Brain Immune Gene Network in Inbred Mouse Models of Anxiety- and Sociability-related Neuropsychiatric Disorders

Tutkimustuotos: OpinnäyteVäitöskirjaArtikkelikokoelma

Kuvaus

Interactions between the brain and the immune system provide a complex microenvironment for brain development. Furthermore, these interactions cause behavioral changes in rodents and humans. Multiple molecules of the immune system in the brain can regulate neural development. Microglia, the resident phagocytes in the central nervous system (CNS), dynamically survey their microenvironment to maintain brain homeostasis. Microglia also actively respond to neuroinflammation induced by insults such as stress, injury, or infection. A dysfunctional immune system in the brain may cause aberrant brain development and adulthood behavior. Dysfunctional immune regulation has also been implicated in the pathophysiological progression of neuropsychiatric disorders in rodents and humans. The major goal of my thesis is to characterize brain immune genes, gene networks, and neuropeptides in inbred mouse strains. These factors might contribute to mouse anxiety- and sociability-like behavior related to symptoms in generalized anxiety disorder and schizophrenia, as inbred strains such as C57BL/6J(N) (C57BL/6J and C57BL/6N) and DBA/2J differ in their anxiety-, sociability- and sensorimotor gating-related behaviors. In this thesis, we utilized eight inbred mouse strains 129S1/SvImJ, A/J, BALB/cByJ, C3H/HeJ, C57BL/6J, DBA/2J, FVB/NJ, and SJL/J to investigate the contributions of brain immune genes and gene networks to social behavioral phenotypes. We first analyzed brain transcriptomics from eight inbred strains to detect differentially expressed immune genes. By correlation analysis, we then predicted the associations of these genes of interest with the animal behavior and brain morphology. Compared to female C57BL/6N mice, we observed high expression of cortical Il1b and Il6 and reduced expression of Cx3cl1 in female DBA/2J mice. Furthermore, male DBA/2J mice had lower levels of C1qb and H2-d1 in the brain compared to male C57BL/6J mice. Interestingly, the hippocampal mRNA level of C1qb was positively correlated with the time spent in social interaction processes in male DBA/2J mice but not C57BL/6J mice. We also investigated differences in cytokine expression and microglial signature gene (for M1-M2 polarization) expression among male C57BL/6J, FVB/N, DBA/2J and 129S2/Sv mice following systemic LPS challenge. Il1b, Il6, and Tnf were highly expressed in the hypothalamus of DBA/2J mice without LPS stimulation. After LPS challenge, the microglial proinflammatory M1-type signature gene Nos2 was highly expressed in the hypothalamus of DBA/2J mice compared to the mouse strains FVB/N, DBA/2J, and 129S2/Sv. We further found that social stress modulated anxiety-like and social behavior in female C57BL/6N and DBA/2J mice in a different manner. The experimental mice were divided into three groups: separate-housed C57BL/6N mice, separate-housed DBA/2J mice, and mix-housed C57BL/6N and DBA/2J mice. Mixed housing made socially active C57BL/6N mice more vulnerable to anxiety and social deficits compared to socially withdrawn DBA/2J mice. Furthermore, expression of glucocorticoid receptor Nr3c1 was attenuated in the hippocampus and cortex of mix-housed C57BL/6N mice compared to the separate-housed C57BL/6N mice. Mix-housed C57BL/6N mice also had a higher level of cortical Avpr1a, but a lower level of hippocampal Oxtr than mix-housed DBA/2J mice. Separate-housed DBA/2J mice had a higher level of hypothalamic Oxtr compared to the separate-housed C57BL/6N mice. These results imply a significant differential impact of social intervention on anxiety-like and social behavior between C57BL/6N mice and DBA/2J mice. In conclusion, my thesis revealed that brain immune genes and neuropeptides are associated with neuropsychiatric-like (anxiety-like and social deficits) behavior in mice. These observations may provide insight on the potential pathogenic molecular mechanisms of neuropsychiatric disorders.
Alkuperäiskielienglanti
JulkaisupaikkaHelsinki
Kustantaja
Painoksen ISBN978-951-51-2702-0
Sähköinen ISBN978-951-51-2703-7
TilaJulkaistu - 9 joulukuuta 2016
OKM-julkaisutyyppiG5 Tohtorinväitöskirja (artikkeli)

