decline, providing further evidence astrocyte dysfunction precedes their accumulation. Lastly, blood flow through neurovascular coupling, which is dependent on astrocytes, is also reduced in aging and dementia [87]. Therefore studies on dementia and aging demonstrate that cognition is inversely proportional to the fitness of the astrocyte: is this because of the quondam notion that neurons are dependent on them for support, or because astrocytes are the reason for cognition themselves?

5. The Vorstellung Cell
5.1 Astrocyte Anatomy in the Hippocampus and Cortex

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].

5.2 Astrocyte Learning and Memory
5.2.1 Excitatory Modulation

In the hippocampus, in order to facilitate cellular learning in the form of LTP and long term depression (LTD), or synaptic changes as defined by “Hebb’s rule”, it was discovered that spike timing is required, and that another element to provide this is required besides pre-synaptic and post-synaptic elements [96]. In initial experiments that included the astrocyte, it was thought they could only respond to intense synaptic activity, but it was soon realized that astrocytes can modulate and control basal activity in a regulated way, and were involved in all synaptic activity in the hippocampus [97]. During retained memory by place cells in the hippocampus and grid cells in the entorhinal cortex, astrocytes could respond to input and facilitation of synaptic strength to control cellular memory in adjacent neurons [98]. Likewise, LTP, long held to be the gold standard of learning and memory at the cellular level, can be caused by increase calcium levels in astrocytes causing the release of NMDA receptor binding D-serine [99]. When CA1 astrocytes were specifically activated, it was demonstrated that astrocytes alone can cause memory enhancement and potentiation in neurons [100]. Reduction of gamma frequency was also observed by impaired performance on the novel object recognition test when hippocampal astrocytes were manipulated. However, fear conditioning as responsible for the amygdala and working memory for the prefrontal cortex remained unchanged [101].

Similarly, astrocytes isolated from human brain, and implanted into mice were preferentially taken up into synaptic circuits. Mice performed better on a battery of learning tasks to assess whether improved LTP by human astrocyte in the hippocampus resulted in improved learning. The mice with human astrocyte implants performed better on auditory fear conditioning, contextual fear conditioning, the Barnes maze and an object recognition test. Human astrocytes were much larger, more complex with more rapid calcium communication and connectivity [102].

Although some conflicting evidence on the neuronal influence and astrocyte control through somatic calcium [54, 103] or transient calcium at fine processes [104], the general evidence supports an astrocyte as the bridge of neuronal input and output in learning and memory in the hippocampus [105]. Recently, the use of designer receptors exclusively activated by designer drugs (DREADDs) to effect Gq and Gi pathways showed that astrocytes drive synaptic potentiation through G-protein coupled receptors (GPCRs) [106].

5.2.2 Inhibitory Modulation

Additionally, astrocytes respond to inhibitory neurons through expression of GABAB receptors and uptake of GABA through GAT-3, which can cause transmitter release from astrocytes that can regulate excitatory transmission in the hippocampus [36, 107]. GABAB receptor activation on astrocytes [108] by somatostatin expressing inhibitory neurons also demonstrated the facilitated repression of excitatory glutamatergic pyramidal neurons in the hippocampus [36, 109]. Astrocytes have also been shown to decode inhibitory signals in the CA3-CA1 glutamatergic synapse to affect hippocampal theta and gamma oscillations [110], two phenomena historically thought to be strictly neural correlates of consciousness regulating hippocampal-cortical communication during episodic memory [111]. Further studies demonstrated that inhibitory neuron activation of barge activity was completely mediated by astrocytes [112].

5.3 Keystone Cell in the Cortex
5.3.1 Excitatory Modulation

Although not as simply measured as unconscious and learning and memory behavioral outcomes, astrocytes unique keystone position in the cortex also provides them with the ability to respond to, assemble and manipulate cortical neuronal communication. For example, it was shown that in the ventrobasal thalamus, CA1 hippocampus and somatosensory cortex, astrocyte gliotransmission can synchronize neurons up to 200 microns away, and that an individual astrocyte determines a neuron’s synchronized network [113]. In the whisker barrel cortex of mice, stimulation of the whisker and subsequent neuronal input will cause increases in astrocytic cytosolic communication [114]. One measureable output, vigilance, demonstrated that cortical astrocytes receiving projections from the locus coeruleus of noradrenergic synapses caused increased vigilance through astrocytic second messenger pathways [115]. Astrocytes have been shown to be responsible for memory consolidation and performance through vigilance and arousal in other experiments on learning and memory as well as cortical communication [116]. Injection of astrocyte toxin L-AA in the prefrontal cortex caused attentional set-shifting, working memory and reversal learning deficits. In surviving neurons in the area of the application of the toxin, dendritic atrophy was widespread [117]. Inhibition of gliotransmission with the controversial dnSNARE technique, which may inhibit some neurotransmission, also disrupted the synchronization of theta oscillations, thought to be essential for cognition, between the dorsal hippocampus and prefrontal cortex [118]. Cortical UP states and synchronization of cortical circuits has shown to be governed by astrocytes, demonstrating astrocytic control of neuronal ensembles in the cortex [119, 120].

