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Social isolation stress-resilient rats reveal energy metabolic shift in hippocampal nonsynaptic mitochondria

ABSTRACT: We investigated the relative quantification of proteins in hippocampal cytosolic and nonsynaptic mitochondrial (NSM) fractions of rats exposed to chronic social isolation (CSIS), an animal model of depression, comparing CSIS-resilient with CSIS-sensitive or control rats, via a comparative subproteomic study. Our aim was to characterize the subproteome changes representing potential long-term changes in protein expression underlying the aforementioned conditions.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Brain

DISEASE(S): Disease Free

SUBMITTER: Victor Costina

LAB HEAD: Peter Findeisen

PROVIDER: PXD016966 | Pride | 2020-05-25

REPOSITORIES: Pride

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			Action	DRS
	NSM_CSIS_resilient_1.msf	Msf
	NSM_CSIS_resilient_1.zip	Other
	NSM_CSIS_resilient_2.msf	Msf
	NSM_CSIS_resilient_2.zip	Other
	NSM_CSIS_resilient_3.msf	Msf

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Publications

Social isolation stress-resilient rats reveal energy shift from glycolysis to oxidative phosphorylation in hippocampal nonsynaptic mitochondria.

Filipović Dragana D Perić Ivana I Costina Victor V Stanisavljević Andrijana A Gass Peter P Findeisen Peter P

Life sciences 20200519

<h4>Aims</h4>To examine the differences in the hippocampal proteome profiles of resilience or susceptibility to chronic social isolation (CSIS), animal model of depression, and to identify biomarkers that can distinguish the two.<h4>Main methods</h4>Comparative subproteomic approach was used to identify changes in hippocampal cytosol and nonsynaptic mitochondria (NSM) of CSIS-resilient compared to CSIS-sensitive or control rats. The resilient and sensitive phenotypes of CSIS rats were distinguis ...[more]

PMID: 32416165

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Hippocampal synaptoproteomic changes of susceptibility and resilience of rats to chronic social isolation

Project description:The susceptibility to chronic social isolation (CSIS) is associated with development of major depression (MD). Recent studies relate MD with altered expression of synaptic proteins in specific brain regions, whereby some individuals exposed to the stressors are resistant to the stress. To explore the neurobiological underpinnings and identify candidate biomarkers for MD, a comparative proteomic approach was used to map hippocampal synaptic protein alterations of rats exposed to 6 weeks of CSIS, an animal model of depression. This model generates two stress-response phenotypes, reflecting CSIS-sensitive (depressive-like behaviour) and CSIS-resilience, assessed by sucrose preference test. Our aim was to characterize the synaptoproteome changes representative of potential long-term changes in protein expression underlying susceptibility or resilience to stress.

2020-11-27 | PXD019790 | Pride

Fluoxetine triggers synaptic vesicle exo/endocytosis, mitochondrial energy metabolism and dynamics in hippocampus of socially isolated rats

Project description:We used comparative proteomic approach to identify proteome changes in purified synaptic terminals (synaptosomes) of rats exposed to chronic social isolation (CSIS) (6 weeks), animal model for depression, followed by chronic Fluoxetine treatment (last 3 weeks of CSIS) (therapeutic effect). Our aim was to examine a subcellular compartment enriched in proteins involved in synaptic function.

2023-03-11 | PXD028816 | Pride

Proteomic analysis of hippocampal synaptosomes in chronically socially isolated rats: effect of antidepressant tianeptine

Project description:Dysregulation of brain synaptic proteins caused by chronic psychosocial stress has been linked with the development of major depression (MD). To gain insights into the pattern of synaptic proteome changes and different biological functions and pathways underlying MD and drug action, a comparative proteomic approach was employed in the hippocampus of rats exposed to chronic social isolation (CSIS, 6 weeks), an animal model of depression, with or without chronic antidepressant tianeptine (Tian) treatment (last 3 weeks of CSIS).

2022-02-16 | PXD021920 | Pride

Chronic fluoxetine treatment of socially isolated rats modulates prefrontal cortex proteome

Project description:Chronic social isolation (CSIS) is a risk factor for human major depressive disorder (MDD). Fluoxetine (Flx) is an antidepressant commonly used for first-line MDD therapy. However, its downstream mechanisms of action, beyond serotonergic signaling, remain elusive. We aimed to analyze the effects of CSIS followed by chronic Flx treatment on proteome changes in the adult male rat prefrontal cortex (PFC) cytosolic and non-synaptic mitochondria (NSM)-enriched fractions. Treatment with Flx ameliorated depression-like behaviors in CSIS-induced rat model of depression as assessed by sucrose preference test and forced swim test. Proteomic data showed that Flx increased the expression of proteins involved in cytoskeleton and regulation of intracellular Ca2+ homeostasis in the cytosol and of enzymes linking the glycolytic pathway to the citric acid cycle (Dlat) and ATPase-coupled ion transmembrane transport in NSM. CSIS resulted in down-regulation of cytosolic proteins involved in proteasome/ubiquitination processes and glutathione antioxidative system and up-regulated expression of key enzymes participating in oxidative phosphorylation. Presence of cytochrome c in the cytosol indicated compromised mitochondrial membrane integrity. Flx treatment in CSIS rats showed predominately an upregulation of vesicle-mediated transport proteins and reduced Uqcrfs1 along with transport in NSM, favoring reduced energy metabolism. Our data suggest that proteins from both cytosol and NSM-enriched fractions are affected by Flx in a key brain region associated with stress response, cognitive process and regulation of emotion.