Tieteenalat

  • 3112 Neurotieteet

Lainaa tätä

@phdthesis{e4653bccd0e84567a73cbb13b5bc600e,
title = "Brain Immune Gene Network in Inbred Mouse Models of Anxiety- and Sociability-related Neuropsychiatric Disorders",
abstract = "Interactions between the brain and the immune system provide a complex microenvironment for brain development. Furthermore, these interactions cause behavioral changes in rodents and humans. Multiple molecules of the immune system in the brain can regulate neural development. Microglia, the resident phagocytes in the central nervous system (CNS), dynamically survey their microenvironment to maintain brain homeostasis. Microglia also actively respond to neuroinflammation induced by insults such as stress, injury, or infection. A dysfunctional immune system in the brain may cause aberrant brain development and adulthood behavior. Dysfunctional immune regulation has also been implicated in the pathophysiological progression of neuropsychiatric disorders in rodents and humans. The major goal of my thesis is to characterize brain immune genes, gene networks, and neuropeptides in inbred mouse strains. These factors might contribute to mouse anxiety- and sociability-like behavior related to symptoms in generalized anxiety disorder and schizophrenia, as inbred strains such as C57BL/6J(N) (C57BL/6J and C57BL/6N) and DBA/2J differ in their anxiety-, sociability- and sensorimotor gating-related behaviors. In this thesis, we utilized eight inbred mouse strains 129S1/SvImJ, A/J, BALB/cByJ, C3H/HeJ, C57BL/6J, DBA/2J, FVB/NJ, and SJL/J to investigate the contributions of brain immune genes and gene networks to social behavioral phenotypes. We first analyzed brain transcriptomics from eight inbred strains to detect differentially expressed immune genes. By correlation analysis, we then predicted the associations of these genes of interest with the animal behavior and brain morphology. Compared to female C57BL/6N mice, we observed high expression of cortical Il1b and Il6 and reduced expression of Cx3cl1 in female DBA/2J mice. Furthermore, male DBA/2J mice had lower levels of C1qb and H2-d1 in the brain compared to male C57BL/6J mice. Interestingly, the hippocampal mRNA level of C1qb was positively correlated with the time spent in social interaction processes in male DBA/2J mice but not C57BL/6J mice. We also investigated differences in cytokine expression and microglial signature gene (for M1-M2 polarization) expression among male C57BL/6J, FVB/N, DBA/2J and 129S2/Sv mice following systemic LPS challenge. Il1b, Il6, and Tnf were highly expressed in the hypothalamus of DBA/2J mice without LPS stimulation. After LPS challenge, the microglial proinflammatory M1-type signature gene Nos2 was highly expressed in the hypothalamus of DBA/2J mice compared to the mouse strains FVB/N, DBA/2J, and 129S2/Sv. We further found that social stress modulated anxiety-like and social behavior in female C57BL/6N and DBA/2J mice in a different manner. The experimental mice were divided into three groups: separate-housed C57BL/6N mice, separate-housed DBA/2J mice, and mix-housed C57BL/6N and DBA/2J mice. Mixed housing made socially active C57BL/6N mice more vulnerable to anxiety and social deficits compared to socially withdrawn DBA/2J mice. Furthermore, expression of glucocorticoid receptor Nr3c1 was attenuated in the hippocampus and cortex of mix-housed C57BL/6N mice compared to the separate-housed C57BL/6N mice. Mix-housed C57BL/6N mice also had a higher level of cortical Avpr1a, but a lower level of hippocampal Oxtr than mix-housed DBA/2J mice. Separate-housed DBA/2J mice had a higher level of hypothalamic Oxtr compared to the separate-housed C57BL/6N mice. These results imply a significant differential impact of social intervention on anxiety-like and social behavior between C57BL/6N mice and DBA/2J mice. In conclusion, my thesis revealed that brain immune genes and neuropeptides are associated with neuropsychiatric-like (anxiety-like and social deficits) behavior in mice. These observations may provide insight on the potential pathogenic molecular mechanisms of neuropsychiatric disorders.",
keywords = "3112 Neurosciences",
author = "Li Ma",
year = "2016",
month = "12",
day = "9",
language = "English",
isbn = "978-951-51-2702-0",
series = "Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis",
publisher = "Helsingin yliopisto",
number = "80",
address = "Finland",

}

Brain Immune Gene Network in Inbred Mouse Models of Anxiety- and Sociability-related Neuropsychiatric Disorders. / Ma, Li.