5.3.2 Inhibitory Modulation

Recently, the idea that inhibitory interneurons are the regulatory element in cortical cognition was challenged when it was observed that astrocytes act as an intermediary through GABAergic interneurons to control gamma oscillation, and that effecting astrocytes themselves could also change gamma oscillations in the cortex [121]. In the visual cortex, photostimulation of astrocytes could enhance both inhibitory and excitatory neuronal firing through type 1a mGLURs, indicating independent astrocytic control of neuronal firing [122]. The observed effect of astrocyte GABAB receptors responding to inhibitory interneurons and in turn effecting other interneurons has also been demonstrated in the cortex [123].

5.4 Computational Considerations of the Astrocyte

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.

6. Discussion

Astrocytes clearly respond to and effect all processes previously linked to cognition and perception. How involved are they? Experimentation has just touched the surface of astrocyte physiology and cognition—for example, observations indicate astrocytes change in early post-natal development—could this be the basis for childhood amnesia [144]? What about the difference in the perception of time in infants and children compared to adults: could this have an astrocytic basis? Consider the recent ground breaking discovery of the glymphatic pathway, where astrocytes provide waste clearance through the CSF during sleep. Is this why we cognitively shut down during sleep, for astrocytes to clean up and repair [145, 146]? Are astrocytes the cells that dream? And what of the various astrocyte subtypes currently being discovered, how do they each contribute to cognition [147]? On an artificial intelligence level, it appears this dichotomy of signaling, neuronal and astrocytic, and not neuronal alone, will be the only way to understand or replicate human perception and intellect.

Taking it further, is it possible astrocytes are the cells that give us the feeling of a separate mind and body so pervasive in human historical religious and philosophical texts—that they are our perception, imagination, moments of inspiration, decision to move, the vijñāna, Kant’s schema and Ryle’s ‘ghost’ in the machine? Are our astrocytes the biological basis for Schopenhauer’s Vorstellung, providing the illusion of reality in our consciousness? This may seem to place astrocytes on a pedestal above neurons. However, consider neurons in this paradigm: they can manipulate and trick astrocytes with false input, or be fine-tuned to send more accurate information to astrocytes about the world around us. They are the messenger, like someone describing the complexities of the infinite with finite tools, as astrocytes contemplate what it means and what to do about it. The objective reality outside space and time that we attempt to perceive, is an illusion cogitating from limited neuronal input. And although this creates a subjective experience, how we handle it is real to us, and as Schopenhauer believed, to be valued beyond our basic wants, and the only way to avoid the objective will and suffering. “The subjective and objective do not form a continuum. That of which we are made immediately conscious is limited by our skin, or rather by the very tips of the nerves which emanate from the cerebral system. Beyond this lies a world of which we have no knowledge except through the pictures in our head”, said Schopenhauer [24].

It may be that astrocytes are the Vorstellung, the subjective pictures in our head, our illusion of objective reality. To use an analogy that draws upon Schopenhauer’s belief that music was the highest form of art that could tap into the objective will—our Vorstellung is the bushy astrocyte guitarist listening, creating and strumming a multitude of neuronal strings.

Unless of course, an astrocytic basis to our imagination, is only in our imagination.

Abbreviations

DREADs, designer receptors exclusively activated by designer drugs; GAT-3, GABA Transporter-3; GPCR, G-protein coupled receptor; IP3, inositol triphosphate; IP3R2, inositol triphosphate receptor 2; mGLUR, metabotropic glutamate receptor; L-AA, L-α-aminoadipate; LTP, long term potentiation; LTD, long term depression; TNFα, tumor necrosis factor alpha.

Author Contributions

All work was conceived and completed by AOK.

Ethics Approval and Consent to Participate

Not applicable.

Acknowledgment

We would like to thank Irene Luccia Pearl for help with manuscript preparation.

Funding

This research received no external funding.

Conflict of Interest

The author declares no conflict of interest.

