Astrocytic Modulation Research Articles

Neuritogenesis and protective effects activated by Angiotensin 1–7 in astrocytes-neuron interaction

The renin angiotensin system (RAS) has been studied for its effects on various neurological disorders. The identification of functional receptors for Ang-(1–7) and Ang II peptides in astrocytes highlights the physiological modulation and the important role of these cells in the central nervous system. The present study aims to understand the role of RAS peptides, particularly Ang-(1–7) and Ang II, in the secretion of trophic factors by astrocytes and their effects on hippocampal neurons. We used primary cultures of astrocytes and neurons from the hippocampus of either sex neonate of Wistar strain rats. In the present study, we demonstrated that the treatment of astrocytes with Ang-(1–7) acts on the modulation of these cells, inducing reactive astrogliosis, identified through the increase in the expression of GFAP. Furthermore, we obtained a conditioned medium from astrocytes treated with Ang-(1–7), which in addition to promoting the secretion of neurotrophic factors essential for neuronal-glial interactions that are fundamental for neuritogenesis and neuronal survival, showed a neuroprotective effect against glutamatergic excitotoxicity. In turn, Ang II does not exhibit the same effects on astrocyte modulation, exacerbating deleterious effects on brain RAS. Neuron-astrocyte interactions have been shown to be an integral part of the central effects mediated by RAS, and this study has significantly contributed to the understanding of the biochemical mechanisms involved in the functioning of this system.

Astrocytic Regulation of Cocaine Locomotor Sensitization in EcoHIV Infected Mice.

Cocaine use disorder (CUD) is highly comorbid with HIV infection and worsens HIV outcomes. Preclinical research on the outcomes of HIV infection may yield crucial information on neurobehavioral changes resulting from chronic drug exposure in people living with HIV (PLWH). Repeated exposure to cocaine alters behavioral responses to cocaine. This includes development of cocaine locomotor sensitization - or increased locomotor responses to the same doses of cocaine - which depends on nucleus accumbens (NAc) neural plasticity. NAc astrocytes are key regulators of neural activity and plasticity, and their function can be impaired by cocaine exposure and HIV infection, thus implicating them as potential regulators of HIV-induced changes in behavioral response to cocaine. To characterize the effects of HIV infection on cocaine locomotor sensitization, we employed the EcoHIV mouse model to assess changes in locomotor responses after repeated cocaine (10mg/kg) exposure and challenge. EcoHIV infection potentiated expression of cocaine sensitization. We also identified EcoHIV-induced increases in expression of the astrocytic nuclear marker Sox9 selectively in the NAc core. To investigate whether modulation of NAc astrocytes could reverse EcoHIV-induced deficits, we employed a chemogenetic approach. We found that chemogenetic activation of NAc astrocyte Gq signaling attenuated EcoHIV-enhanced cocaine sensitization. We propose that HIV infection contributes to cocaine behavioral sensitization and induces adaptations in NAc astrocytes, while promoting NAc astrocytic Gq-signaling can recover EcoHIV-induced behavioral changes. These findings identify potential cellular substrates of disordered cocaine-driven behavior in the context of HIV infection and point toward strategies to reduce cocaine-related behavior in PLWH.

Antidepressant-like effect of riparin I and riparin II against CUMS-induced neuroinflammation via astrocytes and microglia modulation in mice.

Depression is a common mood disorder and many patients do not respond to conventional pharmacotherapy or experience a variety of adverse effects. This work proposed that riparin I (RIP I) and riparin II (RIP II) present neuroprotective effects through modulation of astrocytes and microglia, resulting in the reversal of depressive-like behaviors. To verify our hypothesis and clarify the pathways underlying the effect of RIP I and RIP II on neuroinflammation, we used the chronic unpredictable mild stress (CUMS) depression model in mice. Male Swiss mice were exposed to stressors for 28 days. From 15 th to the 22 nd day, the animals received RIP I or RIP II (50 mg/kg) or fluoxetine (FLU, 10 mg/kg) or vehicle, by gavage. On the 29 th day, behavioral tests were performed. Expressions of microglia (ionized calcium-binding adaptor molecule-1 - Iba-1) and astrocyte (glial fibrillary acidic protein - GFAP) markers and levels of cytokines tumor necrosis factor alfa (TNF-α) and interleukin 1 beta (IL-1β) were measured in the hippocampus. CUMS induced depressive-like behaviors and cognitive impairment, high TNF-α and IL-1β levels, decreased GFAP, and increased Iba-1 expressions. RIP I and RIP II reversed these alterations. These results contribute to the understanding the mechanisms underlying the antidepressant effect of RIP I and RIP II, which may be related to neuroinflammatory suppression.

