Brain-Region-Specific Genes Form the Major Pathways Featuring Their Basic Functional Role: Their Implication in Animal Chronic Stress Model.

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.

Effects of Positive Fighting Experience and Its Subsequent Deprivation on the Expression Profile of Mouse Hippocampal Genes Associated with Neurogenesis.

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.

The Dysfunction of Carcinogenesis- and Apoptosis-Associated Genes that Develops in the Hypothalamus under Chronic Social Defeat Stress in Male Mice.

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.

Altered Expression of Genes Associated with Major Neurotransmitter Systems in the Reward-Related Brain Regions of Mice with Positive Fighting Experience.

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.

SARS-CoV-2 convalescent plasma therapy in pediatric patient after hematopoietic stem cell transplantation.

Immunocompromised patients, including HSCT recipients, may have a poor prognosis after contracting COVID-19 due to the absence of a pathogen-specific adaptive immune response. One of the possible options for severe COVID-19 treatment may be the transfusion of hyperimmune SARS-CoV-2 convalescent plasma. A 9-month-old girl with juvenile myelomonocytic leukemia received an HSCT from a haploidentical donor. On day +99, during routine virologic monitoring, SARS-CoV-2 was detected without any clinical symptoms. On day +144, the child developed a polysegmental bilateral viral pneumonia with 60 % damage to the lung tissue and confirm a positive SARS-Cov-2 results in throat swab. The patient was treated with tocilizumab and three doses of fresh frozen plasma obtained from a SARS-CoV-2 convalescent patient. Therapy with tocilizumab and three doses of fresh frozen plasma was well tolerated. In spite of full resolution of the lung lesions, complete elimination of SARS-CoV-2 has not been achieved 4 months after the first detection, which is due to persistence of secondary immunodeficiency after HSCT and the lack of reconstitution of the adaptive immune response. This case represents a demonstration of an atypical course of COVID-19 and the delayed development of lung lesions, which was most likely associated with the features of the patient's immune status after HSCT. SARS-CoV-2 convalescent plasma in combination with other therapeutic approaches is one of the possible curative options for this clinical situation.

Gene Expression Changes in the Ventral Tegmental Area of Male Mice with Alternative Social Behavior Experience in Chronic Agonistic Interactions.

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.

Altered Slc25 family gene expression as markers of mitochondrial dysfunction in brain regions under experimental mixed anxiety/depression-like disorder.

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.

Dysfunction in Ribosomal Gene Expression in the Hypothalamus and Hippocampus following Chronic Social Defeat Stress in Male Mice as Revealed by RNA-Seq.

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."

Elucidation of the Landscape of Alternatively Spliced Genes and Features in the Dorsal Striatum of Aggressive/Aggression-Deprived Mice in the Model of Chronic Social Conflicts.

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.

Dorsal Striatum Transcriptome Profile Profound Shift in Repeated Aggression Mouse Model Converged to Networks of 12 Transcription Factors after Fighting Deprivation.

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.

Chronic Lithium Treatment Affects Anxious Behaviors and theExpression of Serotonergic Genes in Midbrain Raphe Nuclei of Defeated Male Mice.

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.

Correlation of Expression Changes between Genes Controlling 5-HT Synthesis and Genes Crh and Trh in the Midbrain Raphe Nuclei of Chronically Aggressive and Defeated Male Mice.

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.

Reduced Expression of Slc Genes in the VTA and NAcc of Male Mice with Positive Fighting Experience.

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.

CNS genomic profiling in the mouse chronic social stress model implicates a novel category of candidate genes integrating affective pathogenesis.

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.

Aberrant Expression of Collagen Gene Family in the Brain Regions of Male Mice with Behavioral Psychopathologies Induced by Chronic Agonistic Interactions.

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.

Heterogeneity of Brain Ribosomal Genes Expression Following Positive Fighting Experience in Male Mice as Revealed by RNA-Seq.

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.

Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice.

Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. Insulin/insulin-like growth factor 1 (IGF-1) signaling molecules that have been linked to longevity include DAF-2 and InR and their homologues in mammals, and inactivation of the corresponding genes is followed by increased life span in nematodes, fruit flies and mice. It is possible that the life-prolonging effects of calorie restriction are due to decreasing IGF-1 levels. A search of pharmacological modulators of insulin/IGF-1 signaling pathway (which mimetic effects of life span extending mutations or calorie restriction) could be a perspective direction in regulation of longevity. The chronic treatment of female transgenic HER-2/neu mice with metformin (100 mg/kg in drinking water) slightly decreased the food consumption but failed in reducing the body weight or temperature, slowed down the age-related rise in blood glucose and triglycerides level, as well as the age-related switch-off of estrous function, prolonged the mean life span by 8% (p < 0.05), the mean life span of last 10% survivors by 13.1%, and the maximum life span by 1 month in comparison with control mice. The demographic aging rate represented by the estimate of respective Gompertz's parameter was decreased 2.26 times. The metformin-treatment significantly decreased the incidence and size of mammary adenocarcinomas in mice and increased the mean latency of the tumors.