References
[1]
MacDonald AJ, Robb JL, Morrissey NA, Beall C, Ellacott KLJ. Astrocytes in neuroendocrine systems: an overview. Journal of Neuroendocrinology. 2019; 31: e12726.
[2]
Akther S, Hirase H. Assessment of astrocytes as a mediator of memory and learning in rodents. Glia. 2021. (in press)
[3]
Araque A, Carmignoto G, Haydon P, Oliet SR, Robitaille R, Volterra A. Gliotransmitters Travel in Time and Space. Neuron. 2014; 81: 728–739.
[4]
Savtchouk I, Volterra A. Gliotransmission: beyond Black-and-White. The Journal of Neuroscience. 2018; 38: 14–25.
[5]
Garg U, Yang K, Sengupta A. Emulation of Astrocyte Induced Neural Phase Synchrony in Spin-Orbit Torque Oscillator Neurons. Frontiers in Neuroscience. 2021; 15: 699632.
[6]
Bartels A, Zeki S. The temporal order of binding visual attributes. Vision Research. 2006; 46: 2280–2286.
[7]
Milner PM. A model for visual shape recognition. Psychological Review. 1974; 81: 521–535.
[8]
Oberheim NA, Wang X, Goldman S, Nedergaard M. Astrocytic complexity distinguishes the human brain. Trends in Neurosciences. 2006; 29: 547–553.
[9]
Oberheim NA, Takano T, Han X, He W, Lin JHC, Wang F, et al. Uniquely Hominid Features of Adult Human Astrocytes. Journal of Neuroscience. 2009; 29: 3276–3287.
[10]
Fields RD, Araque A, Johansen-Berg H, Lim S, Lynch G, Nave K, et al. Glial biology in learning and cognition. the Neuroscientist. 2014; 20: 426–431.
[11]
Augusto-Oliveira M, Arrifano GP, Takeda PY, Lopes-Araújo A, Santos-Sacramento L, Anthony DC, et al. Astroglia-specific contributions to the regulation of synapses, cognition and behaviour. Neuroscience and Biobehavioral Reviews. 2020; 118: 331–357.
[12]
Butt A, Verkhratsky A. Neuroglia: Realising their true potential. Brain and Neuroscience Advances. 2018; 2: 2398212818817495.
[13]
Fiacco TA, McCarthy KD. Multiple Lines of Evidence Indicate that Gliotransmission does not Occur under Physiological Conditions. The Journal of Neuroscience. 2018; 38: 3–13.
[14]
Bodhi B. In the Buddha’s Words: An anthology of Discourses from the Pali Canon (The Teachings of the Buddha). 5th edn. Wisdom Press: Somerville, MA. 2005.
[15]
Mitchell S. Bhagavad Gita: A New Translation. Harmony Press: New York, NY. 2002.
[16]
Bennett MR. Development of the concept of mind. The Australian and New Zealand Journal of Psychiatry. 2007; 41: 943–956.
[17]
Cobb M. Timeline: exorcizing the animal spirits: Jan Swammerdam on nerve function. Nature Reviews Neuroscience. 2002; 3: 395–400.
[18]
Smith CUM. Chapter 9: understanding the nervous system in the 18th century. Handbook of Clinical Neurology. 2010; 95: 107–114.
[19]
Lokhorst GJ, Kaitaro TT. The originality of Descartes’ theory about the pineal gland. Journal of the History of the Neurosciences. 2001; 10: 6–18.
[20]
Koestler A. The Ghost in the Machine. Macmillan: New York, NY. 1967.
[21]
Ameriks K. Kant’s Theory of Mind: An Analysis of the Paralogisms of Pure Reason. Clarendon Press: Oxford. 1982.
[22]
Banham G. Kant’s Transcendental Imagination. Palgrave Macmillan: New York, NY. 2006.
[23]
Schopenhauer A. Die Welt als Wille und Vorstellung. 1st edn. Brockhaus: Leipzig. 1819.
[24]
Schopenhauer A. The World as Will and Idea. Abridged in One Volume. Ed: D. Berman, Trans: J. Berman. Tuttle Press, Everyman Library: Vermont. 1995.
[25]
Skinner BF. Cognitive science and behaviourism. British Journal of Psychology. 1985; 76: 291–301.
[26]
Hebb DO. Organization of Behavior. Psychology Press: New York, NY. 1949.
[27]
Galambos R. A glia-neural theory of brain function. Proceedings of the National Academy of Sciences of the United States of America. 1961; 47: 129–136.
[28]
Ramón y Cajal S. Textura del Sistema Nervioso del Hombre y de los Vertebrados. Tomo I. Imprenta y Librería de Nicolás Moya: Madrid. 1899.
[29]
Cornell-Bell AH, Finkbeiner SM, Cooper MS, Smith SJ. Glutamate Induces Calcium Waves in Cultured Astrocytes: Long-Range Glial Signaling. Science. 1990; 247: 470–473.
[30]
Dani JW, Chernjavsky A, Smith SJ. Neuronal activity triggers calcium waves in hippocampal astrocyte networks. Neuron. 1992; 8: 429–440.
[31]
Smith SJ. Do astrocytes process neural information? Progress in Brain Research. 1992; 94: 119–136.
[32]
