Stress-induced depressive-like behavior in male rats is associated with microglial activation and inflammation dysregulation in the hippocampus in adulthood

Brás, João; Suduiraut, Isabelle Guillot de; Zanoletti, Olivia; Monari, Silvia; Meijer, Michiel; Grosse, Jocelyn; Barbosa, Mário A.; Santos, Susana G.; Sandi, Carmen; Almeida, Maria Inês

doi:10.1016/j.bbi.2021.10.018

Cited by 30 publications

(14 citation statements)

References 76 publications

(78 reference statements)

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“…In our study, the use of an inbred mouse strain (C57BL/6J), devoid of genetic variability, allows revealing peripubertal stress as an important risk factor for the development of this combined metabolic and behavioral phenotype. Compared to the CUS protocol, a model classically used to study depression ( 67 , 68 ), our model of unpredictable stress during peripuberty does not show anhedonia, in line with our previous work in rats exposed to peripubertal stress ( 69 ). These differences can be explained by the different duration of the stress protocol, the type of stressors used, and the time window of stress exposure.…”

Section: Discussionsupporting

confidence: 86%

eNAMPT actions through nucleus accumbens NAD ⁺ /SIRT1 link increased adiposity with sociability deficits programmed by peripuberty stress

et al. 2022

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Obesity is frequently associated with impairments in the social domain, and stress at puberty can lead to long-lasting changes in visceral fat deposition and in social behaviors. However, whether stress-induced changes in adipose tissue can affect fat-to-brain signaling, thereby orchestrating behavioral changes, remains unknown. We found that peripubertally stressed male—but not female—mice exhibit concomitant increased adiposity and sociability deficits. We show that reduced levels of the adipokine nicotinamide phosphoribosyltransferase (NAMPT) in fat and its extracellular form eNAMPT in blood contribute to lifelong reductions in sociability induced by peripubertal stress. By using a series of adipose tissue and brain region–specific loss- and gain-of-function approaches, we implicate impaired nicotinamide adenine dinucleotide (NAD + )/SIRT1 pathway in the nucleus accumbens. Impairments in sociability and accumbal neuronal excitability are prevented by normalization of eNAMPT levels or treatment with nicotinamide mononucleotide (NMN), a NAD + -boosting compound. We propose NAD + boosters to treat social deficits of early life stress origin.

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Section: Discussionsupporting

confidence: 86%

eNAMPT actions through nucleus accumbens NAD ⁺ /SIRT1 link increased adiposity with sociability deficits programmed by peripuberty stress

et al. 2022

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“…Previous study [15] showed stress-activated hippocampal microglia and increased hippocampal Iba1 expression in depressive rats. Caspase-1 is the effector protein of the nucleotide-binding domain, leucine-rich-containing family, pyrindomain-containing-3 (NLRP3) inflammasome [16].…”

Section: Introductionmentioning

confidence: 83%

“…The activation of microglia under pathological conditions leads to a decrease in neurogenesis [14] and the release of inflammatory factors, causing depression and anxiety [11]. Previous study [15] showed stress-activated hippocampal microglia and increased hippocampal Iba1 expression in depressive rats. Caspase-1 is the effector protein of the nucleotide-binding domain, leucine-rich-containing family, pyrindomain-containing-3 (NLRP3) inflammasome [16].…”

Section: Introductionmentioning

confidence: 99%

Swimming exercise reverses chronic unpredictable mild stress–induced depression-like behaviors and alleviates neuroinflammation and collapsing response mediator protein-2–mediated neuroplasticity injury in adult male mice

Xie

Sun

et al. 2022

NeuroReport

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Objective Impaired neuroplasticity and neuroinflammation are vital in the mechanisms of depression. Exercise alleviates depressive symptoms and ameliorates body functions. Swimming is one of the most common exercises; however, whether swimming alters depressive behaviors and the underlying mechanism has not been fully elucidated.Methods Male C57/BL6J mice were exposed to chronic unpredictable mild stress (CUMS) for 6 weeks and then were subjected to a 5-week swimming program. Behavioral test, including sucrose preference test (SPT), open field test (OFT), elevated plus-maze (EPM) test, and tail suspension test (TST), was conducted to assess the anxiety-like and depressive behaviors. Western blotting and immunofluorescence staining were carried out after tissue collection. ResultsThis study showed that CUMS-induced depressive behaviors but swimming exercise increased sucrose preference in SPT, increased time and velocity in the center on OFT, decreased time in the closed arm, increased time in the open arm in EPM, and decreased immobility time in TST. We further found swimming exercise increased hippocampal collapsing response mediator protein-2 (CRMP2) expression and decreased p-CRMP2 expression in CUMS mice. CUMS inhibited the levels of α-tubulin and CRMP2, and the expression of ionized calcium-binding adaptor molecule 1 and caspase-1, whereas swimming reversed them in CUMSexercised mice. ConclusionOur study confirmed that swimming exercise reverses CUMS-induced depressive behaviors, and neuroinflammation and CRMP2-mediated neuroplasticity are involved, which may provide a new insight into the antidepression therapy of exercise.

