RESUMEN
The analysis of RNA-Sec data from murine bulk tissue samples taken from five brain regions associated with behavior and stress response was conducted. The focus was on the most contrasting brain region-specific genes (BRSG) sets in terms of their expression rates. These BRSGs are identified as genes with a distinct outlying (high) expression rate in a specific region compared to others used in the study. The analysis suggested that BRSG sets form non-randomly connected compact gene networks, which correspond to the major neuron-mediated functional processes or pathways in each brain region. The number of BRSGs and the connection rate were found to depend on the heterogeneity and coordinated firing rate of neuron types in each brain region. The most connected pathways, along with the highest BRSG number, were observed in the Striatum, referred to as Medium Spiny Neurons (MSNs), which make up 95% of neurons and exhibit synchronous firing upon dopamine influx. However, the Ventral Tegmental Area/Medial Raphe Nucleus (VTA/MRN) regions, although primarily composed of monoaminergic neurons, do not fire synchronously, leading to a smaller BRSG number. The Hippocampus (HPC) region, on the other hand, displays significant neuronal heterogeneity, with glutamatergic neurons being the most numerous and synchronized. Interestingly, the two monoaminergic regions involved in the study displayed a common BRSG subnetwork architecture, emphasizing their proximity in terms of axonal throughput specifics and high-energy metabolism rates. This finding suggests the concerted evolution of monoaminergic neurons, leading to unique adaptations at the genic repertoire scale. With BRSG sets, we were able to highlight the contrasting features of the three groups: control, depressive, and aggressive mice in the animal chronic stress model. Specifically, we observed a decrease in serotonergic turnover in both the depressed and aggressive groups, while dopaminergic emission was high in both groups. There was also a notable absence of dopaminoceptive receptors on the postsynaptic membranes in the striatum in the depressed group. Additionally, we confirmed that neurogenesis BRSGs are specific to HPC, with the aggressive group showing attenuated neurogenesis rates compared to the control/depressive groups. We also confirmed that immune-competent cells like microglia and astrocytes play a crucial role in depressed phenotypes, including mitophagy-related gene Prkcd. Based on this analysis, we propose the use of BRSG sets as a suitable framework for evaluating case-control group-wise assessments of specific brain region gene pathway responses.
Asunto(s)
Dopamina , Neuronas , Ratones , Animales , Neuronas/metabolismo , Dopamina/metabolismo , Área Tegmental Ventral/metabolismo , Núcleo Dorsal del Rafe/metabolismo , Neuronas Dopaminérgicas/metabolismoRESUMEN
Both aggressive and aggression-deprived (AD) individuals represent pathological cases extensively studied in psychiatry and substance abuse disciplines. We employed the animal model of chronic social conflicts curated in our laboratory for over 30 years. In the study, we pursued the task of evaluation of the key events in the dorsal striatum transcriptomes of aggression-experienced mice and AD species, as compared with the controls, using RNA-seq profiling. We evaluated the alternative splicing-mediated transcriptome dynamics based on the RNA-seq data. We confined our attention to the exon skipping (ES) events as the major AS type for animals. We report the concurrent posttranscriptional and posttranslational regulation of the ES events observed in the phosphorylation cycles (in phosphoproteins and their targets) in the neuron-specific genes of the striatum. Strikingly, we found that major neurospecific splicing factors (Nova1, Ptbp1, 2, Mbnl1, 2, and Sam68) related to the alternative splicing regulation of cAMP genes (Darpp-32, Grin1, Ptpn5, Ppp3ca, Pde10a, Prkaca, Psd95, and Adora1) are upregulated specifically in aggressive individuals as compared with the controls and specifically AD animals, assuming intense switching between isoforms in the cAMP-mediated (de)phosphorylation signaling cascade. We found that the coding alternative splicing events were mostly attributed to synaptic plasticity and neural development-related proteins, while the nonsense-mediated decay-associated splicing events are mostly attributed to the mRNA processing of genes, including the spliceosome and splicing factors. In addition, considering the gene families, the transporter (Slc) gene family manifested most of the ES events. We found out that the major molecular systems employing AS for their plasticity are the 'spliceosome', 'chromatin rearrangement complex', 'synapse', and 'neural development/axonogenesis' GO categories. Finally, we state that approximately 35% of the exon skipping variants in gene coding regions manifest the noncoding variants subject to nonsense-mediated decay, employed as a homeostasis-mediated expression regulation layer and often associated with the corresponding gene expression alteration.
