Altered serotonergic gene expression in the brain regions of male mice with anxiety/depression-like state and pathology of aggressive behaviour

Aggressive behaviour associated with territorial defence is widespread and has fitness consequences. However, excess aggression can interfere with other important biological functions such as immunity and energy homeostasis. How the expression of complex behaviours such as aggression is regulated in the brain has long intrigued ethologists, but has only recently become amenable for molecular dissection in non-model organisms. We investigated the transcriptomic response to territorial intrusion in four brain regions in breeding male threespined sticklebacks using expression microarrays and quantitative polymerase chain reaction (qPCR). Each region of the brain had a distinct genomic response to a territorial challenge. We identified a set of genes that were upregulated in the diencephalon and downregulated in the cerebellum and the brain stem. Cis -regulatory network analysis suggested transcription factors that regulated or co-regulated genes that were consistently regulated in all brain regions and others that regulated gene expression in opposing directions across brain regions. Our results support the hypothesis that territorial animals respond to social challenges via transcriptional regulation of genes in different brain regions. Finally, we found a remarkably close association between gene expression and aggressive behaviour at the individual level. This study sheds light on the molecular mechanisms in the brain that underlie the response to social challenges.

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Transcriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer’s disease

Nature Communications ◽

10.1038/s41467-021-22399-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Angela M. Crist ◽

Kelly M. Hinkle ◽

Xue Wang ◽

Christina M. Moloney ◽

Billie J. Matchett ◽

...

Keyword(s):

Gene Expression ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Digital Pathology ◽

Selective Vulnerability ◽

Brain Regions ◽

Biochemical Analyses ◽

The Brain ◽

Relevant Gene ◽

Tau Expression

AbstractSelective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable in Alzheimer’s disease (AD), however the degree of involvement of the different brain regions differs among patients. We classified corticolimbic patterns of neurofibrillary tangles in postmortem tissue to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. We identified hippocampal gene expression changes associated with hippocampal vulnerability and used machine learning to identify genes that were associated with AD neuropathology, including SERPINA5, RYBP, SLC38A2, FEM1B, and PYDC1. Further histologic and biochemical analyses suggested SERPINA5 expression is associated with tau expression in the brain. Our study highlights the importance of embracing heterogeneity of the human brain in disease to identify disease-relevant gene expression.

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Physical positioning markedly enhances brain transduction after intrathecal AAV9 infusion

Science Advances ◽

10.1126/sciadv.aau9859 ◽

2018 ◽

Vol 4 (11) ◽

pp. eaau9859 ◽

Cited By ~ 7

Author(s):

Michael J. Castle ◽

Yuhsiang Cheng ◽

Aravind Asokan ◽

Mark H. Tuszynski

Keyword(s):

Gene Expression ◽

Gene Delivery ◽

Neurological Disorders ◽

Fold Increase ◽

Brain Regions ◽

Intrathecal Administration ◽

Simple Method ◽

Virus Serotype ◽

Cortical Regions ◽

The Brain

Several neurological disorders may benefit from gene therapy. However, even when using the lead vector candidate for intrathecal administration, adeno-associated virus serotype 9 (AAV9), the strength and distribution of gene transfer to the brain are inconsistent. On the basis of preliminary observations that standard intrathecal AAV9 infusions predominantly drive reporter gene expression in brain regions where gravity might cause cerebrospinal fluid to settle, we tested the hypothesis that counteracting vector “settling” through animal positioning would enhance vector delivery to the brain. When rats are either inverted in the Trendelenburg position or continuously rotated after intrathecal AAV9 infusion, we find (i) a significant 15-fold increase in the number of transduced neurons, (ii) a marked increase in gene delivery to cortical regions, and (iii) superior animal-to-animal consistency of gene expression. Entorhinal, prefrontal, frontal, parietal, hippocampal, limbic, and basal forebrain neurons are extensively transduced: 95% of transduced cells are neurons, and greater than 70% are excitatory. These findings provide a novel and simple method for broad gene delivery to the cortex and are of substantial relevance to translational programs for neurological disorders, including Alzheimer’s disease and related dementias, stroke, and traumatic brain injury.

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Transcriptomic analysis of frontotemporal lobar degeneration with TDP-43 pathology reveals cellular alterations across multiple brain regions

10.1101/2021.10.06.21264635 ◽

2021 ◽

Author(s):

Rahat Hasan ◽

Jack Humphrey ◽

Conceicao Bettencourt ◽

Tammaryn Lashley ◽

Pietro Fratta ◽

...