Porter JT, McCarthy KD. Hippocampal astrocytes in situ respond to glutamate released from synaptic terminals. The Journal of Neuroscience. 1996; 16: 5073–5081.
[33]
Balázs R, Miller S, Romano C, de Vries A, Chun Y, Cotman CW. Metabotropic glutamate receptor mGluR5 in astrocytes: pharmacological properties and agonist regulation. Journal of Neurochemistry. 1997; 69: 151–163.
[34]
Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG. Glutamate-mediated astrocyte–neuron signalling. Nature. 1994; 369: 744–747.
[35]
Pasti L, Volterra A, Pozzan T, Carmignoto G. Intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ. The Journal of Neuroscience. 1997; 17: 7817–7830.
[36]
Kang J, Jiang L, Goldman SA, Nedergaard M. Astrocyte-mediated potentiation of inhibitory synaptic transmission. Nature Neuroscience. 1998; 1: 683–692.
[37]
Yang Y, Ge W, Chen Y, Zhang Z, Shen W, Wu C, et al. Contribution of astrocytes to hippocampal long-term potentiation through release of D-serine. Proceedings of the National Academy of Sciences of the United States of America 2003; 100: 15194–15199.
[38]
Newman EA. Glial cell inhibition of neurons by release of ATP. The Journal of Neuroscience. 2003; 23: 1659–1666.
[39]
Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses: glia, the unacknowledged partner. Trends in Neurosciences. 1999; 22: 208–215.
[40]
Koob AO, Cirillo J, Babbs CF. A novel open field activity detector to determine spatial and temporal movement of laboratory animals after injury and disease. Journal of Neuroscience Methods. 2006; 157: 330–336.
[41]
Christopherson KS, Ullian EM, Stokes CCA, Mullowney CE, Hell JW, Agah A, et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell. 2005; 120: 421–433.
[42]
Stogsdill JA, Ramirez J, Liu D, Kim YH, Baldwin KT, Enustun E, et al. Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis. Nature. 2017; 551: 192–197.
[43]
Allen NJ, Bennett ML, Foo LC, Wang GX, Chakraborty C, Smith SJ, et al. Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. Nature. 2012; 486: 410–414.
[44]
Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006; 440: 1054–1059.
[45]
Seifert G, Schilling K, Steinhäuser C. Astrocyte dysfunction in neurological disorders: a molecular perspective. Nature Reviews Neuroscience. 2006; 7: 194–206.
[46]
Syková E, Nicholson C. Diffusion in brain extracellular space. Physiological Reviews. 2008; 88: 1277–1340.
[47]
Schafer DP, Lehrman EK, Stevens B. The “quad-partite” synapse: Microglia-synapse interactions in the developing and mature CNS. Glia. 2013; 61: 24–36.
[48]
Iadecola C. The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease. Neuron. 2017; 96: 17–42.
[49]
Fujita T, Chen MJ, Li B, Smith NA, Peng W, Sun W, et al. Neuronal transgene expression in dominant-negative SNARE mice. The Journal of Neuroscience. 2014; 34: 16594–16604.
[50]
Sun W, McConnell E, Pare J, Xu Q, Chen M, Peng W, et al. Glutamate-dependent neuroglial calcium signaling differs between young and adult brain. Science. 2013; 339: 197–200.
[51]
Umpierre AD, West PJ, White JA, Wilcox KS. Conditional Knock-out of mGluR5 from Astrocytes during Epilepsy Development Impairs High-Frequency Glutamate Uptake. The Journal of Neuroscience. 2019; 39: 727–742.
[52]
Porter JT, McCarthy KD. Astrocytic neurotransmitter receptors in situ and in vivo. Progress in Neurobiology. 1997; 51: 439–455.
[53]
Bazargani N, Attwell D. Astrocyte calcium signaling: the third wave. Nature Neuroscience. 2016; 19: 182–189.
[54]
Agulhon C, Fiacco TA, McCarthy KD. Hippocampal short- and long-term plasticity are not modulated by astrocyte Ca2+ signaling. Science. 2010; 327: 1250–1254.
[55]
Srinivasan R, Huang BS, Venugopal S, Johnston AD, Chai H, Zeng H, et al. Ca (2+) signaling in astrocytes from Ip3r2−/− mice in brain slices and during startle responses in vivo. Nature Neuroscience. 2015; 18: 708–717.
[56]
Shigetomi E, Tong X, Kwan KY, Corey DP, Khakh BS. TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy through GAT-3. Nature Neuroscience. 2011; 15: 70–80.
[57]
Stobart JL, Ferrari KD, Barrett MJP, Glück C, Stobart MJ, Zuend M, et al. Cortical Circuit Activity Evokes Rapid Astrocyte Calcium Signals on a Similar Timescale to Neurons. Neuron. 2018; 98: 726–735.e4.