Asunto(s)
Empalme Alternativo , ADN Recombinante , Ratones , Animales , Empalme Alternativo/genética , Empalme del ARN , Factores de Empalme de ARN/genética , AgresiónRESUMEN
The hippocampus is known as the brain region implicated in visuospatial processes and processes associated with learning and short- and long-term memory. An important functional characteristic of the hippocampus is lifelong neurogenesis. A decrease or increase in adult hippocampal neurogenesis is associated with a wide range of neurological diseases. We have previously shown that in adult male mice with a chronic positive fighting experience in daily agonistic interactions, there is an increase in the proliferation of progenitor neurons and the production of young neurons in the dentate gyrus (in hippocampus), and these neurogenesis parameters remain modified during 2 weeks of deprivation of further fights. The aim of the present work was to identify hippocampal genes associated with neurogenesis and involved in the formation of behavioral features in mice with the chronic experience of wins in aggressive confrontations, as well as during the subsequent 2-week deprivation of agonistic interactions. Hippocampal gene expression profiles were compared among three groups of adult male mice: chronically winning for 20 days in the agonistic interactions, chronically victorious for 20 days followed by the 2-week deprivation of fights, and intact (control) mice. Neurogenesis-associated genes were identified whose transcription levels changed during the social confrontations and in the subsequent period of deprivation of fights. In the experimental males, some of these genes are associated with behavioral traits, including abnormal aggression-related behavior, an abnormal anxiety-related response, and others. Two genes encoding transcription factors (Nr1d1 and Fmr1) were likely to contribute the most to the between-group differences. It can be concluded that the chronic experience of wins in agonistic interactions alters hippocampal levels of transcription of multiple genes in adult male mice. The transcriptome changes get reversed only partially after the 2-week period of deprivation of fights. The identified differentially expressed genes associated with neurogenesis and involved in the control of a behavior/neurological phenotype can be used in further studies to identify targets for therapeutic correction of the neurological disturbances that develop in winners under the conditions of chronic social confrontations.
Asunto(s)
Hipocampo , Aprendizaje , Ratones , Animales , Masculino , Hipocampo/metabolismo , Encéfalo/metabolismo , Neuronas/metabolismo , Neurogénesis/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismoRESUMEN
The main neurotransmitters in the brain-dopamine, γ-aminobutyric acid (GABA), glutamate, and opioids-are recognized to be the most important for the regulation of aggression and addiction. The aim of this work was to study differentially expressed genes (DEGs) in the main reward-related brain regions, including the ventral tegmental area (VTA), dorsal striatum (STR), ventral striatum (nucleus accumbens, NAcc), prefrontal cortex (PFC), and midbrain raphe nuclei (MRNs), in male mice with 20-day positive fighting experience in daily agonistic interactions. Expression of opioidergic, catecholaminergic, glutamatergic, and GABAergic genes was analyzed to confirm or refute the influence of repeated positive fighting experience on the development of "addiction-like" signs shown in our previous studies. High-throughput RNA sequencing was performed to identify differentially expressed genes in the brain regions of chronically aggressive mice. In the aggressive mice, upregulation of opioidergic genes was shown (Oprk1 in VTA, Pdyn in NAcc, Penk in PFC, and Oprd1 in MRNs and PFC), as was downregulation of genes Opcml and Oprk1 in STR and Pomc in VTA and NAcc. Upregulation of catecholaminergic genes in VTA (Ddc and Slc6a2) and in NAcc (Th and Drd2) and downregulation of some differentially expressed genes in MRNs (Th, Ddc, Dbh, Drd2, Slc18a2, and Sncg) and in VTA (Adra2c, Sncg, and Sncb) were also documented. The expression of GABAergic and glutamatergic genes that participate in drug addiction changed in all brain regions. According to literature data, the proteins encoded by genes Drd2, Oprk1, Oprd1, Pdyn, Penk, and Pomc are directly involved in drug addiction in humans. Thus, our results confirm our earlier claim about the formation of addiction-like signs following repeated positive fighting experience in mice, as shown previously in our biobehavioral studies.