Astrocyte Modulation of Blood-Brain Barrier Functional Changes Induced by Circulating Small Extracellular Vesicles in Preeclampsia Plasma

Astrocyte Modulation of Blood-Brain Barrier Functional Changes Induced by Circulating Small Extracellular Vesicles in Preeclampsia Plasma

Glutamatergic and purinergic transmitters and astrocyte modulation in the synaptic transmission in the NTS of rats exposed to short-term sustained hypoxia.

There is evidence that astrocytes modulate synaptic transmission in the nucleus tractus solitarius (NTS) interacting with glutamatergic and purinergic mechanisms. Here, using in situ working heart-brainstem preparations, we evaluated the involvement of astrocyte and glutamatergic/purinergic neurotransmission in the processing of autonomic and respiratory pathways in the NTS of control and rats exposed to sustained hypoxia (SH). Baseline autonomic and respiratory activities and the responses to chemoreflex activation (KCN) were evaluated before and after microinjections of fluorocitrate (FCt, an astrocyte metabolic inhibitor), kynurenic acid, and pyridoxalphosphate-6-azophenyl-2',4'-disulfonate (PPADS) (nonselective antagonists of glutamatergic and purinergic receptors) into the rostral aspect of the caudal commissural NTS. FCt had no effects on the baseline parameters evaluated but reduced the bradycardic response to chemoreflex activation in SH rats. FCt combined with kynurenic acid and PPADS in control rats reduced the baseline duration of expiration, which was attenuated after SH. FCt produced a large increase in PN frequency discharge in control rats, which was reduced after SH, indicating a reduction in the astrocyte modulation after SH. The data show that 1) the bradycardic component of the peripheral chemoreflex is reduced in SH rats after astrocytes inhibition, 2) the inhibition of astrocytes in the presence of double antagonists in the NTS affects the modulation of baseline duration of expiration in control but not in SH rats, and 3) the autonomic and respiratory responses to chemoreflex activation are mediated by glutamatergic and purinergic receptors in the rostral aspect of the caudal commissural NTS.NEW & NOTEWORTHY Our findings indicate that the neurotransmission of autonomic and respiratory components of the peripheral chemoreflex in the nucleus tractus solitarius (NTS) is mediated by glutamatergic and purinergic mechanisms and reveal a selective involvement of NTS astrocytes in controlling the chemoreflex parasympathetic response in rats exposed to sustained hypoxia (SH) and the baseline duration of expiration mainly in control rats, indicating a selective role for astrocytes modulation in the NTS of control and SH rats.

Microglia and Astrocytes Responses Contribute to Alleviating Inflammatory Damage by Repetitive Transcranial Magnetic Stimulation in Rats with Traumatic Brain Injury.

Repetitive transcranial magnetic stimulation (rTMS) is a therapeutic strategy that shows promise in ameliorating the clinical sequelae following traumatic brain injury (TBI). These improvements are associated with neuroplastic changes in neurons and their synaptic connections. However, it has been hypothesized that rTMS may also modulate microglia and astrocytes, potentially potentiating their neuroprotective capabilities. This study aims to investigate the effects of high-frequency rTMS on microglia and astrocytes that may contribute to its neuroprotective effects. Feeney's weight-dropping method was used to establish rat models of moderate TBI. To evaluate the neuroprotective effect of high frequency rTMS on rats by observing the synaptic ultrastructure and the level of neuron apoptosis. The levels of several important inflammation-related proteins within microglia and astrocytes were assessed through immunofluorescence staining and western blot. Our findings demonstrate that injured neurons can be rescued through the modulation of microglia and astrocytes by rTMS. This modulation plays a key role in preserving the synaptic ultrastructure and inhibiting neuronal apoptosis. Among microglia, we observed that rTMS inhibited the levels of proinflammatory factors (CD16, IL-6 and TNF-α) and promoted the levels of anti-inflammatory factors (CD206, IL-10 and TNF-β). rTMS also reduced the levels of pyroptosis within microglia and pyroptosis-related proteins (NLRP3, Caspase-1, GSDMD, IL-1β and IL-18). Moreover, rTMS downregulated P75NTR expression and up-regulated IL33 expression in astrocytes. These findings suggest that regulation of microglia and astrocytes is the mechanism through which rTMS attenuates neuronal inflammatory damage after moderate TBI.