[58]
Gourine AV, Kasymov V, Marina N, Tang F, Figueiredo MF, Lane S, et al. Astrocytes control breathing through pH-dependent release of ATP. Science. 2010; 329: 571–575.
[59]
Oliet SHR. Functional consequences of morphological neuroglial changes in the magnocellular nuclei of the hypothalamus. Journal of Neuroendocrinology. 2002; 14: 241–246.
[60]
Tso CF, Simon T, Greenlaw AC, Puri T, Mieda M, Herzog ED. Astrocytes Regulate Daily Rhythms in the Suprachiasmatic Nucleus and Behavior. Current Biology. 2017; 27: 1055–1061.
[61]
Brancaccio M, Patton AP, Chesham JE, Maywood ES, Hastings MH. Astrocytes Control Circadian Timekeeping in the Suprachiasmatic Nucleus via Glutamatergic Signaling. Neuron. 2017; 93: 1420–1435.e5.
[62]
Barca-Mayo O, Pons-Espinal M, Follert P, Armirotti A, Berdondini L, De Pietri Tonelli D. Astrocyte deletion of Bmal1 alters daily locomotor activity and cognitive functions via GABA signalling. Nature Communications. 2017; 8: 14336.
[63]
Kim JG, Suyama S, Koch M, Jin S, Argente-Arizon P, Argente J, et al. Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nature Neuroscience. 2014; 17: 908–910.
[64]
Wells T. Vesicular osmometers, vasopression secretion and aquaporin-4: a new mechanism for osmoreception? Molecular and Cellular Endocrinology. 1998; 136: 103–107.
[65]
Hussy N, Brès V, Rochette M, Duvoid A, Alonso G, Dayanithi G, et al. Osmoregulation of vasopressin secretion via activation of neurohypophysial nerve terminals glycine receptors by glial taurine. The Journal of Neuroscience. 2001; 21: 7110–7116.
[66]
Martin-Fernandez M, Jamison S, Robin LM, Zhao Z, Martin ED, Aguilar J, et al. Synapse-specific astrocyte gating of amygdala-related behavior. Nature Neuroscience. 2017; 20: 1540–1548.
[67]
Corkrum M, Covelo A, Lines J, Bellocchio L, Pisansky M, Loke K, et al. Dopamine-Evoked Synaptic Regulation in the Nucleus Accumbens Requires Astrocyte Activity. Neuron. 2020; 105: 1036–1047.e5.
[68]
Corkrum M, Rothwell PE, Thomas MJ, Kofuji P, Araque A. Opioid-Mediated Astrocyte-Neuron Signaling in the Nucleus Accumbens. Cells 2019; 8: 586.
[69]
Masliah E, Mallory M, Hansen L, DeTeresa R, Terry RD. Quantitative synaptic alterations in the human neocortex during normal aging. Neurology. 1993; 43: 192–197.
[70]
DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Annals of Neurology. 1990; 27: 457–464.
[71]
Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathologica. 2010; 119: 7–35.
[72]
Anderson MA, Ao Y, Sofroniew MV. Heterogeneity of reactive astrocytes. Neuroscience Letters. 2014; 565: 23–29.
[73]
Damisah EC, Hill RA, Rai A, Chen F, Rothlin CV, Ghosh S, et al. Astrocytes and microglia play orchestrated roles and respect phagocytic territories during neuronal corpse removal in vivo. Science Advances. 2020; 6: eaba3239.
[74]
Escartin C, Galea E, Lakatos A, O’Callaghan JP, Petzold GC, Serrano-Pozo A, et al. Reactive astrocyte nomenclature, definitions, and future directions. Nature Neuroscience 2021; 24: 312–325.
[75]
Kashon ML, Ross GW, O’Callaghan JP, Miller DB, Petrovitch H, Burchfiel CM, et al. Associations of cortical astrogliosis with cognitive performance and dementia status. Journal of Alzheimer’s Disease. 2004; 6: 595–604.
[76]
Ownby RL. Neuroinflammation and cognitive aging. Current Psychiatry Reports. 2010; 12: 39–45.
[77]
Rodríguez-Arellano JJ, Parpura V, Zorec R, Verkhratsky A. Astrocytes in physiological aging and Alzheimer’s disease. Neuroscience. 2016; 323: 170–182.
[78]
Yeh CY, Vadhwana B, Verkhratsky A, Rodríguez JJ. Early astrocytic atrophy in the entorhinal cortex of a triple transgenic animal model of Alzheimer’s disease. ASN Neuro. 2011; 3: 271–279.
[79]
Boisvert MM, Erikson GA, Shokhirev MN, Allen NJ. The Aging Astrocyte Transcriptome from Multiple Regions of the Mouse Brain. Cell Reports. 2018; 22: 269–285.
[80]
Han X, Zhang T, Liu H, Mi Y, Gou X. Astrocyte Senescence and Alzheimer’s Disease: A Review. Frontiers in Aging Neuroscience. 2020; 12: 148.
[81]
Galea E, Weinstock LD, Larramona-Arcas R, Pybus AF, Giménez-Llort L, Escartin C, et al. Multi-transcriptomic analysis points to early organelle dysfunction in human astrocytes in Alzheimer’s disease. Neurobiology of Disease. 2022; 166: 105655.
