Early stress-induced impaired microglial pruning of excitatory synapses on immature CRH-expressing neurons provokes aberrant adult stress responses

Cell Reports, Год журнала: 2022, Номер 38(13), С. 110600 - 110600

Опубликована: Март 1, 2022

Several mental illnesses, characterized by aberrant stress reactivity, often arise after early-life adversity (ELA). However, it is unclear how ELA affects stress-related brain circuit maturation, provoking these enduring vulnerabilities. We find that increases functional excitatory synapses onto stress-sensitive hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, resulting from disrupted developmental synapse pruning adjacent microglia. Microglial process dynamics and synaptic element engulfment were attenuated in mice, associated with deficient signaling of the microglial phagocytic receptor MerTK. Accordingly, selective chronic chemogenetic activation microglia increased reduced density to control levels. Notably, normalized adult acute responses, including stress-induced secretion behavioral threat as well adrenal hypertrophy mice. Thus, actions during development are powerful contributors mechanisms which sculpts connectivity stress-regulating promoting vulnerability illnesses.

Язык: Английский

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Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer’s disease

Cell Reports, Год журнала: 2022, Номер 40(8), С. 111280 - 111280

Опубликована: Авг. 1, 2022

Dysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer's disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate local neuronal healthy brain, their involvement hyperactivity AD is unknown. We show increased FC human cingulate cortex several years before amyloid deposition. find same disruption AppNL-F mice. Crucially, these disruptions are accompanied by decreased astrocyte calcium signaling. Recovery astrocytic normalizes FC, as well seizure susceptibility day/night behavioral disruptions. In conclusion, we that astrocytes mediate initial features drive clinically relevant phenotypes.

Язык: Английский

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

Glia, Год журнала: 2023, Номер 71(9), С. 2071 - 2095

Опубликована: Май 24, 2023

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

Язык: Английский

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Chronic Gq activation of ventral hippocampal neurons and astrocytes differentially affects memory and behavior

Neurobiology of Aging, Год журнала: 2023, Номер 125, С. 9 - 31

Опубликована: Янв. 31, 2023

Язык: Английский

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Basolateral Amygdala Astrocytes Are Engaged by the Acquisition and Expression of a Contextual Fear Memory

Journal of Neuroscience, Год журнала: 2023, Номер 43(27), С. 4997 - 5013

Опубликована: Июнь 2, 2023

Astrocytes are key cellular regulators within the brain. The basolateral amygdala (BLA) is implicated in fear memory processing, yet most research has entirely focused on neuronal mechanisms, despite a significant body of work implicating astrocytes learning and memory. In present study, we used

Язык: Английский

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Prefrontal cortex astroglia modulate anhedonia-like behavior

Molecular Psychiatry, Год журнала: 2023, Номер 28(11), С. 4632 - 4641

Опубликована: Сен. 11, 2023

Abstract Reductions of astroglia expressing glial fibrillary acidic protein (GFAP) are consistently found in the prefrontal cortex (PFC) patients with depression and rodent chronic stress models. Here, we examine consequences PFC GFAP+ cell depletion activity enhancement on depressive-like behaviors rodents. Using viral expression diphtheria toxin receptor cells, which allows experimental these cells following administration, demonstrated that induced anhedonia-like behavior within 2 days lasting up to 8 days, but no anxiety-like deficits. Conversely, activating for 3 weeks using designer exclusively activated by drugs (DREADDs) reversed restraint stress-induced deficits, not Our results highlight a critical role cortical development anhedonia further support idea targeting treatment depression.