Astrocyte modulation of synaptic plasticity mediated by activity-dependent Sonic hedgehog signaling.

The influence of neural activity on astrocytes and their reciprocal interactions with neurons has emerged as an important modulator of synapse function. Astrocytes exhibit activity-dependent changes in gene expression, yet the molecular mechanisms by which they accomplish this have remained largely unknown. The molecular signaling pathway, Sonic hedgehog (Shh), mediates neuron-astrocyte communication and regulates the organization of cortical synapses. Here, we demonstrate that neural activity stimulates Shh signaling in cortical astrocytes and upregulates expression of Hevin and SPARC, astrocyte derived molecules that modify synapses. Whisker stimulation and chemogenetic activation both increase Shh activity in deep layers of the somatosensory cortex, where neuron-astrocyte Shh signaling is predominantly found. Experience-dependent Hevin and SPARC require intact Shh signaling and selective loss of pathway activity in astrocytes occludes experience-dependent structural plasticity. Taken together, these data identify Shh signaling as an activity-dependent, neuronal derived cue that stimulates astrocyte interactions with synapses and promotes synaptic plasticity.

Astrocytes as a mechanism for contextually-guided network dynamics and function.

Astrocytes are a ubiquitous and enigmatic type of non-neuronal cell and are found in the brain of all vertebrates. While traditionally viewed as being supportive of neurons, it is increasingly recognized that astrocytes play a more direct and active role in brain function and neural computation. On account of their sensitivity to a host of physiological covariates and ability to modulate neuronal activity and connectivity on slower time scales, astrocytes may be particularly well poised to modulate the dynamics of neural circuits in functionally salient ways. In the current paper, we seek to capture these features via actionable abstractions within computational models of neuron-astrocyte interaction. Specifically, we engage how nested feedback loops of neuron-astrocyte interaction, acting over separated time-scales, may endow astrocytes with the capability to enable learning in context-dependent settings, where fluctuations in task parameters may occur much more slowly than within-task requirements. We pose a general model of neuron-synapse-astrocyte interaction and use formal analysis to characterize how astrocytic modulation may constitute a form of meta-plasticity, altering the ways in which synapses and neurons adapt as a function of time. We then embed this model in a bandit-based reinforcement learning task environment, and show how the presence of time-scale separated astrocytic modulation enables learning over multiple fluctuating contexts. Indeed, these networks learn far more reliably compared to dynamically homogeneous networks and conventional non-network-based bandit algorithms. Our results fuel the notion that neuron-astrocyte interactions in the brain benefit learning over different time-scales and the conveyance of task-relevant contextual information onto circuit dynamics.

Modulation by Astrocytes of AMPA Currents in the NTS Neurons of Mice Is Reduced by Short Term-Sustained Hypoxia