Asunto(s)
Proopiomelanocortina , Área Tegmental Ventral , Humanos , Animales , Ratones , Masculino , Proopiomelanocortina/metabolismo , Área Tegmental Ventral/metabolismo , Núcleo Accumbens/metabolismo , Encéfalo/metabolismo , Neurotransmisores/metabolismo , Recompensa , Ácido Glutámico/metabolismo , Moléculas de Adhesión Celular/metabolismo , Proteínas Ligadas a GPI/metabolismoRESUMEN
Chronic social stress caused by daily agonistic interactions in male mice leads to a mixed anxiety/depression-like disorder that is accompanied by the development of psychogenic immunodeficiency and stimulation of oncogenic processes concurrently with many neurotranscriptomic changes in brain regions. The aim of the study was to identify carcinogenesis- and apoptosis-associated differentially expressed genes (DEGs) in the hypothalamus of male mice with depression-like symptoms and, for comparison, in aggressive male mice with positive social experience. To obtain two groups of animals with the opposite 20-day social experiences, a model of chronic social conflict was used. Analysis of RNA-Seq data revealed similar expression changes for many DEGs between the aggressive and depressed animals in comparison with the control group; however, the number of DEGs was significantly lower in the aggressive than in the depressed mice. It is likely that the observed unidirectional changes in the expression of carcinogenesis- and apoptosis-associated genes in the two experimental groups may be a result of prolonged social stress (of different severity) caused by the agonistic interactions. In addition, 26 DEGs were found that did not change expression in the aggressive animals and could be considered genes promoting carcinogenesis or inhibiting apoptosis. Akt1, Bag6, Foxp4, Mapk3, Mapk8, Nol3, Pdcd10, and Xiap were identified as genes whose expression most strongly correlated with the expression of other DEGs, suggesting that their protein products play a role in coordination of the neurotranscriptomic changes in the hypothalamus. Further research into functions of these genes may be useful for the development of pharmacotherapies for psychosomatic pathologies.
Asunto(s)
Hipotálamo , Derrota Social , Animales , Apoptosis , Carcinogénesis/metabolismo , Hipotálamo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Chaperonas Moleculares/metabolismo , Proteínas Nucleares/metabolismo , Estrés Psicológico/metabolismoRESUMEN
Midbrain raphe nuclei (MRNs) contain a large number of serotonergic neurons associated with the regulation of numerous types of psychoemotional states and physiological processes. The aim of this work was to study alterations of the MRN transcriptome in mice with prolonged positive or negative fighting experience and to identify key gene networks associated with the regulation of serotonergic system functioning. Numerous genes underwent alterations of transcription in the MRNs of male mice that either manifested aggression or experienced social defeat in daily agonistic interactions. The expression of the Tph2 gene encoding the rate-limiting enzyme of the serotonin synthesis pathway correlated with the expression of many genes, 31 of which were common between aggressive and defeated mice and were downregulated in the MRNs of mice of both experimental groups. Among these common differentially expressed genes (DEGs), there were genes associated with behavior, learning, memory, and synaptic signaling. These results suggested that, in the MRNs of the mice, the transcriptome changes associated with serotonergic regulation of various processes are similar between the two groups (aggressive and defeated). In the MRNs, more DEGs correlating with Tph2 expression were found in defeated mice than in the winners, which is probably a consequence of deeper Tph2 downregulation in the losers. It was shown for the first time that, in both groups of experimental mice, the changes in the transcription of genes controlling the synthesis and transport of serotonin directly correlate with the expression of genes Crh and Trh, which control the synthesis of corticotrophin- and thyrotropin-releasing hormones. Our findings indicate that CRH and TRH locally produced in MRNs are related to serotonergic regulation of brain processes during a chronic social conflict.