Helsinki : Helsingin yliopisto, 2016. 97 s.

Tutkimustuotos: OpinnäyteVäitöskirjaArtikkelikokoelma

TY - THES

T1 - Brain Immune Gene Network in Inbred Mouse Models of Anxiety- and Sociability-related Neuropsychiatric Disorders

AU - Ma, Li

PY - 2016/12/9

Y1 - 2016/12/9

N2 - Interactions between the brain and the immune system provide a complex microenvironment for brain development. Furthermore, these interactions cause behavioral changes in rodents and humans. Multiple molecules of the immune system in the brain can regulate neural development. Microglia, the resident phagocytes in the central nervous system (CNS), dynamically survey their microenvironment to maintain brain homeostasis. Microglia also actively respond to neuroinflammation induced by insults such as stress, injury, or infection. A dysfunctional immune system in the brain may cause aberrant brain development and adulthood behavior. Dysfunctional immune regulation has also been implicated in the pathophysiological progression of neuropsychiatric disorders in rodents and humans. The major goal of my thesis is to characterize brain immune genes, gene networks, and neuropeptides in inbred mouse strains. These factors might contribute to mouse anxiety- and sociability-like behavior related to symptoms in generalized anxiety disorder and schizophrenia, as inbred strains such as C57BL/6J(N) (C57BL/6J and C57BL/6N) and DBA/2J differ in their anxiety-, sociability- and sensorimotor gating-related behaviors. In this thesis, we utilized eight inbred mouse strains 129S1/SvImJ, A/J, BALB/cByJ, C3H/HeJ, C57BL/6J, DBA/2J, FVB/NJ, and SJL/J to investigate the contributions of brain immune genes and gene networks to social behavioral phenotypes. We first analyzed brain transcriptomics from eight inbred strains to detect differentially expressed immune genes. By correlation analysis, we then predicted the associations of these genes of interest with the animal behavior and brain morphology. Compared to female C57BL/6N mice, we observed high expression of cortical Il1b and Il6 and reduced expression of Cx3cl1 in female DBA/2J mice. Furthermore, male DBA/2J mice had lower levels of C1qb and H2-d1 in the brain compared to male C57BL/6J mice. Interestingly, the hippocampal mRNA level of C1qb was positively correlated with the time spent in social interaction processes in male DBA/2J mice but not C57BL/6J mice. We also investigated differences in cytokine expression and microglial signature gene (for M1-M2 polarization) expression among male C57BL/6J, FVB/N, DBA/2J and 129S2/Sv mice following systemic LPS challenge. Il1b, Il6, and Tnf were highly expressed in the hypothalamus of DBA/2J mice without LPS stimulation. After LPS challenge, the microglial proinflammatory M1-type signature gene Nos2 was highly expressed in the hypothalamus of DBA/2J mice compared to the mouse strains FVB/N, DBA/2J, and 129S2/Sv. We further found that social stress modulated anxiety-like and social behavior in female C57BL/6N and DBA/2J mice in a different manner. The experimental mice were divided into three groups: separate-housed C57BL/6N mice, separate-housed DBA/2J mice, and mix-housed C57BL/6N and DBA/2J mice. Mixed housing made socially active C57BL/6N mice more vulnerable to anxiety and social deficits compared to socially withdrawn DBA/2J mice. Furthermore, expression of glucocorticoid receptor Nr3c1 was attenuated in the hippocampus and cortex of mix-housed C57BL/6N mice compared to the separate-housed C57BL/6N mice. Mix-housed C57BL/6N mice also had a higher level of cortical Avpr1a, but a lower level of hippocampal Oxtr than mix-housed DBA/2J mice. Separate-housed DBA/2J mice had a higher level of hypothalamic Oxtr compared to the separate-housed C57BL/6N mice. These results imply a significant differential impact of social intervention on anxiety-like and social behavior between C57BL/6N mice and DBA/2J mice. In conclusion, my thesis revealed that brain immune genes and neuropeptides are associated with neuropsychiatric-like (anxiety-like and social deficits) behavior in mice. These observations may provide insight on the potential pathogenic molecular mechanisms of neuropsychiatric disorders.

