Social isolation as a promising animal model of PTSD comorbid suicide: neurosteroids and cannabinoids as possible treatment options

Abstract. Inflammational-immunological processes within the pathophysiology of schizophrenia seem to play an important role. Early signals of neurobiological changes in the embryonal phase of brain in later patients with schizophrenia might lead to activation of the immunological system, for example, of cytokines and microglial cells. Microglia then induces – via the neurotoxic activities of these cells as an overreaction – a rarification of synaptic connections in frontal and temporal brain regions, that is, reduction of the neuropil. Promising inflammational animal models for schizophrenia with high validity can be used today to mimic behavioral as well as neurobiological findings in patients, for example, the well-known neurochemical alterations of dopaminergic, glutamatergic, serotonergic, and other neurotransmitter systems. Also the microglial activation can be modeled well within one of this models, that is, the inflammational PolyI:C animal model of schizophrenia, showing a time peak in late adolescence/early adulthood. The exact mechanism, by which activated microglia cells then triggers further neurodegeneration, must now be investigated in broader detail. Thus, these animal models can be used to understand the pathophysiology of schizophrenia better especially concerning the interaction of immune activation, inflammation, and neurodegeneration. This could also lead to the development of anti-inflammational treatment options and of preventive interventions.

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Long-lasting effects of stress in adolescence: behavioural and molecular characterization of an animal model of social isolation

10.26226/morressier.5b681764b56e9b005965c579 ◽

2018 ◽

Author(s):

Veronica Begni ◽

Marco Andrea Riva

Keyword(s):

Animal Model ◽

Molecular Characterization ◽

Social Isolation ◽

Effects Of Stress

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M9. RATS REARED IN SOCIAL ISOLATION INDUCES EPIGENETIC MODIFICATIONS IN THE NMDA RECEPTOR SUBUNITS

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa030.321 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S136-S136

Author(s):

Camila Loureiro ◽

Fachim Helene Aparecida ◽

Corsi-Zuelli Fabiana ◽

Shuhama Rosana ◽

Joca Sâmia Regiane Lourenço ◽

...

Keyword(s):

Dna Methylation ◽

Animal Model ◽

Social Isolation ◽

Wistar Rats ◽

Cognitive Impairments ◽

Glutamatergic System ◽

Isolation Rearing ◽

Protein Levels ◽

The Brain ◽

Nmdar Subunits

Abstract Background Early-life stress is a key risk for psychiatric disorders that may produce changes in the neurodevelopment. N-methyl-d-aspartate receptor (NMDAR) have been associated with the pathophysiology of schizophrenia and evidence supports that epigenetic changes in NMDAR imply deficiencies in excitatory neurotransmission suggest its role in the neurobiology of psychoses (Uno and Coyle, 2019; Fachim et al., 2019; Gulchina et al., 2017). Aims: Although previous studies have shown abnormalities in the glutamatergic system in animal model of schizophrenia, it is not known if there are equivalent mRNA/protein alterations and DNA methylation changes in the brains of rats reared in isolation. Thus, in order to improve the knowledge of glutamatergic system role in psychosis, we investigated the NR1 and NR2 mRNA/protein and the DNA methylation levels of Grin1, Grin2a and Grin2b promoter region in the prefrontal cortex (PFC) and hippocampus (HIPPO) of male Wistar rats after isolation rearing. Furthermore, because the Parvalbumin (PV) deficit is the most consistent finding across animal models and schizophrenia itself, we also evaluated the expression of PV and other related GABAergic genes (REL and GAD1) in the brain of rats undergoing social isolation rearing as a validation of this animal model. We hypothesized that isolation rearing reduces mRNA and protein expressions of NMDAR subunits and cause DNA methylation changes. Methods Wistar rats were kept isolated or grouped (n=10/group) from weaning (21 days after birth) to 10 weeks and then exposed to the Open Field Test to assess locomotion. Afterwards the behavioural tests, the tissues were dissected for RNA/DNA extraction and NMDAR subunits were analysed using qRT-PCR, ELISA and pyrosequencing. Data were analysed by parametric tests. Results Isolated-reared animals presented: (i) decreased mRNA levels of Grin1 (p=0.011), Grin2a (p=0.039) and Grin2b (p=0.037) in the PFC followed by reduction in the GABAergic markers; (ii) increased NR1 protein levels in the HIPPO (p=0.001); (iii) hypermethylation of Grin1 at CpG5 in the PFC (p=0.047) and Grin2b CpG4 in the HIPPO when compared to grouped (p=0.024). Moreover, isolated and grouped animals presented a negative correlation between Grin1 mRNA and Grin1 methylation levels at CpG5 in the PFC (r: -0.577; p=0.010) and isolated rats presented a negative correlation between Grin2b methylation at CpG4 and NR2 protein levels in the HIPPO (r: -0.753; p=0.012). Discussion This study supports the hypothesis that the NMDAR methylation changes found in the brain tissues may underlie the NMDAR mRNA/protein expression alterations caused by the isolation period. These results highlighted the importance of the environmental influence during the development that may lead to cognitive impairments in adulthood. Moreover, we demonstrated that the social isolation rearing during 10 weeks causes long-lasting behavioral changes that may be more associated with late stages of schizophrenia. Our study contributes to the identification of the epigenetic mechanisms involved in the neuropathophysiology of schizophrenia, which can bring new pharmacotherapeutic strategies and to identify biomarkers that can improve the early interventions in schizophrenia patients. Finally, our data thus reinforce the validity of rats reared in social isolation after weaning in modelling aspects of schizophrenia, highlighting the glutamatergic and GABAergic features involved principally in the cognitive impairments related to prefrontal cortex.