Asunto(s)
Agresión , Hormona Liberadora de Corticotropina/metabolismo , Núcleos del Rafe/metabolismo , Serotonina/biosíntesis , Derrota Social , Hormona Liberadora de Tirotropina/metabolismo , Animales , Hormona Liberadora de Corticotropina/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Serotonina/genética , Hormona Liberadora de Tirotropina/genética , Triptófano Hidroxilasa/genética , Triptófano Hidroxilasa/metabolismoRESUMEN
There is experimental evidence that chronic social defeat stress is accompanied by the development of an anxiety, development of a depression-like state, and downregulation of serotonergic genes in midbrain raphe nuclei of male mice. Our study was aimed at investigating the effects of chronic lithium chloride (LiCl) administration on anxiety behavior and the expression of serotonergic genes in midbrain raphe nuclei of the affected mice. A pronounced anxiety-like state in male mice was induced by chronic social defeat stress in daily agonistic interactions. After 6 days of this stress, defeated mice were chronically treated with saline or LiCl (100 mg/kg, i.p., 2 weeks) during the continuing agonistic interactions. Anxiety was assessed by behavioral tests. RT-PCR was used to determine Tph2, Htr1a, Htr5b, and Slc6a4 mRNA expression. The results revealed anxiolytic-like effects of LiCl on social communication in the partition test and anxiogenic-like effects in both elevated plus-maze and social interaction tests. Chronic LiCl treatment upregulated serotonergic genes in midbrain raphe nuclei. Thus, LiCl effects depend on the treatment mode, psycho-emotional state of the animal, and experimental context (tests). It is assumed that increased expression of serotonergic genes is accompanied by serotonergic system activation and, as a side effect, by higher anxiety.
RESUMEN
A range of several psychiatric medications targeting the activity of solute carrier (SLC) transporters have proved effective for treatment. Therefore, further research is needed to elucidate the expression profiles of the Slc genes, which may serve as markers of altered brain metabolic processes and neurotransmitter activities in psychoneurological disorders. We studied the Slc differentially expressed genes (DEGs) using transcriptomic profiles in the ventral tegmental area (VTA), nucleus accumbens (NAcc), and prefrontal cortex (PFC) of control and aggressive male mice with psychosis-like behavior induced by repeated experience of aggression accompanied with wins in daily agonistic interactions. The majority of the Slc DEGs were shown to have brain region-specific expression profiles. Most of these genes in the VTA and NAcc (12 of 17 and 25 of 26, respectively) were downregulated, which was not the case in the PFC (6 and 5, up- and downregulated, respectively). In the VTA and NAcc, altered expression was observed for the genes encoding the transporters of neurotransmitters as well as inorganic and organic ions, amino acids, metals, glucose, etc. This indicates an alteration in transport functions for many substrates, which can lead to the downregulation or even disruption of cellular and neurotransmitter processes in the VTA and NAcc, which are attributable to chronic stimulation of the reward systems induced by positive fighting experience. There is not a single Slc DEG common to all three brain regions. Our findings show that in male mice with repeated experience of aggression, altered activity of neurotransmitter systems leads to a restructuring of metabolic and neurotransmitter processes in a way specific for each brain region. We assume that the scoring of Slc DEGs by the largest instances of significant expression co-variation with other genes may outline a candidate for new prognostic drug targets. Thus, we propose that the Slc genes set may be treated as a sensitive genes marker scaffold in brain RNA-Seq studies.
