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Astrocytes play crucial roles in brain homeostasis and are regulatory elements of neuronal and synaptic physiology. Astrocytic alterations have been found in Major Depressive Disorder (MDD) patients; however, the consequences of astrocyte Ca2+ signaling in MDD are poorly understood. Here, we found that corticosterone-treated mice (Cort-mice) showed altered astrocytic Ca2+ dynamics in mPFC both in resting conditions and during social interactions, in line with altered mice behavior. Additionally, Cort-mice displayed reduced serotonin (5-HT)-mediated Ca2+ signaling in mPFC astrocytes, and aberrant 5-HT-driven synaptic plasticity in layer 2/3 mPFC neurons. Downregulation of astrocyte Ca2+ signaling in naïve animals mimicked the synaptic deficits found in Cort-mice. Remarkably, boosting astrocyte Ca2+ signaling with Gq-DREADDS restored mood and cognitive deficits in Cort-mice to control levels. This study highlights the important role of astrocyte Ca2+ signaling for homeostatic control of brain circuits and behavior, but also reveals its potential therapeutic value for depressive-like states.

Background: Identifying the structured distribution (or lack thereof) of a given feature over a point cloud is a general research question. In the neuroscience field, this problem arises while investigating representations over neural manifolds (e.g., spatial coding), in the analysis of neurophysiological signals (e.g., auditory coding) or in anatomical image segmentation. New method: We introduce the Structure Index (SI) as a graph-based topological metric to quantify the distribution of feature values projected over data in arbitrary D-dimensional spaces (neurons, time stamps, pixels). The SI is defined from the overlapping distribution of data points sharing similar feature values in a given neighborhood. Results: Using model data clouds we show how the SI provides quantification of the degree of local versus global organization of feature distribution. SI can be applied to both scalar and vectorial features permitting quantification of the relative contribution of related variables. When applied to experimental studies of head-direction cells, it is able to retrieve consistent feature structure from both the high- and low-dimensional representations. Finally, we provide two general-purpose examples (sound and image categorization), to illustrate the potential application to arbitrary dimensional spaces. Comparison with existing methods: Most methods for quantifying structure depend on cluster analysis, which are suboptimal for continuous features and non-discrete data clouds. SI unbiasedly quantifies structure from continuous data in any dimensional space. Conclusions: The method provides versatile applications in the neuroscience and data science fields.

Sleep disturbances are common during aging. Compared to young animals, old mice show altered sleep structure, with changes in both slow and fast electrocorticographic (ECoG) activity and fewer transitions between sleep and wake stages. Insulin-like growth factor I (IGF-I), which is involved in adaptive changes during aging, was previously shown to increase ECoG activity in young mice and monkeys. Furthermore, IGF-I shapes sleep architecture by modulating the activity of mouse orexin neurons in the lateral hypothalamus (LH). We now report that both ECoG activation and excitation of orexin neurons by systemic IGF-I are abrogated in old mice. Moreover, orthodromical responses of LH neurons are facilitated by either systemic or local IGF-I in young mice, but not in old ones. As orexin neurons of old mice show dysregulated IGF-I receptor (IGF-IR) expression, suggesting disturbed IGF-I sensitivity, we treated old mice with AIK3a305, a novel IGF-IR sensitizer, and observed restored responses to IGF-I and rejuvenation of sleep patterns. Thus, disturbed sleep structure in aging mice may be related to impaired IGF-I signaling onto orexin neurons, reflecting a broader loss of IGF-I activity in the aged mouse brain., This work was funded by a grant from Ciberned and is part of the project SAF2016-76462 funded by MCIN/AEI/https://doi.org/10.13039/501100011033. J.A. ZegarraValdivia acknowledges the fnancial support of the National Council of Science, Technology and Technological Innovation (CONCYTEC, Perú) through the National Fund for Scientifc and Technological Development (FONDECYT, Perú). J. Fernandes received a post-doc fellowship from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP: # 2017/14742–0; # 2019/03368–5).

Astrocytes are key elements of brain circuits that are involved in different aspects of the neuronal physiology relevant to brain functions. Although much effort is being made to understand how the biology of astrocytes affects brain circuits, astrocytic network heterogeneity and plasticity is still poorly defined. Here, we have combined structural and functional imaging of astrocyte activity using the Ca2+-modulated photoactivatable ratiometric integrator and specific optostimulation of glutamatergic pathways to map the functional neuron-astrocyte circuitries in the nucleus accumbens (NAc). We showed pathway-specific astrocytic responses induced by selective optostimulation of main inputs from the prefrontal cortex, basolateral amygdala, and ventral hippocampus. Furthermore, the differences in basal Ca2+ dynamics between the NAc shell and core astrocytes were associated with differences in mitochondrial DNA copy number, exhibiting molecular heterogeneity in the regulation of their mitochondrial genomes. Finally, co-stimulation of glutamatergic pathways induced non-linear Ca2+-signaling integration, revealing integrative properties of NAc astrocytes. All these results demonstrate the existence of specific neuron-astrocyte circuits in the NAc, a critical insight to the understanding of how the NAc integrates information.

Astrocytes are key elements of brain circuits that are involved in different aspects of the neuronal physiology relevant to brain functions. Although much effort is being made to understand how the biology of astrocytes affects brain circuits, astrocytic network heterogeneity and plasticity is still poorly defined. Here, we have combined structural and functional imaging of astrocyte activity recorded in mice using the Ca

GABA interneurons play a critical role in higher brain functions. Astrocytic glial cells interact with synapses throughout the whole brain and are recognized as regulatory elements of excitatory synaptic transmission. However, it is largely unknown how GABAergic interneurons and astrocytes interact and contribute to stable performance of complex behaviors. Here, we found that genetic ablation of GABA receptors in medial prefrontal cortex astrocytes altered low-gamma oscillations and firing properties of cortical neurons, which affected goal-directed behaviors. Remarkably, working memory deficits were restored by optogenetic stimulation of astrocytes with melanopsin. Furthermore, melanopsin-activated astrocytes in wild-type mice enhanced the firing rate of cortical neurons and gamma oscillations, as well as improved cognition. Therefore, our work identifies astrocytes as a hub for controlling inhibition in cortical circuits, providing a novel pathway for the behaviorally relevant midrange time-scale regulation of cortical information processing and consistent goal-directed behaviors., We thank the T. Korotkova Lab, C. González-Arias and C. Heikenfeld for technical support; the Molecular and Cellular Biology Unit from the Cajal Institute for technical assistance; B. Bettler, A. Araque, M. Navarrete, E. D. Martín and A. Fernández-Ruiz for critical review of the manuscript; and Buzsáki Lab members for valuable suggestions. This work was supported by the MCIU/AEI/FEDER, UE (BES-2014-067594) to S.M.; a European Molecular Biology Organization (EMBO) postdoctoral fellowship (EMBO ALTF 1161-2017) and a Human Frontiers Science Program (HFSP) postdoctoral fellowship (LT0000717/2018) to M.V.; the Deutsche Forschungsgemeinschaft (DFG: SPP1665, 1799/1-2 and Heisenberg Program 1799/2-1 and 1799/3-1) to A.P.; the MCIU/AEI/FEDER, UE (BFU2016-75107-P), and MCIU/AEI/FEDER, UE (PID2019- 106579RB-I00), 202020E073 from the CSIC, and the Cajal Blue Brain Project (C080020- 09; the Spanish partner of the Blue Brain Project initiat.