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Evaluation of the silkworm lemon mutant as an invertebrate animal model for human sepiapterin reductase deficiency

Royal Society Open Science ◽

10.1098/rsos.191888 ◽

2020 ◽

Vol 7 (3) ◽

pp. 191888

Author(s):

Guihua Jiang ◽

Jiangbo Song ◽

Hai Hu ◽

Xiaoling Tong ◽

Fangyin Dai

Keyword(s):

Animal Model ◽

Genetic Basis ◽

Treatment Options ◽

Gene Mutations ◽

Dopamine Level ◽

Inherited Disease ◽

Serotonin Content ◽

Phenylalanine Level ◽

Sepiapterin Reductase ◽

Invertebrate Animal

Human sepiapterin reductase (SR) deficiency is an inherited disease caused by SPR gene mutations and is a monoamine neurotransmitter disorder. Here, we investigated whether the silkworm lemon mutant could serve as a model of SR deficiency. A point mutation in the BmSPR gene led to a five amino acid deletion at the carboxyl terminus in the lemon mutant. In addition, classical phenotypes seen in SR deficient patients were observed in the lemon mutant, including a normal phenylalanine level, a decreased dopamine and serotonin content, and an increased neopterin level. A recovery test showed that the replenishment of l -dopa significantly increased the dopamine level in the lemon mutant. The silkworm lemon mutant also showed negative behavioural abilities. These results suggest that the silkworm lemon mutant has an appropriate genetic basis and meets the biochemical requirements to be a model of SR deficiency. Thus, the silkworm lemon mutant can serve as a candidate animal model of SR deficiency, which may be helpful in facilitating accurate diagnosis and effective treatment options of SR deficiency.

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Establishment of a schizophrenic animal model through chronic administration of MK-801 in infancy and social isolation in childhood

Infant Behavior and Development ◽

10.1016/j.infbeh.2017.01.003 ◽

2017 ◽

Vol 46 ◽

pp. 135-143 ◽

Cited By ~ 3

Author(s):

Weiqing Liu ◽

Xiuyan Wang ◽

Wenjuan Hong ◽

Dong Wang ◽

Xiaogang Chen

Keyword(s):

Animal Model ◽

Social Isolation ◽

Chronic Administration ◽

Mk 801

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Suicide trends in the elderly during the ongoing COVID-19 Pandemic- a public health urgency

The Southwest Respiratory and Critical Care Chronicles ◽

10.12746/swrccc.v9i40.865 ◽

2021 ◽

Vol 9 (40) ◽

pp. 31-36

Author(s):

Ashish Sarangi ◽

Sozan Fares ◽

Noha Eskander

Keyword(s):

Older Adults ◽

Social Isolation ◽

Treatment Options ◽

The Elderly ◽

Interpersonal Theory ◽

Ethical Guidelines ◽

Interpersonal Theory Of Suicide ◽

Increased Risk ◽

The Many ◽

Main Components

Background: Older adults experience an increased risk for suicide compared to the overall population, and therefore the circumstances surrounding the Coronavirus Disease 2019 (COVID-19) may potentiate this risk. COVID-19 pandemic social distancing policies and ethical guidelines for COVID-19 treatment may exacerbate experiences of social isolation, perceived expendability, and exposure to suffering, which are associated with the three main components of the Interpersonal Theory of Suicide (i.e., thwarted belongingness, perceived burdensomeness to society, and capability for suicide). The COVID-19 pandemic poses a drain on services and has drawn ethical debates about policies around treating younger adults first. These experiences may lead older adults to possess reduced access to needed medical and psychiatric services and should convey damaging messages of expendability. Furthermore, the potential prolonged stress related to the COVID-19 pandemic may affect neurological, immunological, and health functioning—exacerbating suicide risk. Potential venues to extend treatment options and reduce social isolation are discussed. Conclusion: We acknowledge optimistic effects also, like “pulling together” as a society and therefore the many valuable ways older adults may contribute during this crisis.

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Influence of Gender on Ischemia-Reperfusion Injury in Lungs in an Animal Model

Physiological Research ◽

10.33549/physiolres.933273 ◽

2016 ◽

pp. 953-958 ◽

Cited By ~ 2

Author(s):

H. MRAZKOVA ◽

R. LISCHKE ◽

J. HERGET

Keyword(s):

Animal Model ◽

Lung Transplantation ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ex Vivo ◽

Ischemia Reperfusion ◽

Treatment Options ◽

Subsequent Treatment ◽

Organ Systems ◽

Significant Difference

As with other organ transplants even lung transplantation raises the question of the possibility of the influence of gender on ischemia-reperfusion injury. This is a current topic especially for increasingly utilized method of lung transplantation from non-heart-beating donors, where reperfusion preceded by a period of warm and cold ischemia with subsequent treatment options for lung graft reperfusion. For measurements we used our laboratory previously created and validated animal model for ex vivo lung transplantation. As with other organ systems of our monitoring resulted protective effect of female sex on ischemia reperfusion lung injury. In two of the three parameters that were monitored, we found a significant difference. In females, higher oxygen transfer ability after reperfusion was manifested as well as lower perfusion pressure (vascular compliance). Conversely, weight gain (the development of pulmonary edema) in males was not significant difference from the females. These conclusions could cause further studies leading to influence the selection of appropriate donor grafts.

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