[82]
Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces aβ plaques in Alzheimer’s disease. Nature. 2016; 537: 50–56.
[83]
Knopman DS, Jones DT, Greicius MD. Failure to demonstrate efficacy of aducanumab: an analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimer’s and Dementia. 2021; 17: 696–701.
[84]
Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease. New England Journal of Medicine. 2018; 378: 321–330.
[85]
Livingston NR, Calsolaro V, Hinz R, Nowell J, Raza S, Gentleman S, et al. Relationship between astrocyte reactivity, using novel (11) C-BU99008 PET, and glucose metabolism, grey matter volume and amyloid load in cognitively impaired individuals. Molecular Psychiatry. 2022. (in press)
[86]
Wong C-O. Endosomal-Lysosomal Processing of Neurodegeneration-Associated Proteins in Astrocytes. International Journal of Molecular Medicine. 2020; 21: 5149.
[87]
Stackhouse TL, Mishra A. Neurovascular Coupling in Development and Disease: Focus on Astrocytes. Frontiers in Cell and Developmental Biology. 2021; 9: 702832.
[88]
Livet J, Weissman TA, Kang H, Draft RW, Lu J, Bennis RA, et al. Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature. 2007; 450: 56–62.
[89]
Bushong EA, Martone ME, Jones YZ, Ellisman MH. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. The Journal of Neuroscience. 2002; 22: 183–192.
[90]
Fellin T, Pascual O, Gobbo S, Pozzan T, Haydon PG, Carmignoto G. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron. 2004; 43: 729–743.
[91]
Volterra A, Meldolesi J. Astrocytes, from brain glue to communication elements: the revolution continues. Nature Reviews Neuroscience. 2005; 6: 626–640.
[92]
Haydon PG, Carmignoto G. Astrocyte control of synaptic transmission and neurovascular coupling. Physiological Reviews. 2006; 86: 1009–1031.
[93]
Eroglu C, Barres BA. Regulation of synaptic connectivity by glia. Nature. 2010; 468: 223–231.
[94]
Oberheim NA, Goldman SA, Nedergaard M. Heterogeneity of astrocytic form and function. Methods in Molecular Biology. 2012; 814: 23–45.
[95]
Lim EY, Ye L, Paukert M. Potential and Realized Impact of Astroglia Ca 2+ Dynamics on Circuit Function and Behavior. Frontiers in Cellular Neuroscience. 2021; 15: 682888.
[96]
Bi G, Poo M. Synaptic Modifications in Cultured Hippocampal Neurons: Dependence on Spike Timing, Synaptic Strength, and Postsynaptic Cell Type. The Journal of Neuroscience. 1998; 18: 10464–10472.
[97]
Panatier A, Vallée J, Haber M, Murai KK, Lacaille JC, Robitaille R. Astrocytes are endogenous regulators of basal transmission at central synapses. Cell. 2011; 146: 785–798.
[98]
Hassanpoor H, Fallah A, Raza M. Mechanisms of hippocampal astrocytes mediation of spatial memory and theta rhythm by gliotransmitters and growth factors. Cell Biology International. 2014; 38: 1355–1366.
[99]
Henneberger C, Papouin T, Oliet SHR, Rusakov DA. Long-term potentiation depends on release of D-serine from astrocytes. Nature. 2010; 463: 232–236.
[100]
Adamsky A, Kol A, Kreisel T, Doron A, Ozeri-Engelhard N, Melcer T, et al. Astrocytic Activation Generates De Novo Neuronal Potentiation and Memory Enhancement. Cell. 2018; 174: 59–71.e14.
[101]
Lee HS, Ghetti A, Pinto-Duarte A, Wang X, Dziewczapolski G, Galimi F, et al. Astrocytes contribute to gamma oscillations and recognition memory. Proceedings of the National Academy of Sciences of the United States of America. 2014; 111: E3343–E3352.
[102]
Han X, Chen M, Wang F, Windrem M, Wang S, Shanz S, et al. Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell. 2013; 12: 342–353.
[103]
Nakayama R, Sasaki T, Tanaka KF, Ikegaya Y. Subcellular calcium dynamics during juvenile development in mouse hippocampal astrocytes. The European Journal of Neuroscience. 2016; 43: 923–932.
[104]
Lia A, Henriques VJ, Zonta M, Chiavegato A, Carmignoto G, Gómez-Gonzalo M, et al. Calcium Signals in Astrocyte Microdomains, a Decade of Great Advances. Frontiers in Cellular Neuroscience. 2021; 15: 673433.
[105]
Semyanov A, Henneberger C, Agarwal A. Making sense of astrocytic calcium signals — from acquisition to interpretation. Nature Reviews Neuroscience. 2020; 21: 551–564.
[106]