Asunto(s)
Agresión/fisiología , Proteínas Transportadoras de Solutos/genética , Transcriptoma/genética , Animales , Encéfalo/metabolismo , Dopamina/metabolismo , Expresión Génica/genética , Perfilación de la Expresión Génica/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Neurotransmisores/metabolismo , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiología , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiología , Proteínas Transportadoras de Solutos/metabolismo , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/fisiologíaRESUMEN
Both aggressive and aggression-deprived (AD) species represent pathologic cases intensely addressed in psychiatry and substance abuse disciplines. Previously, we reported that AD mice displayed a higher aggressive behavior score than the aggressive group, implying the manifestation of a withdrawal effect. We employed an animal model of chronic social conflicts, curated in our lab for more than 30 years. In the study, we pursued the task of evaluating key events in the dorsal striatum transcriptome of aggression experienced mice and AD species compared to controls using RNA-Seq profiling. Aggressive species were subjected to repeated social conflict encounters (fights) with regular positive (winners) experience in the course of 20 consecutive days (A20 group). This led to a profoundly shifted transcriptome expression profile relative to the control group, outlined by more than 1000 differentially expressed genes (DEGs). RNA-Seq cluster analysis revealed that elevated cyclic AMP (cAMP) signaling cascade and associated genes comprising 170 differentially expressed genes (DEGs) in aggressive (A20) species were accompanied by a downturn in the majority of other metabolic/signaling gene networks (839 DEGs) via the activation of transcriptional repressor DEGs. Fourteen days of a consecutive fighting deprivation period (AD group) featured the basic restoration of the normal (control) transcriptome expression profile yielding only 62 DEGs against the control. Notably, we observed a network of 12 coordinated DEG Transcription Factor (TF) activators from 62 DEGs in total that were distinctly altered in AD compared to control group, underlining the distinct transcription programs featuring AD group, partly retained from the aggressive encounters and not restored to normal in 14 days. We found circadian clock TFs among them, reported previously as a withdrawal effect factor. We conclude that the aggressive phenotype selection with positive reward effect (winning) manifests an addiction model featuring a distinct opioid-related withdrawal effect in AD group. Along with reporting profound transcriptome alteration in A20 group and gaining some insight on its specifics, we outline specific TF activator gene networks associated with transcriptional repression in affected species compared to controls, outlining Nr1d1 as a primary candidate, thus offering putative therapeutic targets in opioid-induced withdrawal treatment.
Asunto(s)
Agresión/fisiología , Regulación de la Expresión Génica/genética , Factores de Transcripción/genética , Transcriptoma/genética , Animales , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica/métodos , Masculino , Redes y Vías Metabólicas/genética , Ratones , Ratones Endogámicos C57BL , Fenotipo , RNA-Seq/métodosRESUMEN
Despite high prevalence, medical impact and societal burden, anxiety, depression and other affective disorders remain poorly understood and treated. Clinical complexity and polygenic nature complicate their analyses, often revealing genetic overlap and cross-disorder heritability. However, the interplay or overlaps between disordered phenotypes can also be based on shared molecular pathways and 'crosstalk' mechanisms, which themselves may be genetically determined. We have earlier predicted (Kalueff et al., 2014) a new class of 'interlinking' brain genes that do not affect the disordered phenotypes per se, but can instead specifically determine their interrelatedness. To test this hypothesis experimentally, here we applied a well-established rodent chronic social defeat stress model, known to progress in C57BL/6J mice from the Anxiety-like stage on Day 10 to Depression-like stage on Day 20. The present study analyzed mouse whole-genome expression in the prefrontal cortex and hippocampus during the Day 10, the Transitional (Day 15) and Day 20 stages in this model. Our main question here was whether a putative the Transitional stage (Day 15) would reveal distinct characteristic genomic responses from Days 10 and 20 of the model, thus reflecting unique molecular events underlining the transformation or switch from anxiety to depression pathogenesis. Overall, while in the Day 10 (Anxiety) group both brain regions showed major genomic alterations in various neurotransmitter signaling pathways, the Day 15 (Transitional) group revealed uniquely downregulated astrocyte-related genes, and the Day 20 (Depression) group demonstrated multiple downregulated genes of cell adhesion, inflammation and ion transport pathways. Together, these results reveal a complex temporal dynamics of mouse affective phenotypes as they develop. Our genomic profiling findings provide first experimental support to the idea that novel brain genes (activated here only during the Transitional stage) may uniquely integrate anxiety and depression pathogenesis and, hence, determine the progression from one pathological state to another. This concept can potentially be extended to other brain conditions as well. This preclinical study also further implicates cilial and astrocytal mechanisms in the pathogenesis of affective disorders.
