Biology subjects

Abreu, D. S.

Publications and source records attributed to Abreu, D. S..

4 recordsLinked to original sources

bioRxiv2026

Hippocampal astrocytes contribute to encoding context-specific aversive stimuli to regulate fear-related behavior

In contextual fear conditioning, subjects learn to associate a neutral environment with an aversive stimulus and exhibit fear responses to that context, signaling danger. Neuronal activity in hippocampal-amygdala circuits has been shown extensively to underlie the conditioning and recall of contextual fear memories, yet the direct contribution of astrocytes to integrating stimulus and contextual information in this task remains unknown. In this study, we monitor astrocyte activity in real time in the hippocampus and simultaneously during performance in the contextual fear conditioning task. We find that shock-evoked astrocyte responses during conditioning predict the magnitude of freezing during recall in a context-specific manner. Importantly, astrocytic Ca2+ activity progressively precedes freezing onset specifically in the shock-associated context, indicating that hippocampal astrocytes contribute to encoding context-specific shock information. This work reveals an unprecedented contribution of astrocytes to the encoding of context-related information about aversive stimuli in fear-related behavior.

neuroscience↗

bioRxiv2025

An astrocytic AMPK clock drives circadian behaviour

Circadian clocks coordinate behaviour and physiology with daily cycles of light and nutrient availability, but how metabolic signals influence brain timing remains incompletely understood. Astrocytes integrate metabolic and hormonal cues and exhibit time-of-day-dependent responses, suggesting that they may convey temporal information to hypothalamic circuits. Here, we show that hypothalamic AMP-activated protein kinase (AMPK) exhibits circadian regulation independently of light and feeding cues, is modulated by nutrient availability and astrocytic Ca{superscript 2} signalling, and regulates the temporal organisation of the hypothalamic phosphoproteome. Genetic manipulation of astrocytic AMPK signalling alters PER2 abundance and phosphorylation, including at a conserved residue implicated in circadian period regulation. At the behavioural level, AMPK and PER2 in ventromedial hypothalamic astrocytes contribute to food-anticipatory activity, whereas disruption of astrocytic AMPK signalling alters SCN-dependent circadian locomotor rhythms and energy homeostasis in a sex-dependent manner. Together, these findings identify astrocytic AMPK signalling as a temporally regulated pathway that couples metabolic signals to hypothalamic circadian timing and systemic homeostasis.

neuroscience↗

bioRxiv2025

Astrocytic mGluR5 signaling tunes emotional and cognitive processing in the adult brain

The hippocampus is a brain region involved in both emotion regulation and higher cognitive functions. Astrocytes have emerged as active modulators of synaptic activity, capable of sensing, integrating, and responding to neuronal signals. At glutamatergic synapses, astrocytes detect glutamate through the activation of the metabotropic glutamate receptor 5 (mGluR5). However, most existing research has focused on the role of mGluR5 in developing rodents or in pathological contexts, likely because of the reported lower astrocytic mGluR5 expression levels in adulthood compared to postnatal stages. Importantly, prior studies and our preliminary data have demonstrated mGluR5-mediated signaling in astrocytes of adult mice, supporting a role for this receptor. Therefore, the main objectives of this study were (1) to determine whether these lower levels of mGluR5 are sufficient to activate astrocytes in the adult brain and (2) to investigate whether this activation is involved in regulating circuit function and behavior. To address these objectives, we evaluated adult mice employing a combination of calcium imaging in astrocytes, and loss- and gain-of-function manipulations to assess synaptic plasticity and behavior in adult mice. First, we found that astrocytes of adult mice display fully functional mGluR5-dependent calcium activity. To examine the role of this activity, we induced the deletion of mGluR5 in astrocytes across the entire brain of adult mice. These mice developed anxious- and depression-like behaviors, along with reduced sociability and recognition memory, but showed increased behavioral flexibility. These results highlighted the hippocampus as a key region for mGluR5-mediated astrocytic influence on behavior, leading us to specifically target hippocampal astrocytes. A viral-driven ablation in this area demonstrated that astrocytic mGluR5 plays a role in both basal transmission and the regulation of synaptic plasticity. Behaviorally, the deletion of astrocytic mGluR5 in the hippocampus recapitulated anxious-like behaviors, social deficits, and impaired long-term recognition memory. Surprisingly, it improved place recognition memory but reduced behavioral flexibility. Lastly, overexpressing this receptor to enhance mGluR5 signaling specifically in hippocampal astrocytes impaired place recognition memory but improved behavioral flexibility, revealing a role for astrocytic mGluR5 in regulating these behaviors. Overall, our results confirmed the biological relevance of astrocytic mGluR5 during adulthood, specifically in modulating hippocampal function.

neuroscience↗

bioRxiv2023

Astrocytic Foxo1 regulates hippocampal spinogenesis and synaptic plasticity to enhance fear memory

Astrocytes are active players in brain circuits, sensing and responding to neuronal activity, impacting behavior production. Activation of astrocytes triggers intracellular calcium elevations displaying complex spatiotemporal properties. Intracellular calcium activity is thought to underlie synaptic transmission, metabolism, and brain homeostasis modulation. However, the calcium-dependent signaling pathways involved in these processes are poorly understood, representing a critical knowledge gap in this field. To reveal calcium-dependent signaling pathways involved in circuit structure and function, we performed a multi-level analysis of the inositol 1,4,5-triphosphate receptor type 2 knockout (IP3R2 KO) mouse model which lacks somatic calcium elevations specifically in astrocytes. We focused on the hippocampus, a brain region responsible for cognitive function and emotional behaviors. The transcriptomic analysis of hippocampal tissue revealed that the lack of astrocytic somatic calcium causes the differential expression of hundreds of genes. Among these, 76 genes are regulated by the astrocyte-specific Foxo1 transcription factor. This transcription factor is over-expressed in the hippocampal astrocytes of this mouse model and regulates the expression of genes involved in spinogenesis and synaptic coverage. A detailed morphological analysis of hippocampal pyramidal neurons revealed dendrites with a shift to a more immature spine profile. This spine profile shift may underlie previously described a reduction of long-term depression and performance in fear memory tasks observed in this mouse model. Indeed, we confirmed that these mice lacking astrocytic somatic calcium display an enhancement of long-term fear memory. To verify a causal relationship between these structural, synaptic, and behavioral observations, we used a viral approach to induce the over-expression of Foxo1 in hippocampal astrocytes in naive C57BL/6J mice. This viral-driven over-expression of Foxo1 in astrocytes of the stratum radiatum replicated the shift to an immature spine profile in dendrites of pyramidal neurons crossing the territory of these astrocytes and led to a reduction of long-term depression in the same region. Finally, this manipulation was sufficient to enhance long-term fear memory. The detailed characterization of the mouse model lacking astrocytic somatic calcium revealed that astrocytes modulate hippocampal circuit structure and function through Foxo1 signaling to enhance fear memory.

neuroscience↗