2023-11-10 | PXD026202 | Pride

Prefrontal cortical synaptoproteome profile combined with machine learning predict resilience towards chronic social isolation in rats

Project description:Chronic social isolation (CSIS), an animal model of depression, generates two stress-response phenotypes: CSIS-resilient and CSIS-susceptible. However, the molecular mechanism underlying resilience to CSIS remains unclear. We aimed to investigate the prefrontal cortical synaptoproteome profile between CSIS-resilient, CSIS-susceptible and control rats in order to identify predictive proteins for the resilience phenotype. Comparison of CSIS-resilient versus CSIS-susceptible rats revealed downregulated glycolysis intermediate Aldoc and upregulated Cltc, Cam2a, Syn and Fasn proteins involved in neuronal transmission, synaptic vesicle trafficking and fatty acid synthesis. Comparison of CSIS-resilient and control rats revealed downregulated mitochondrial proteins Atp5f1b and Cs, and upregulated Prkcg, Slc17a7, and Sv2a proteins involved in signal transduction and synaptic trafficking. These proteins make the animal groups linearly separable, and 100% validation accuracy is achieved by standard machine learning models. In addition, we identified the most significant proteins for discriminating CSIS-resilient vs. CSIS-susceptible or control rats by using Support Vector Machine with greedy forward search and Random Forest, resulting in four panels of discriminative proteins. Proteomics-data-driven machine learning algorithms can provide a platform for accessing predictive features and provide additional insight into the molecular mechanisms of synaptic neurotransmission involved in stress resilience.

2024-04-23 | PXD047159 | Pride

Fluoxetine stimulates synaptic vesicular dynamic and mitochondrial energy metabolism in prefrontal cortex of socially isolated rats

Project description:Identifying adequate biomarkers of major depressive disorder (MDD) and therapy has been the goal of many studies. Many molecular alterations associated with the pathophysiology of MDD reside within the synapse. Fluoxetine (Flx) is the most commonly prescribed antidepressant, but the mechanism of its action is unclear. Hence, we performed a comparative proteomics of synaptosomal-enriched fractions from prefrontal cortex of adult male Wistar rats exposed to CSIS (6 weeks) and after chronic Flx treatment of controls (3 weeks) and CSIS-exposed rats (lasting 3 weeks of 6-week-CSIS). Our aim was to profile synaptosomal proteome changes representative of possible time-consuming events underlying the CSIS-induced depressive-like behavior and antidepressant property of Flx. Bioinformatic data of Flx-treated control rats revealed down-expression of proteins that mainly participate in proteasome system and vesicle mediated transport as well as predominantly increases expression of exocytosis-associated proteins. CSIS led to decreased expression of proteins involved in ATP metabolic process, synaptic vesicle endocytosis and proteasome system, while increased energy yielding glycolytic pathway. Flx treatment of CSIS rats predominantly increases expression of exo/endocytosis-associated proteins and Cox5a, mitochondria-associated proteins involved in oxidative phosphorylation. Overall, synaptoproteomic profiling indicated that Flx stimulated synaptic vesicular dynamics by enhancing endo/exocytosis and mitochondrial energy metabolism in CSIS rats that might be critical targets for pharmacological treatments for MDD.

2023-11-10 | PXD029575 | Pride

Prefrontal cortex cytoplasmic proteome and machine learning-based predictors of resilience towards chronic social isolation in rats

Project description:Chronic social isolation (CSIS) generates two stress-related phenotypes, resilience and susceptibility. Although brain energy metabolism is important in regulating social behaviors, the molecular mechanisms underlying CSIS resilience remain unclear. To identify protein changes and altered biochemical pathways and processes for resilience to CSIS, prefrontal cortical cytosolic proteomic profiling was performed comparing CSIS-resilient with CSIS-susceptible and control rats. Potential predictive proteins discriminating between the CSIS-resilient and CSIS-susceptible groups were identified by support vector machine-based sequential feature selection and random forest-based feature importance scores. Predominantly decreased levels of glycolytic enzymes, G protein-coupled receptor proteins, Ras subfamily of GTPase proteins, and antioxidant proteins were found in CSIS-resilient vs. CSIS-susceptible groups. Altered levels of Gapdh and proteins involved in microtubule and cytoskeletal organization, and calcium-binding proteins were identified between the two phenotypes. These dynamic changes were accompanied by increased levels of proteins involved in GABA synthesis, the proteasome system, nitrogen metabolism, and chaperone-mediated protein folding. The overall ratio of significantly up- and down-regulated cytosolic proteins suggests adaptive cellular alterations as part of the stress-coping process specific for the CSIS-resilient phenotype.

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Project description:We carried out untargeted metabolomics of the prefrontal cortex of rats exposed to chronic social isolation (CSIS), a rat model of depression, and/or fluoxetine treatment using liquid chromatography-high resolution mass spectrometry.

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