Asunto(s)
Afecto/fisiología , Trastornos de Ansiedad/genética , Hipocampo/metabolismo , Corteza Prefrontal/metabolismo , Estrés Psicológico/genética , Animales , Ansiedad/genética , Ansiedad/metabolismo , Trastornos de Ansiedad/metabolismo , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Genoma , Ratones , Conducta Social , Estrés Psicológico/metabolismoRESUMEN
Daily agonistic interactions of mice are an effective experimental approach to elucidate the molecular mechanisms underlying the excitation of the brain neurons and the formation of alternative social behavior patterns. An RNA-Seq analysis was used to compare the ventral tegmental area (VTA) transcriptome profiles for three groups of male C57BL/6J mice: winners, a group of chronically winning mice, losers, a group of chronically defeated mice, and controls. The data obtained show that both winners and defeated mice experience stress, which however, has a more drastic effect on defeated animals causing more significant changes in the levels of gene transcription. Four genes (Nrgn, Ercc2, Otx2, and Six3) changed their VTA expression profiles in opposite directions in winners and defeated mice. It was first shown that Nrgn (neurogranin) expression was highly correlated with the expression of the genes involved in dopamine synthesis and transport (Th, Ddc, Slc6a3, and Drd2) in the VTA of defeated mice but not in winners. The obtained network of 31 coregulated genes, encoding proteins associated with nervous system development (including 24 genes associated with the generation of neurons), may be potentially useful for studying their role in the VTA dopaminergic neurons maturation under the influence of social stress.
Asunto(s)
Conducta Agonística/fisiología , Predominio Social , Área Tegmental Ventral/metabolismo , Animales , Estudios de Casos y Controles , Análisis por Conglomerados , Dopamina/biosíntesis , Perfilación de la Expresión Génica , Masculino , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Medium spiny neurons (MSNs) comprise the main body (95% in mouse) of the dorsal striatum neurons and represent dopaminoceptive GABAergic neurons. The cAMP (cyclic Adenosine MonoPhosphate)-mediated cascade of excitation and inhibition responses observed in MSN intracellular signal transduction is crucial for neuroscience research due to its involvement in the motor and behavioral functions. In particular, all types of addictions are related to MSNs. Shedding the light on the mechanics of the above-mentioned cascade is of primary importance for this research domain. RESULTS: A mouse model of chronic social conflicts in daily agonistic interactions was used to analyze dorsal striatum neurons genes implicated in cAMP-mediated phosphorylation activation pathways specific for MSNs. Based on expression correlation analysis, we succeeded in dissecting Drd1- and Drd2-dopaminoceptive neurons (D1 and D2, correspondingly) gene pathways. We also found that D1 neurons genes clustering are split into two oppositely correlated states, passive and active ones, the latter apparently corresponding to D1 firing stage upon protein kinase A (PKA) activation. We observed that under defeat stress in chronic social conflicts the loser mice manifest overall depression of dopamine-mediated MSNs activity resulting in previously reported reduced motor activity, while the aggressive mice with positive fighting experience (aggressive mice) feature an increase in both D1-active phase and D2 MSNs genes expression leading to hyperactive behavior pattern corresponded by us before. Based on the alternative transcript isoforms expression analysis, it was assumed that many genes (Drd1, Adora1, Pde10, Ppp1r1b, Gnal), specifically those in D1 neurons, apparently remain transcriptionally repressed via the reversible mechanism of promoter CpG island silencing, resulting in alternative promoter usage following profound reduction in their expression rate. CONCLUSION: Based on the animal stress model dorsal striatum pooled tissue RNA-Seq data restricted to cAMP related genes subset we elucidated MSNs steady states exhaustive projection for the first time. We correspond the existence of D1 active state not explicitly outlined before, and connected with dynamic dopamine neurotransmission cycles. Consequently, we were also able to indicate an oscillated postsynaptic dopamine vs glutamate action pattern in the course of the neurotransmission cycles.