Hypoxia due to reduction in the partial pressure of oxygen in the arterial blood (PaO2) activates the afferents of peripheral chemoreflex to produce cardiovascular and respiratory adjustments to bring PaO2 back to the normal range. Herein we evaluated the possible changes of astrocytic modulation on glutamatergic transmission in NTS neurons of mice submitted to short term-sustained hypoxia (SH). To reach this goal, we used Male C57Bl/6J mice (18-20g), which were submitted to SH (FiO2 0.1) or normoxia for 24 hours. Brainstem slices and whole-cell patch clamp technique were used to evaluate the synaptic transmission in NTS neurons. The intracellular calcium concentration in NTS astrocytes was evaluated by multiphoton microscopy and transgenic Aldh-CRE-GCAMP6f mice (Institutional Ethical Committee Approvals: #016/2018 and #1109/2022R1). SH increased the amplitude of TS-evoked AMPA currents [control: -72.8 ± 13.3 pA ( n = 12) vs SH: -120 ± 14.4 pA ( n = 21)] in NTS neurons with no changes on the rise- or decay-time. SH also increased the amplitude [control: 35.88 ± 7.9 pA ( n = 12) vs SH: 72.74 ± 15.47 pA ( n = 10)] and decay time [control: 61.8 ± 15.2 ms ( n = 9) vs SH: 286 ± 86.7 ms ( n = 10)] of TS evoked-NMDA currents in neurons, while the amplitude of extrasynaptic NMDA currents [control: 28.7 ± 7.4 pA ( n = 10) vs SH: 24.7 ± 3.2 pA ( n = 7)] was not affected. Perfusion with fluoracetate (FAC), a glial metabolism inhibitor, decreased the amplitude of TS-evoked AMPA currents in control group [aCSF: -54.29 ± 16.1 pA vs aCSF + FAC: -24.43 ± 6.82 pA ( n =9)] without affecting AMPA currents in SH neurons [aCSF: -124.5 ± 35.27 pA vs aCSF + FAC: -130.5 ± 50.16 pA ( n =8)]. The passive properties of astrocytes did not change after SH [RMP: -83.73 ± 11.85 mV ( n =10) vs −83.63 ± 11.86 mV ( n =10); Rinput: 123 ± 127.5 MΩ ( n =9) vs 208 ± 212.7 MΩ ( n =10)]. The increase in intracellular calcium concentration induced by AMPA in the astrocytes of control and SH mice was similar [Control: 112.8 ± 15.41 ΔF/F0 (n=68 ROIs) vs SH: 56.38 ± 18.31 ΔF/F0 (n=13 ROIs)]. The data shows that SH increased the evoked glutamatergic currents in NTS neurons of mice, probably due to a reduction in the astrocytic modulation of excitatory transmission by mechanisms apparently independent of astrocytic intracellular calcium. FAPESP (2018/15957-2, 2018/02336-0 and 2022/05237-8), CNPq (309338/2020-4) and CAPES-PROEX (23038.006922/2021-31). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Network-level encoding of local neurotransmitters in cortical astrocytes

Astrocytes, the most abundant non-neuronal cell type in the mammalian brain, are crucial circuit components that respond to and modulate neuronal activity through calcium (Ca2+) signalling1–7. Astrocyte Ca2+ activity is highly heterogeneous and occurs across multiple spatiotemporal scales—from fast, subcellular activity3,4 to slow, synchronized activity across connected astrocyte networks8–10—to influence many processes5,7,11. However, the inputs that drive astrocyte network dynamics remain unclear. Here we used ex vivo and in vivo two-photon astrocyte imaging while mimicking neuronal neurotransmitter inputs at multiple spatiotemporal scales. We find that brief, subcellular inputs of GABA and glutamate lead to widespread, long-lasting astrocyte Ca2+ responses beyond an individual stimulated cell. Further, we find that a key subset of Ca2+ activity—propagative activity—differentiates astrocyte network responses to these two main neurotransmitters, and may influence responses to future inputs. Together, our results demonstrate that local, transient neurotransmitter inputs are encoded by broad cortical astrocyte networks over a minutes-long time course, contributing to accumulating evidence that substantial astrocyte–neuron communication occurs across slow, network-level spatiotemporal scales12–14. These findings will enable future studies to investigate the link between specific astrocyte Ca2+ activity and specific functional outputs, which could build a consistent framework for astrocytic modulation of neuronal activity.

The Impact of Treadmill Training on Tissue Integrity, Axon Growth, and Astrocyte Modulation.

Spinal cord injury (SCI) presents a complex challenge in neurorehabilitation, demanding innovative therapeutic strategies to facilitate functional recovery. This study investigates the effects of treadmill training on SCI recovery, emphasizing motor function enhancement, neural tissue preservation, and axonal growth. Our research, conducted on a rat model, demonstrates that controlled treadmill exercises significantly improve motor functions post-SCI, as evidenced by improved scores on the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale and enhanced electromyography readings. Notably, the training facilitates the preservation of spinal cord tissue, effectively reducing secondary damage and promoting the maintenance of neural fibers in the injured area. A key finding is the significant stimulation of axonal growth around the injury epicenter in trained rats, marked by increased growth-associated protein 43 (GAP43) expression. Despite these advancements, the study notes a limited impact of treadmill training on motoneuron adaptation and highlights minimal changes in the astrocyte and neuron-glial antigen 2 (NG2) response. This suggests that, while treadmill training is instrumental in functional improvements post-SCI, its influence on certain neural cell types and glial populations is constrained.

NF-κB and JAK/STAT Signaling Pathways as Crucial Regulators of Neuroinflammation and Astrocyte Modulation in Spinal Cord Injury.