Язык: Английский

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Hippocampal astrocytes induce sex-dimorphic effects on memory

Cell Reports, Год журнала: 2024, Номер 43(6), С. 114278 - 114278

Опубликована: Май 24, 2024

Astrocytic receptors influence cognitive function and can promote behavioral deficits in disease. These effects may vary based on variables such as biological sex, but it is not known if the of astrocytic are dependent sex. We leveraged vivo gene editing chemogenetics to examine roles spatial memory other processes. show that reductions metabotropic glutamate receptor 3 (mGluR3), main adults, impair females enhance males. Similarly, increases mGluR3 levels have sex-dependent females. manipulations also alter search strategies during recall a sex-specific manner. In addition, acute chemogenetic stimulation G

Язык: Английский

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Astrocytic MicroRNAs and Transcription Factors in Alzheimer’s Disease and Therapeutic Interventions

Cells, Год журнала: 2022, Номер 11(24), С. 4111 - 4111

Опубликована: Дек. 17, 2022

Astrocytes are important for maintaining cholesterol metabolism, glutamate uptake, and neurotransmission. Indeed, inflammatory processes neurodegeneration contribute to the altered morphology, gene expression, function of astrocytes. Astrocytes, in collaboration with numerous microRNAs, regulate brain levels as well glutamatergic signaling, all which general homeostasis. Neural electrical activity, synaptic plasticity processes, learning, memory dependent on astrocyte–neuron crosstalk. Here, we review involvement astrocytic microRNAs that potentially inflammation Alzheimer’s disease (AD). The interaction between long non-coding RNA transcription factors specific astrocytes also contributes pathogenesis AD. Thus, arise a promising target, AD conditions worldwide public health problem. This examines novel therapeutic strategies target astrocyte dysfunction AD, such lipid nanodiscs, engineered G protein-coupled receptors, extracellular vesicles, nanoparticles.

Язык: Английский

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Comparative assessment of the effects of DREADDs and endogenously expressed GPCRs in hippocampal astrocytes on synaptic activity and memory

Frontiers in Cellular Neuroscience, Год журнала: 2023, Номер 17

Опубликована: Март 27, 2023

Designer Receptors Exclusively Activated by Drugs (DREADDs) have proven themselves as one of the key in vivo techniques modern neuroscience, allowing for unprecedented access to cellular manipulations living animals. With respect astrocyte research, DREADDs become a popular method examine functional aspects activity, particularly G-protein coupled receptor (GPCR)-mediated intracellular calcium (Ca2+) and cyclic adenosine monophosphate (cAMP) dynamics. this it has possible directly link physiological astrocytic function cognitive processes such memory. As result, multitude studies explored impact DREADD activation astrocytes on synaptic activity However, emergence varying results prompts us reconsider degree which expressed accurately mimic endogenous GPCR activity. Here we compare major downstream signaling mechanisms, synaptic, behavioral effects stimulating Gq-, Gs-, Gi-DREADDs hippocampal adult mice those endogenously GPCRs.

Язык: Английский

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Brainstem astrocytes control homeostatic regulation of caloric intake

The Journal of Physiology, Год журнала: 2023, Номер 601(4), С. 801 - 829

Опубликована: Янв. 25, 2023

Abstract Prolonged high‐fat diet (HFD) exposure is associated with hyperphagia, excess caloric intake and weight gain. After initial to a HFD, brief (24–48 h) period of hyperphagia followed by the regulation restoration energy balance within an acute (3–5 day) period. Previous studies have demonstrated this occurs via vagally mediated signalling cascade that increases glutamatergic transmission activation NMDA receptors located on gastric‐projecting neurons dorsal motor nucleus vagus (DMV). The present study used electrophysiological recordings from thin brainstem slice preparations, in vivo gastric motility tone, measurement emptying rates, food investigate hypothesis astrocytes response HFD responsible for increased drive DMV balance. Pharmacological chemogenetic inhibition reduced excitability, dysregulated tone motility, attenuated homeostatic delay emptying, prevented decrease observed during following HFD. Understanding mechanisms involved may provide critical insights into as well develops these are overcome. image Key points Initial high fat before restored. This (DMV) synaptic receptors. demonstrates pharmacological neuronal exposure. Astrocyte appears involve release gliotransmitters glutamate ATP.

Язык: Английский

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