Asunto(s)
Cuerpo Estriado/metabolismo , AMP Cíclico/genética , Dopamina/genética , Neuronas GABAérgicas/metabolismo , Expresión Génica , Neuronas/metabolismo , Animales , AMP Cíclico/metabolismo , Dopamina/metabolismo , Redes Reguladoras de Genes , Hipocampo/metabolismo , Hipotálamo/metabolismo , Masculino , Ratones Endogámicos C57BL , Núcleos del Rafe/metabolismo , Transducción de Señal/genética , Estrés Psicológico/genética , Área Tegmental Ventral/metabolismoRESUMEN
Chronic agonistic interactions promote the development of experimental psychopathologies in animals: a depression-like state in chronically defeated mice and the pathology of aggressive behavior in the mice with repeated wins. The abundant research data indicate that such psychopathological states are associated with significant molecular and cellular changes in the brain. This paper aims to study the influence of a 20-day period of agonistic interactions on the expression patterns of collagen family genes encoding the proteins which are basic components of extracellular matrix (ECM) in different brain regions of mice using the RNA-Seq database. Most of differentially expressed collagen genes were shown to be upregulated in the hypothalamus and striatum of chronically aggressive and defeated mice and in the hippocampus of defeated mice, whereas downregulation of collagen genes was demonstrated in the ventral tegmental areas in both experimental groups. Aberrant expression of collagen genes induced by chronic agonistic interactions may be indicative of specific ECM defects in the brain regions of mice with alternative social experience. This is the first study demonstrating remodeling of ECM under the development of experimental disorders.
Asunto(s)
Agresión/fisiología , Encéfalo/fisiología , Colágeno/genética , Depresión/genética , Animales , Conducta Animal/fisiología , Encéfalo/metabolismo , Encéfalo/patología , Depresión/fisiopatología , Matriz Extracelular/genética , Regulación de la Expresión Génica/genética , Humanos , Masculino , Ratones , Familia de Multigenes/genéticaRESUMEN
BACKGROUND: Development of anxiety- and depression-like states under chronic social defeat stress in mice has been shown by many experimental studies. In this article, the differentially expressed Slc25* family genes encoding mitochondrial carrier proteins were analyzed in the brain of depressive (defeated) mice versus aggressive mice winning in everyday social confrontations. The collected samples of brain regions were sequenced at JSC Genoanalytica ( http://genoanalytica.ru/ , Moscow, Russia). RESULTS: Changes in the expression of the 20 Slc25* genes in the male mice were brain region- and social experience (positive or negative)-specific. In particular, most Slc25* genes were up-regulated in the hypothalamus of defeated and aggressive mice and in the hippocampus of defeated mice. In the striatum of defeated mice and in the ventral tegmental area of aggressive mice expression of mitochondrial transporter genes changed specifically. Significant correlations between expression of most Slc25* genes and mitochondrial Mrps and Mrpl genes were found in the brain regions. CONCLUSION: Altered expression of the Slc25* genes may serve as a marker of mitochondrial dysfunction in brain, which accompanies the development of many neurological and psychoemotional disorders.