AB - Interactions between the brain and the immune system provide a complex microenvironment for brain development. Furthermore, these interactions cause behavioral changes in rodents and humans. Multiple molecules of the immune system in the brain can regulate neural development. Microglia, the resident phagocytes in the central nervous system (CNS), dynamically survey their microenvironment to maintain brain homeostasis. Microglia also actively respond to neuroinflammation induced by insults such as stress, injury, or infection. A dysfunctional immune system in the brain may cause aberrant brain development and adulthood behavior. Dysfunctional immune regulation has also been implicated in the pathophysiological progression of neuropsychiatric disorders in rodents and humans. The major goal of my thesis is to characterize brain immune genes, gene networks, and neuropeptides in inbred mouse strains. These factors might contribute to mouse anxiety- and sociability-like behavior related to symptoms in generalized anxiety disorder and schizophrenia, as inbred strains such as C57BL/6J(N) (C57BL/6J and C57BL/6N) and DBA/2J differ in their anxiety-, sociability- and sensorimotor gating-related behaviors. In this thesis, we utilized eight inbred mouse strains 129S1/SvImJ, A/J, BALB/cByJ, C3H/HeJ, C57BL/6J, DBA/2J, FVB/NJ, and SJL/J to investigate the contributions of brain immune genes and gene networks to social behavioral phenotypes. We first analyzed brain transcriptomics from eight inbred strains to detect differentially expressed immune genes. By correlation analysis, we then predicted the associations of these genes of interest with the animal behavior and brain morphology. Compared to female C57BL/6N mice, we observed high expression of cortical Il1b and Il6 and reduced expression of Cx3cl1 in female DBA/2J mice. Furthermore, male DBA/2J mice had lower levels of C1qb and H2-d1 in the brain compared to male C57BL/6J mice. Interestingly, the hippocampal mRNA level of C1qb was positively correlated with the time spent in social interaction processes in male DBA/2J mice but not C57BL/6J mice. We also investigated differences in cytokine expression and microglial signature gene (for M1-M2 polarization) expression among male C57BL/6J, FVB/N, DBA/2J and 129S2/Sv mice following systemic LPS challenge. Il1b, Il6, and Tnf were highly expressed in the hypothalamus of DBA/2J mice without LPS stimulation. After LPS challenge, the microglial proinflammatory M1-type signature gene Nos2 was highly expressed in the hypothalamus of DBA/2J mice compared to the mouse strains FVB/N, DBA/2J, and 129S2/Sv. We further found that social stress modulated anxiety-like and social behavior in female C57BL/6N and DBA/2J mice in a different manner. The experimental mice were divided into three groups: separate-housed C57BL/6N mice, separate-housed DBA/2J mice, and mix-housed C57BL/6N and DBA/2J mice. Mixed housing made socially active C57BL/6N mice more vulnerable to anxiety and social deficits compared to socially withdrawn DBA/2J mice. Furthermore, expression of glucocorticoid receptor Nr3c1 was attenuated in the hippocampus and cortex of mix-housed C57BL/6N mice compared to the separate-housed C57BL/6N mice. Mix-housed C57BL/6N mice also had a higher level of cortical Avpr1a, but a lower level of hippocampal Oxtr than mix-housed DBA/2J mice. Separate-housed DBA/2J mice had a higher level of hypothalamic Oxtr compared to the separate-housed C57BL/6N mice. These results imply a significant differential impact of social intervention on anxiety-like and social behavior between C57BL/6N mice and DBA/2J mice. In conclusion, my thesis revealed that brain immune genes and neuropeptides are associated with neuropsychiatric-like (anxiety-like and social deficits) behavior in mice. These observations may provide insight on the potential pathogenic molecular mechanisms of neuropsychiatric disorders.

KW - 3112 Neurosciences

M3 - Doctoral Thesis

SN - 978-951-51-2702-0

T3 - Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis

PB - Helsingin yliopisto

CY - Helsinki

ER -

Ma L. Brain Immune Gene Network in Inbred Mouse Models of Anxiety- and Sociability-related Neuropsychiatric Disorders. Helsinki: Helsingin yliopisto, 2016. 97 s. (Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis; 80).