Van Den Herrewegen Y, Sanderson TM, Sahu S, De Bundel D, Bortolotto ZA, Smolders I. Side-by-side comparison of the effects of Gq- and Gi-DREADD-mediated astrocyte modulation on intracellular calcium dynamics and synaptic plasticity in the hippocampal CA1. Molecular Brain. 2021; 14: 144.
[107]
Boddum K, Jensen TP, Magloire V, Kristiansen U, Rusakov DA, Pavlov I, et al. Astrocytic GABA transporter activity modulates excitatory neurotransmission. Nature Communications. 2016; 7: 13572.
[108]
MacVicar B, Tse F, Crichton S, Kettenmann H. GABA-activated Cl- channels in astrocytes of hippocampal slices. The Journal of Neuroscience. 1989; 9: 3577–3583.
[109]
Matos M, Bosson A, Riebe I, Reynell C, Vallée J, Laplante I, et al. Astrocytes detect and upregulate transmission at inhibitory synapses of somatostatin interneurons onto pyramidal cells. Nature Communications. 2018; 9: 4254.
[110]
Perea G, Gómez R, Mederos S, Covelo A, Ballesteros JJ, Schlosser L, et al. Activity-dependent switch of GABAergic inhibition into glutamatergic excitation in astrocyte-neuron networks. eLife. 2016; 5: e20362.
[111]
Tort ABL, Komorowski RW, Manns JR, Kopell NJ, Eichenbaum H. Theta-gamma coupling increases during the learning of item-context associations. Proceedings of the National Academy of Sciences of the United States of America. 2009; 106: 20942–20947.
[112]
Deemyad T, Lüthi J, Spruston N. Astrocytes integrate and drive action potential firing in inhibitory subnetworks. Nature Communications. 2018; 9: 4336.
[113]
Pirttimaki TM, Sims RE, Saunders G, Antonio SA, Codadu NK, Parri HR. Astrocyte-Mediated Neuronal Synchronization Properties Revealed by False Gliotransmitter Release. The Journal of Neuroscience. 2017; 37: 9859–9870.
[114]
Wang X, Lou N, Xu Q, Tian G, Peng WG, Han X, et al. Astrocytic Ca2+ signaling evoked by sensory stimulation in vivo. Nature Neuroscience. 2006; 9: 816–823.
[115]
Oe Y, Wang X, Patriarchi T, Konno A, Ozawa K, Yahagi K, et al. Distinct temporal integration of noradrenaline signaling by astrocytic second messengers during vigilance. Nature Communications. 2020; 11: 471.
[116]
Santello M, Toni N, Volterra A. Astrocyte function from information processing to cognition and cognitive impairment. Nature Neuroscience. 2019; 22: 154–166.
[117]
Lima A, Sardinha VM, Oliveira AF, Reis M, Mota C, Silva MA, et al. Astrocyte pathology in the prefrontal cortex impairs the cognitive function of rats. Molecular Psychiatry. 2014; 19: 834–841.
[118]
Sardinha VM, Guerra-Gomes S, Caetano I, Tavares G, Martins M, Reis JS, et al. Astrocytic signaling supports hippocampal-prefrontal theta synchronization and cognitive function. Glia. 2017; 65: 1944–1960.
[119]
Poskanzer KE, Yuste R. Astrocytes regulate cortical state switching in vivo. Proceedings of the National Academy of Sciences of the United States of America. 2016; 113: E2675–E2684.
[120]
Poskanzer KE, Yuste R. Astrocytic regulation of cortical up states. Proceedings of the National Academy of Sciences of the United States of America. 2011; 108: 18453–18458.
[121]
Mederos S, Sánchez-Puelles C, Esparza J, Valero M, Ponomarenko A, Perea G. GABAergic signaling to astrocytes in the prefrontal cortex sustains goal-directed behaviors. Nature Neuroscience. 2021; 24: 82–92.
[122]
Perea G, Yang A, Boyden ES, Sur M. Optogenetic astrocyte activation modulates response selectivity of visual cortex neurons in vivo. Nature Communications. 2014; 5: 3262.
[123]
Mariotti L, Losi G, Lia A, Melone M, Chiavegato A, Gómez-Gonzalo M, et al. Interneuron-specific signaling evokes distinctive somatostatin-mediated responses in adult cortical astrocytes. Nature Communications. 2018; 9: 82.
[124]
Manninen T, Havela R, Linne M. Computational Models for Calcium-Mediated Astrocyte Functions. Frontiers in Computational Neuroscience. 2018; 12: 14.
[125]
Kastanenka KV, Moreno‐Bote R, De Pittà M, Perea G, Eraso‐Pichot A, Masgrau R, et al. A roadmap to integrate astrocytes into Systems Neuroscience. Glia. 2020; 68: 5–26.
[126]
Turrigiano GG. The Self-Tuning Neuron: Synaptic Scaling of Excitatory Synapses. Cell. 2008; 135: 422–435.
[127]
Tsodyks M, Pawelzik K, Markram H. Neural networks with dynamic synapses. Neural Computation. 1998; 10: 821–835.