Altered Hippocampal Neurogenesis and Amygdalar Neuronal Activity in Adult Mice with Repeated Experience of Aggression.

Repeated experience of winning in a social conflict setting elevates levels of aggression and may lead to violent behavioral patterns. Here, we use a paradigm of repeated aggression and fighting deprivation to examine changes in behavior, neurogenesis, and neuronal activity in mice with positive fighting experience. We show that for males, repeated positive fighting experience induces persistent demonstration of aggression and stereotypic behaviors in daily agonistic interactions, enhances aggressive motivation, and elevates levels of anxiety. When winning males are deprived of opportunities to engage in further fights, they demonstrate increased levels of aggressiveness. Positive fighting experience results in increased levels of progenitor cell proliferation and production of young neurons in the hippocampus. This increase is not diminished after a fighting deprivation period. Furthermore, repeated winning experience decreases the number of activated (c-fos-positive) cells in the basolateral amygdala and increases the number of activated cells in the hippocampus; a subsequent no-fight period restores the number of c-fos-positive cells. Our results indicate that extended positive fighting experience in a social conflict heightens aggression, increases proliferation of neuronal progenitors and production of young neurons in the hippocampus, and decreases neuronal activity in the amygdala; these changes can be modified by depriving the winners of the opportunity for further fights.

Features of endometrial cancer in patients with 'metabolically healthy' versus 'standard' obesity: the decreasing frequency of metabolically healthy obesity.

BACKGROUND: As endometrial cancer (EC) prevalence increases with obesity, we aimed to determine whether EC characteristics depend upon obesity type: 'standard' (SO) or 'metabolically healthy obesity' (MHO). PATIENTS & METHODS: 258 EC patients were included. Data on anthropometry, blood hormones, lipids and glucose, and tumor features were collected. RESULTS: EC clinicopathologic characteristics and clinical stage correlate differently with BMI and obesity type. BMI is related inversely with tumor grade while SO patients are characterized by a more advanced clinical stage than those with MHO. Besides typical insulin resistance signs, EC patients with SO often display a higher serum leptin/adiponectin ratio compared with MHO patients. Historical data suggest a gradual increase in EC patient height and weight, and a decrease in MHO prevalence. CONCLUSION: It is currently unknown whether the latter observation reflects the evolution of EC, or obesity alongside the current epidemic. Regardless, the reduced MHO prevalence demonstrates the need for more intensive preventive measures aimed at obesity and obesity-associated conditions, including different EC subtypes.

CYP17 genetic polymorphism in endometrial cancer: are only steroids involved?

Initiation and/or promotion of endometrial cancer is known to be associated with estrogen and androgen (androstenedione) excess as well as with hyperinsulinemia/insulin resistance. It is possible that some allelic polymorphisms of the genes involved in steroidogenesis or steroid metabolism contribute to endometrial cancer susceptibility. We evaluated here the role of CYP17 biallelic (MspAI) polymorphism in 114 endometrial cancer patients compared with 182 healthy women. Our data demonstrated that A2/A2 CYP17 genotype, considered on the basis of initial breast cancer studies as 'unfavorable', was under-represented in endometrial cancer group (odds ratio 0.48, 95% confidence interval 0.25-0.89) that confirmed results of two other recent investigations. Carriers of this genotype were characterized by having lower blood insulin (by 120 min of oral glucose tolerance test 36.7+/-3.9 microU/ml vs. 90.4+/-16.7 microU/ml in postmenopausal women with A1/A1 genotype, P=0.04) and C-peptide levels (after night fasting 575.2+/-78.3 pg/ml vs. 978.9+/-115.7 pg/ml, respectively, P=0.04). No significant difference was found between the mean concentrations of testosterone, dehydroepiandrosterone sulfate and estradiol concentrations in patients-carriers of separate CYP17 genotypes. Thus, CYP17 polymorphism (namely, carrying the 'normal' A1/A1 genotype) might be one of the risk factors for endometrial cancer development. A1/A1 CYP17 variant may be associated with untraditional (non-steroidal) pathways that calls for corresponding preventive measures in high-risk groups.