Asunto(s)
Trastornos de Ansiedad/metabolismo , Encéfalo/metabolismo , Trastorno Depresivo/metabolismo , Enfermedades Mitocondriales/metabolismo , Proteínas Mitocondriales/metabolismo , Agresión/fisiología , Empalme Alternativo , Animales , Trastornos de Ansiedad/genética , Trastorno Depresivo/genética , Modelos Animales de Enfermedad , Dominación-Subordinación , Expresión Génica , Regulación de la Expresión Génica , Masculino , Ratones Endogámicos C57BL , Enfermedades Mitocondriales/genética , Proteínas Mitocondriales/genética , Análisis de Secuencia de ARN , Estrés Psicológico/genética , Estrés Psicológico/metabolismo , TranscriptomaRESUMEN
Repeated positive fighting experience in daily agonistic interactions is accompanied by changes of brain neurotransmitter activity and genes' expression in male mice. This paper is focused on the analysis of ribosomal genes expression data as revealed by whole-transcriptome analysis (RNA-Seq) in five brain regions of male mice with long repeated experience of aggression accompanied by wins (winners). Downregulation of most Rps, Rpl, Mrps, and Mrpl genes was found in the midbrain raphe nuclei and striatum and upregulation-in the hippocampus and hypothalamus of the winners. There were no changes in ribosomal gene expression in the ventral tegmental area. The data allow considering the alteration in ribosomal gene expression as an animal model of ribosomal dysfunction developed under positive fighting experience in male mice.
Asunto(s)
Agresión/fisiología , Encéfalo/fisiología , Proteínas Ribosómicas/biosíntesis , Proteínas Ribosómicas/genética , Análisis de Secuencia de ARN/métodos , Animales , Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Chronic social defeat stress leads to the development of anxiety- and depression-like states in male mice and is accompanied by numerous molecular changes in brain. The influence of 21-day period of social stress on ribosomal gene expression in five brain regions was studied using the RNA-Seq database. Most Rps, Rpl, Mprs, and Mprl genes were upregulated in the hypothalamus and downregulated in the hippocampus, which may indicate ribosomal dysfunction following chronic social defeat stress. There were no differentially expressed ribosomal genes in the ventral tegmental area, midbrain raphe nuclei, or striatum. This approach may be used to identify a pharmacological treatment of ribosome biogenesis abnormalities in the brain of patients with "ribosomopathies."
Asunto(s)
Dominación-Subordinación , Expresión Génica , Hipocampo/metabolismo , Hipotálamo/metabolismo , Ribosomas/genética , Estrés Psicológico/genética , Animales , Conducta Animal/fisiología , Hipotálamo/fisiopatología , Masculino , Ratones , Ribosomas/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Regulación hacia ArribaRESUMEN
Individuals exposed to social stress in childhood are more predisposed to developing psychoemotional disorders in adulthood. Here we use an animal model to determine the influence of hostile social environment in adolescence on behavior during adult life. One-month-old adolescent male mice were placed for 2 weeks in a common cage with an adult aggressive male. Animals were separated by a transparent perforated partition, but the adolescent male was exposed daily to short attacks from the adult male. After exposure to social stress, some of the adolescent mice were placed for 3 weeks in comfortable conditions. Following this rest period, stressed young males and adult males were studied in a range of behavioral tests to evaluate the levels of anxiety, depressiveness, and communicativeness with an unfamiliar partner. In addition, adult mice exposed to social stress in adolescence were engaged in agonistic interactions. We found that 2 weeks of social stress result in a decrease of communicativeness in the home cage and diminished social interactions on the novel territory. Stressed adolescents demonstrated a high level of anxiety in the elevated plus-maze test and helplessness in the Porsolt test. Furthermore, the number of dividing (BrdU-positive) cells in the subgranular zone of the dentate gyrus was significantly lower in stressed adolescents. After 3 weeks of rest, most behavioral characteristics in different tests, as well as the number of BrdU-positive cells in the hippocampus, did not differ from those of the respective control mice. However, the level of anxiety remained high in adult males exposed to chronic social stress in childhood. Furthermore, these males were more aggressive in the agonistic interactions. Thus, hostile social environment in adolescence disturbs psychoemotional state and social behaviors of animals in adult life.