Keyword(s):

Gene Expression ◽

Frontotemporal Lobar Degeneration ◽

Molecular Mechanisms ◽

Rna Binding ◽

Temporal Cortex ◽

Neuronal Loss ◽

Underlying Disease ◽

Brain Regions ◽

Neuronal Markers ◽

The Brain

Frontotemporal lobar degeneration (FTLD) is a group of heterogeneous neurodegenerative disorders affecting the frontal and temporal lobes of the brain. Nuclear loss and cytoplasmic aggregation of the RNA-binding protein TDP-43 represents the major FTLD pathology, known as FTLD-TDP. To date, there is no effective treatment for FTLD-TDP due to an incomplete understanding of the molecular mechanisms underlying disease development. Here we compared post-mortem tissue RNA-seq transcriptomes from the frontal cortex, temporal cortex and cerebellum between 28 controls and 30 FTLD-TDP patients to profile changes in cell-type composition, gene expression and transcript usage. We observed downregulation of neuronal markers in all three regions of the brain, accompanied by upregulation of microglia, astrocytes, and oligodendrocytes, as well as endothelial cells and pericytes, suggesting shifts in both immune activation and within the vasculature. We validate our estimates of neuronal loss using neuropathological atrophy scores and show that neuronal loss in the cortex can be mainly attributed to excitatory neurons, and that increases in microglial and endothelial cell expression are highly correlated with neuronal loss. All our analyses identified a strong involvement of the cerebellum in the neurodegenerative process of FTLD-TDP. Altogether, our data provides a detailed landscape of gene expression alterations to help unravel relevant disease mechanisms in FTLD.

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

Neural Plasticity ◽

10.1155/2016/3289187 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 22

Author(s):

Dmitry A. Smagin ◽

Irina L. Kovalenko ◽

Anna G. Galyamina ◽

Anatoly O. Bragin ◽

Yuriy L. Orlov ◽

...

Keyword(s):

Gene Expression ◽

Social Stress ◽

Ribosome Biogenesis ◽

Social Defeat ◽

Brain Regions ◽

Ribosomal Gene ◽

Rna Seq ◽

Male Mice ◽

Social Defeat Stress ◽

Chronic Social Defeat Stress

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. MostRps, Rpl, Mprs, andMprlgenes 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.”

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Abnormal social behaviors and dysfunction of autism-related genes associated with daily agonistic interactions in mice

10.1101/125674 ◽

2017 ◽

Author(s):

Natalia N. Kudryavtseva ◽

Irina L. Kovalenko ◽

Dmitry A. Smagin ◽

Anna G. Galyamina ◽

Vladimir N. Babenko

Keyword(s):

Social Behavior ◽

Social Environment ◽

Social Behaviors ◽

Brain Regions ◽

Autistic Spectrum Disorders ◽

Male Mice ◽

Agonistic Interactions ◽

Autistic Spectrum ◽

Spectrum Disorders ◽

The Brain

AbstractBackgroundThe ability of people to communicate with each other is a necessary component of social behavior and the normal development of individuals who live in a community. An apparent decline in sociability may be the result of a negative social environment or the development of affective and neurological disorders, including autistic spectrum disorders. The behavior of these humans may be characterized by the deterioration of socialization, low communication, and repetitive and restricted behaviors. This study aimed to analyze changes in the social behaviors of male mice induced by daily agonistic interactions and investigate the involvement of genes, related with autistic spectrum disorders in the process of the impairment of social behaviors.MethodsAbnormal social behavior is induced by repeated experiences of aggression accompanied by wins (winners) or chronic social defeats (losers) in daily agonistic interactions in male mice. The collected brain regions (the midbrain raphe nuclei, ventral tegmental area, striatum, hippocampus, and hypothalamus) were sequenced at JSC Genoanalytica (http://genoanalytica.ru/, Moscow, Russia). The Cufflinks program was used to estimate the gene expression levels. Bioinformatic methods were used for the analysis of differentially expressed genes in male mice.ResultsThe losers exhibited an avoidance of social contacts toward unfamiliar conspecific, immobility and low communication on neutral territory. The winners demonstrated aggression and hyperactivity in this condition. The exploratory activity (rearing) and approaching behavior time towards the partner were decreased, and the number of episodes of repetitive self-grooming behavior was increased in both social groups. These symptoms were similar to the symptoms observed in animal models of autistic spectrum disorders. In an analysis of the RNA-Seq database of the whole transcriptome in the brain regions of the winners and losers, we identified changes in the expression of the following genes, which are associated with autism in humans: Tph2, Maoa, Slc6a4, Htr7,Gabrb3, Nrxn1, Nrxn2, Nlgn1, Nlgn2, Nlgn3, Shank2, Shank3, Fmr1, Ube3a, Pten, Cntn3, Foxp2, Oxtr, Reln, Cadps2, Pcdh10, Ctnnd2, En2, Arx, Auts2, Mecp2, and Ptchd1.Common and specific changes in the expression of these genes in different brain regions were identified in the winners and losers.ConclusionsThis research demonstrates for the first time that abnormalities in social behaviors that develop under a negative social environment in adults may be associated with alterations in expression of genes, related with autism in the brain.