Spinal cord injury (SCI) leads to significant functional impairments below the level of the injury, and astrocytes play a crucial role in the pathophysiology of SCI. Astrocytes undergo changes and form a glial scar after SCI, which has traditionally been viewed as a barrier to axonal regeneration and functional recovery. Astrocytes activate intracellular signaling pathways, including nuclear factor κB (NF-κB) and Janus kinase-signal transducers and activators of transcription (JAK/STAT), in response to external stimuli. NF-κB and STAT3 are transcription factors that play a pivotal role in initiating gene expression related to astrogliosis. The JAK/STAT signaling pathway is essential for managing secondary damage and facilitating recovery processes post-SCI: inflammation, glial scar formation, and astrocyte survival. NF-κB activation in astrocytes leads to the production of pro-inflammatory factors by astrocytes. NF-κB and STAT3 signaling pathways are interconnected: NF-κB activation in astrocytes leads to the release of interleukin-6 (IL-6), which interacts with the IL-6 receptor and initiates STAT3 activation. By modulating astrocyte responses, these pathways offer promising avenues for enhancing recovery outcomes, illustrating the crucial need for further investigation into their mechanisms and therapeutic applications in SCI treatment.

Neuroinflammation in the paraventricular nucleus of the hypothalamus precipitates visceral pain induced by pancreatic cancer in mice.

Given the pivotal role of neuroinflammation in chronic pain and that the paraventricular nucleus of the hypothalamus (PVN) is a crucial brain region involved in visceral pain regulation, we sought to investigate whether the targeted modulation of microglia and astrocytes in the PVN could ameliorate pancreatic cancer-induced visceral pain (PCVP) in mice. Using a mouse model of PCVP, achieved by tumor cell injection at the head of the pancreas, we measure the number of glial cells, and at the same time we employed minocycline to inhibit microglia and chemogenetic methods to suppress astrocytes in order to investigate the respective roles of microglia and astrocytes within the PVN in PCVP. Mice exhibited visceral pain at 12, 15 and 18 days post-tumor cell injection. We observed a significant increase in the population of both microglia and astrocytes. Inhibition of microglial activity through minocycline microinjection into the PVN resulted in alleviation of visceral pain within 30 and 60 min. Similarly, chemogenetic inhibition of astrocyte function at 14 and 21 days post-injection also led to relief from visceral pain. This study found that PVN microglia and astrocytes were involved in regulating PCVP. Our results suggest that targeting glia may be a potential approach for alleviating visceral pain in patients with pancreatic cancer.

Artificial neural network with dynamic synapse model

The purpose of this study is to develop and investigate a new short-term memory model based on an artificial neural network without short-term memory effect and a dynamic short-term memory model with astrocytic modulation. Methods. The artificial neural network is represented by a classical convolutional neural network that does not have short-term memory. Short-term memory is modeled in our hybrid model using the Tsodyks-Markram model, which is a system of third-order ordinary differential equations. Astrocyte dynamics is modeled by a mean field model of gliotransmitter concentration. Results. A new hybrid short-term memory model was developed and investigated using a convolutional neural network and a dynamic synapse model for an image recognition problem. Graphs of dependence of accuracy and error on the number of epochs for the presented model are given. The sensitivity metric of image recognition d-prime has been introduced. The developed model was compared with the recurrent neural network and the configuration of the new model without taking into account astrocytic modulation. A comparative table has been constructed showing the best recognition accuracy for the introduced model. Conclusion. As a result of the study, the possibility of combining an artificial neural network and a dynamic model that expands its functionality is shown. Comparison of the proposed model with short-term memory using a convolutional neural network and a dynamic synapse model with astrocytic modulation with a recurrent network showed the effectiveness of the proposed approach in simulating short-term memory.