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“…Those results indicated that steroid synthesis-related pathways were significantly affected and consistent with previous findings that the CORT was increased in murine sepsis survivors and exhibited a behavioral neuroendocrine syndrome ( Spencer-Segal et al, 2020 ). Furthermore, CORT was reported to induce neuroinflammation and bring depression-like behaviors or other neuron dysfunction syndromes in the hippocampus ( Komoltsev et al, 2021 ; Bras et al, 2022 ), which indicated that the increase of CORT is a critical factor in the progression of SAE. Additionally, other enriched steroids were precursors of CORT, but their functions are still unknown.…”

Section: Discussionmentioning

confidence: 99%

Integrated transcriptomics and metabolomics analysis of the hippocampus reveals altered neuroinflammation, downregulated metabolism and synapse in sepsis-associated encephalopathy

Zhang

et al. 2022

Front. Pharmacol.

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Sepsis-associated encephalopathy (SAE) is an intricated complication of sepsis that brings abnormal emotional and memory dysfunction and increases patients’ mortality. Patients’ alterations and abnormal function seen in SAE occur in the hippocampus, the primary brain region responsible for memory and emotional control, but the underlying pathophysiological mechanisms remain unclear. In the current study, we employed an integrative analysis combining the RNA-seq-based transcriptomics and liquid chromatography/mass spectrometry (LC-MS)-based metabolomics to comprehensively obtain the enriched genes and metabolites and their core network pathways in the endotoxin (LPS)-injected SAE mice model. As a result, SAE mice exhibited behavioral changes, and their hippocampus showed upregulated inflammatory cytokines and morphological alterations. The omics analysis identified 81 differentially expressed metabolites (variable importance in projection [VIP] > 1 and p < 0.05) and 1747 differentially expressed genes (Foldchange >2 and p < 0.05) were detected in SAE-grouped hippocampus. Moreover, 31 compounds and 100 potential target genes were employed for the Kyoto Encyclopedia of Genes and Genomes (KEGG) Markup Language (KGML) network analysis to explore the core signaling pathways for the progression of SAE. The integrative pathway analysis showed that various dysregulated metabolism pathways, including lipids metabolism, amino acids, glucose and nucleotides, inflammation-related pathways, and deregulated synapses, were tightly associated with hippocampus dysfunction at early SAE. These findings provide a landscape for understanding the pathophysiological mechanisms of the hippocampus in the progression of SAE and pave the way to identify therapeutic targets in future studies.

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Stress-induced depressive-like behavior in male rats is associated with microglial activation and inflammation dysregulation in the hippocampus in adulthood

Cited by 30 publications

References 76 publications

eNAMPT actions through nucleus accumbens NAD ⁺ /SIRT1 link increased adiposity with sociability deficits programmed by peripuberty stress

eNAMPT actions through nucleus accumbens NAD ⁺ /SIRT1 link increased adiposity with sociability deficits programmed by peripuberty stress

Swimming exercise reverses chronic unpredictable mild stress–induced depression-like behaviors and alleviates neuroinflammation and collapsing response mediator protein-2–mediated neuroplasticity injury in adult male mice

Integrated transcriptomics and metabolomics analysis of the hippocampus reveals altered neuroinflammation, downregulated metabolism and synapse in sepsis-associated encephalopathy

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Stress-induced depressive-like behavior in male rats is associated with microglial activation and inflammation dysregulation in the hippocampus in adulthood

Cited by 30 publications

References 76 publications

eNAMPT actions through nucleus accumbens NAD + /SIRT1 link increased adiposity with sociability deficits programmed by peripuberty stress

eNAMPT actions through nucleus accumbens NAD + /SIRT1 link increased adiposity with sociability deficits programmed by peripuberty stress

Swimming exercise reverses chronic unpredictable mild stress–induced depression-like behaviors and alleviates neuroinflammation and collapsing response mediator protein-2–mediated neuroplasticity injury in adult male mice

Integrated transcriptomics and metabolomics analysis of the hippocampus reveals altered neuroinflammation, downregulated metabolism and synapse in sepsis-associated encephalopathy

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eNAMPT actions through nucleus accumbens NAD ⁺ /SIRT1 link increased adiposity with sociability deficits programmed by peripuberty stress

eNAMPT actions through nucleus accumbens NAD ⁺ /SIRT1 link increased adiposity with sociability deficits programmed by peripuberty stress