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Circadian influences on dopamine circuits of the brain: regulation of striatal rhythms of clock gene expression and implications for psychopathology and disease

F1000Research ◽

10.12688/f1000research.9180.1 ◽

2016 ◽

Vol 5 ◽

pp. 2062 ◽

Cited By ~ 23

Author(s):

Michael Verwey ◽

Sabine Dhir ◽

Shimon Amir

Keyword(s):

Gene Expression ◽

Circadian Rhythms ◽

Circadian Clock ◽

Clock Gene ◽

Dorsal Striatum ◽

Brain Regions ◽

Physiological Importance ◽

Clock Gene Expression ◽

Dopamine Circuits ◽

The Brain

Circadian clock proteins form an autoregulatory feedback loop that is central to the endogenous generation and transmission of daily rhythms in behavior and physiology. Increasingly, circadian rhythms in clock gene expression are being reported in diverse tissues and brain regions that lie outside of the suprachiasmatic nucleus (SCN), the master circadian clock in mammals. For many of these extra-SCN rhythms, however, the region-specific implications are still emerging. In order to gain important insights into the potential behavioral, physiological, and psychological relevance of these daily oscillations, researchers have begun to focus on describing the neurochemical, hormonal, metabolic, and epigenetic contributions to the regulation of these rhythms. This review will highlight important sites and sources of circadian control within dopaminergic and striatal circuitries of the brain and will discuss potential implications for psychopathology and disease. For example, rhythms in clock gene expression in the dorsal striatum are sensitive to changes in dopamine release, which has potential implications for Parkinson’s disease and drug addiction. Rhythms in the ventral striatum and limbic forebrain are sensitive to psychological and physical stressors, which may have implications for major depressive disorder. Collectively, a rich circadian tapestry has emerged that forces us to expand traditional views and to reconsider the psychopathological, behavioral, and physiological importance of these region-specific rhythms in brain areas that are not immediately linked with the regulation of circadian rhythms.

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Probabilistic Critical Controllability Analysis of Protein Interaction Networks Integrating Normal Brain Ageing Gene Expression Profiles

International Journal of Molecular Sciences ◽

10.3390/ijms22189891 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9891

Author(s):

Eimi Yamaguchi ◽

Tatsuya Akutsu ◽

Jose C. Nacher

Keyword(s):

Gene Expression ◽

Biological Networks ◽

Expression Profiles ◽

Dominating Set ◽

Gene Expression Profiles ◽

Brain Regions ◽

Normal Brain ◽

Age Related ◽

Brain Ageing ◽

The Brain

Recently, network controllability studies have proposed several frameworks for the control of large complex biological networks using a small number of life molecules. However, age-related changes in the brain have not been investigated from a controllability perspective. In this study, we compiled the gene expression profiles of four normal brain regions from individuals aged 20–99 years and generated dynamic probabilistic protein networks across their lifespan. We developed a new algorithm that efficiently identified critical proteins in probabilistic complex networks, in the context of a minimum dominating set controllability model. The results showed that the identified critical proteins were significantly enriched with well-known ageing genes collected from the GenAge database. In particular, the enrichment observed in replicative and premature senescence biological processes with critical proteins for male samples in the hippocampal region led to the identification of possible new ageing gene candidates.

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Distribution of Kakugo Virus and Its Effects on the Gene Expression Profile in the Brain of the Worker Honeybee Apis mellifera L.

Journal of Virology ◽

10.1128/jvi.00519-09 ◽

2009 ◽

Vol 83 (22) ◽

pp. 11560-11568 ◽

Cited By ~ 20

Author(s):

Tomoko Fujiyuki ◽

Emiko Matsuzaka ◽

Takayoshi Nakaoka ◽

Hideaki Takeuchi ◽

Akiko Wakamoto ◽

...

Keyword(s):

Gene Expression ◽

Leucine Zipper ◽

Expression Profiles ◽

Parasitic Wasp ◽

Gene Expression Profiles ◽

Hypothetical Protein ◽

Brain Regions ◽

Gene Encoding ◽

Brain Functions ◽

The Brain

ABSTRACT We previously identified a novel insect picorna-like virus, termed Kakugo virus (KV), obtained from the brains of aggressive honeybee worker bees that had counterattacked giant hornets. Here we examined the tissue distribution of KV and alterations of gene expression profiles in the brains of KV-infected worker bees to analyze possible effects of KV infection on honeybee neural and physiological states. By use of in situ hybridization, KV was broadly detected in the brains of the naturally KV-infected worker bees. When inoculated experimentally into bees, KV was detected in restricted parts of the brain at the early infectious stage and was later detected in various brain regions, including the mushroom bodies, optic lobes, and ocellar nerve. KV was detected not only in the brain but also in the hypopharyngeal glands and fat bodies, indicating systemic KV infection. Next, we compared the gene expression profiles in the brains of KV-inoculated and noninoculated bees. The expression of 11 genes examined was not significantly affected in KV-infected worker bees. cDNA microarray analysis, however, identified a novel gene whose expression was induced in the periphery of the brains of KV-infected bees, which was commonly observed in naturally infected and experimentally inoculated bees. The gene encoded a novel hypothetical protein with a leucine zipper motif. A gene encoding a similar protein was found in the parasitic wasp Nasonia genome but not in other insect genomes. These findings suggest that KV infection may affect brain functions and/or physiological states in honeybees.

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