Bursting activity in the reduced mean-field model of neuron-glial interaction

The study of neural activity synchronization in the brain is a central focus of modern neurobiology and neurodynamics. In a healthy brain, cognitive functions necessitate the accurate integration of neural activity at specific spatiotemporal scales. Some neurological and psychiatric disorders exhibit observable variations in patterns of synchronous population activity. One of the most significant and compelling synchronous population activity patterns is the bursting activity that participates in various informational and physiological processes, including epilepsy. Several mathematical models have been proposed to explain the mechanisms of formation of the bursting activity. The most intriguing and scientifically sound models enable incorporation of astrocytic modulation of neural activity [1]. In this paper, we present a novel phenomenological model for accurately replicating the bursting neural population activity. Our model builds upon the Tsodyks-Markram [2] model and incorporates vital aspects of neuron-glial interaction through a tripartite synapse. The presented model is a simplified version of the previously proposed model [3]. During astrocyte activity (which lasts seconds), we can set the probability of neurotransmitter release, u, which is determined in fractions of a second. This enables the proposed model to be written in the following manner: r=–E+α ln(1+exp((Ju(Y)xE+I0)/α)), =(1–x)/τD–u(Y)xE, =–y/τY+βσy(X). Here, E(t) represents the average neuronal activity of the excitatory population, while x(t) denotes the quantity of available neurotransmitter. Additionally, y(t) describes the concentration of gliotransmitters, which are released as a result of biochemical reactions during neuron-astrocyte interactions. The function describes the alteration in the likelihood of neurotransmitter release when gliotransmitters are present u(y)=u0+(∆u0)/(1+exp(–50(y–ythr)). Here u0 represents the probability of neurotransmitter release without astrocytic influence; ∆u0 indicates the change in the probability of neurotransmitter release caused by the interaction of the gliotransmitter with the presynaptic terminal, and ythr represents the threshold value that determines the change in the probability of neurotransmitter release due to the effect of a gliotransmitter. The function describes the influence of neurotransmitter on the concentration of the gliotransmitter σy(x)=1/(1+exp(–20(x–xthr)), where xthr is the astrocyte activation threshold. Note that the proposed model does not account for synaptic depression’s mechanism. Therefore, various dynamical regimes’ formation in the model is solely controlled by astrocytic dynamics. In the study, control parameters I0 and u0 were selected while the remaining parameters were held constant. Specifically, τ=0.013, τD=0.08, α=1.58, J=3.07. Changes in the concentration of neurotransmitters and gliotransmitters were characterized by parameters ∆u0=0.305, τν=3.3, β=0.3, xxthr=0.75, ythr=0.4. The research was conducted using computer modeling and numerical methods in nonlinear dynamics. The proposed model exhibits a diverse range of population activity patterns, such as spiking and bursting regular and chaotic activity. Chaotic dynamics zones are identified in the control parameter plane. An account is given of the mechanisms behind the emergence of these activity patterns through bifurcation analysis. It is shown that the occurrence of chaotic activity in the system can be associated both with the cascade of period doubling bifurcations and with the further development of chaos, as a result of which a homoclinic attractor appears in the system according to the Shilnikov scenario. It was also shown that multistability is observed in the system in a certain range of parameters. Note that the emergence of multistability and bursting activity in the model is independent of the intricacy of neuron and glial cell dynamics. These dynamics are instead influenced by the feedback loop between the presynaptic neuron and the glial cell. The effects of neuron-like dynamics and neural-glial interaction demonstrated are generally applicable, without specifying particular characteristics of neural-glial interaction, network architecture, or single-cell neuron dynamics. It should be noted that our proposed model solely concerns the potentiation of synaptic transmission by astrocytes. In summary, the proposed phenomenological model for population activity can replicate various patterns of neuron activity found in a wide range of dynamic memory and information processing studies. This research can potentially lead to the development of new, effective treatment methods for neurological diseases that involve neuron-glial interaction. Another potential application for these results is in the development of an optimized live chip that has preset functions. This requires a deeper understanding of rhythmogenesis in neural networks and brain function.

Optoα1AR activation in astrocytes modulates basal hippocampal synaptic excitation and inhibition in a stimulation-specific manner.