[128]
Wade J, McDaid L, Harkin J, Crunelli V, Kelso S. Biophysically based computational models of astrocyte neuron coupling and their functional significance. Frontiers in Computational Neuroscience. 2013; 7: 44.
[129]
Allegrini P, Fronzoni L, Pirino D. The influence of the astrocyte field on neuronal dynamics and synchronization. Journal of Biological Physics. 2009; 35: 413–423.
[130]
Min R, Santello M, Nevian T. The computational power of astrocyte mediated synaptic plasticity. Frontiers in Computational Neuroscience. 2012; 6: 93.
[131]
Allam SL, Ghaderi VS, Bouteiller JC, Legendre A, Ambert N, Greget R, et al. A computational model to investigate astrocytic glutamate uptake influence on synaptic transmission and neuronal spiking. Frontiers in Computational Neuroscience. 2012; 6: 70.
[132]
De Pittà M, Volman V, Berry H, Parpura V, Volterra A, Ben-Jacob E. Computational quest for understanding the role of astrocyte signaling in synaptic transmission and plasticity. Frontiers in Computational Neuroscience. 2012; 6: 98.
[133]
Oschmann F, Berry H, Obermayer K, Lenk K. From in silico astrocyte cell models to neuron-astrocyte network models: a review. Brain Research Bulletin. 2018; 136: 76–84.
[134]
De Pittà M, Brunel N, Volterra A. Astrocytes: Orchestrating synaptic plasticity? Neuroscience. 2016; 323: 43–61.
[135]
De Pittà M, Brunel N. Modulation of Synaptic Plasticity by Glutamatergic Gliotransmission: A Modeling Study. Neural Plasticity. 2016; 2016: 7607924.
[136]
De Pittà M, Goldberg M, Volman V, Berry H, Ben-Jacob E. Glutamate regulation of calcium and IP3 oscillating and pulsating dynamics in astrocytes. Journal of Biological Physics. 2009; 35: 383–411.
[137]
Valenza G, Tedesco L, Lanata A, De Rossi D, Scilingo EP. Novel Spiking Neuron-Astrocyte Networks based on nonlinear transistor-like models of tripartite synapses. Annual International Conference of the IEEE Engineering in Medicine and Biology - Proceedings. 2013; 2013: 6559–6562.
[138]
Postnov DE, Ryazanova LS, Brazhe NA, Brazhe AR, Maximov GV, Mosekilde E, et al. Giant Glial Cell: New Insight through Mechanism-Based Modeling. Journal of Biological Physics. 2008; 34: 441–457.
[139]
Postnov DE, Koreshkov RN, Brazhe NA, Brazhe AR, Sosnovtseva OV. Dynamical patterns of calcium signaling in a functional model of neuron–astrocyte networks. Journal of Biological Physics. 2009; 35: 425–445.
[140]
Nazari S, Amiri M, Faez K, Van Hulle MM. Information Transmitted from Bioinspired Neuron–Astrocyte Network Improves Cortical Spiking Network’s Pattern Recognition Performance. IEEE Transactions on Neural Networks and Learning Systems. 2020; 31: 464–474.
[141]
Lenk K, Satuvuori E, Lallouette J, Ladrón-de-Guevara A, Berry H, Hyttinen JAK. A Computational Model of Interactions Between Neuronal and Astrocytic Networks: The Role of Astrocytes in the Stability of the Neuronal Firing Rate. Frontiers in Computational Neuroscience. 2020; 13: 92.
[142]
Amiri M, Hosseinmardi N, Bahrami F, Janahmadi M. Astrocyte- neuron interaction as a mechanism responsible for generation of neural synchrony: a study based on modeling and experiments. Journal of Computational Neuroscience. 2013; 34: 489–504.
[143]
Aleksin SG, Zheng K, Rusakov DA, Savtchenko LP. ARACHNE: a neural-neuroglial network builder with remotely controlled parallel computing. PLoS Computational Biology. 2017; 13: e1005467.
[144]
Colombo JA, Lipina S, Yáñez A, Puissant V. Postnatal development of interlaminar astroglial processes in the cerebral cortex of primates. International Journal of Developmental Neuroscience. 1997; 15: 823–833.
[145]
Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Science Translational Medicine. 2012; 4: 147ra111.
[146]
Benveniste H, Heerdt PM, Fontes M, Rothman DL, Volkow ND. Glymphatic System Function in Relation to Anesthesia and Sleep States. Anesthesia and Analgesia. 2019; 128: 747–758.
[147]
Batiuk MY, Martirosyan A, Wahis J, de Vin F, Marneffe C, Kusserow C, et al. Identification of region-specific astrocyte subtypes at single cell resolution. Nature Communications. 2020; 11: 1220.
Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Share
Back to top