Astrocytes play active roles at synapses and can monitor, respond, and adapt to local synaptic activity. While there is abundant evidence that astrocytes modulate excitatory transmission in the hippocampus, evidence for astrocytic modulation of hippocampal synaptic inhibition remains more limited. Furthermore, to better investigate roles for astrocytes in modulating synaptic transmission, more tools that can selectively activate native G protein signaling pathways in astrocytes with both spatial and temporal precision are needed. Here, we utilized AAV8-GFAP-Optoα1AR-eYFP (Optoα1AR), a viral vector that enables activation of Gq signaling in astrocytes via light-sensitive α1-adrenergic receptors. To determine if stimulating astrocytic Optoα1AR modulates hippocampal synaptic transmission, recordings were made in CA1 pyramidal cells with surrounding astrocytes expressing Optoα1AR, channelrhodopsin (ChR2), or GFP. Both high-frequency (20 Hz, 45-ms light pulses, 5 mW, 5 min) and low-frequency (0.5 Hz, 1-s pulses at increasing 1, 5, and 10 mW intensities, 90 s per intensity) blue light stimulation were tested. 20 Hz Optoα1AR stimulation increased both inhibitory and excitatory postsynaptic current (IPSC and EPSC) frequency, and the effect on miniature IPSCs (mIPSCs) was largely reversible within 20 min. However, low-frequency stimulation of Optoα1AR did not modulate either IPSCs or EPSCs, suggesting that astrocytic Gq -dependent modulation of basal synaptic transmission in the hippocampus is stimulation-dependent. By contrast, low-frequency stimulation of astrocytic ChR2 was effective in increasing both synaptic excitation and inhibition. Together, these data demonstrate that Optoα1AR activation in astrocytes changes basal GABAergic and glutamatergic transmission, but only following high-frequency stimulation, highlighting the importance of temporal dynamics when using optical tools to manipulate astrocyte function.

Artificial Neural Network Model with Astrocyte-Driven Short-Term Memory.

In this study, we introduce an innovative hybrid artificial neural network model incorporating astrocyte-driven short-term memory. The model combines a convolutional neural network with dynamic models of short-term synaptic plasticity and astrocytic modulation of synaptic transmission. The model's performance was evaluated using simulated data from visual change detection experiments conducted on mice. Comparisons were made between the proposed model, a recurrent neural network simulating short-term memory based on sustained neural activity, and a feedforward neural network with short-term synaptic depression (STPNet) trained to achieve the same performance level as the mice. The results revealed that incorporating astrocytic modulation of synaptic transmission enhanced the model's performance.

Astrocytes adjust the dynamic range of cortical network activity to control modality-specific sensory information processing

Cortical neuron-astrocyte communication in response to peripheral sensory stimulation occurs in a topographic-, frequency-, and intensity-dependent manner. However, the contribution of this functional interaction to the processing of sensory inputs and consequent behavior remains unclear. We investigate the role of astrocytes in sensory information processing at circuit and behavioral levels by monitoring and manipulating astrocytic activity invivo. We show that astrocytes control the dynamic range of the cortical network activity, optimizing its responsiveness to incoming sensory inputs. The astrocytic modulation of sensory processing contributes to setting the detection threshold for tactile and thermal behavior responses. The mechanism of such astrocytic control is mediated through modulation of inhibitory transmission to adjust the gain and sensitivity of responding networks. These results uncover a role for astrocytes in maintaining the cortical network activity in an optimal range to control behavior associated with specific sensory modalities.

Astrocytic modulation of neuronal signalling.

Neuronal signalling is a key element in neuronal communication and is essential for the proper functioning of the CNS. Astrocytes, the most prominent glia in the brain play a key role in modulating neuronal signalling at the molecular, synaptic, cellular, and network levels. Over the past few decades, our knowledge about astrocytes and their functioning has evolved from considering them as merely a brain glue that provides structural support to neurons, to key communication elements. Astrocytes can regulate the activity of neurons by controlling the concentrations of ions and neurotransmitters in the extracellular milieu, as well as releasing chemicals and gliotransmitters that modulate neuronal activity. The aim of this review is to summarise the main processes through which astrocytes are modulating brain function. We will systematically distinguish between direct and indirect pathways in which astrocytes affect neuronal signalling at all levels. Lastly, we will summarize pathological conditions that arise once these signalling pathways are impaired focusing on neurodegeneration.

Chemogenetic modulation of astrocytes and microglia: State-of-the-art and implications in neuroscience.

Insights into the role astrocytes and microglia play in normal and diseased brain functioning has expanded drastically over the last decade. Recently, chemogenetic tools have emerged as cutting-edge techniques, allowing targeted and spatiotemporal precise manipulation of a specific glial cell type. As a result, significant advances in astrocyte and microglial cell function have been made, showing how glial cells can intervene in central nervous system (CNS) functions such as cognition, reward and feeding behavior in addition to their established contribution in brain diseases, pain, and CNS inflammation. Here, we discuss the latest insights in glial functions in health and disease that have been made through the application of chemogenetics. We will focus on the manipulation of intracellular signaling pathways induced by activation of the designer receptors exclusively activated by designer drugs (DREADDs) in astrocytes and microglia. We will also elaborate on some of the potential pitfalls and the translational potential of the DREADD technology.