scholarly journals Long-Term Social Isolation Reduces Expression of the BDNF Precursor and Prolyl Endopeptidase in the Rat Brain

2021 ◽  
Vol 86 (6) ◽  
pp. 704-715
Author(s):  
Sofie D. Shirenova ◽  
Nadezhda N. Khlebnikova ◽  
Nataliya A. Krupina
Keyword(s):  
Western Blot ◽  
Frontal Cortex ◽  
Rat Brain ◽  
Social Isolation ◽  
Early Life ◽  
Wistar Rats ◽  
Cognitive Impairments ◽  
Brain Structures ◽  
Prolyl Endopeptidase ◽  
The Brain

Abstract Early-life stress is a risk factor for the development of behavioral and cognitive disorders in humans and animals. Such stressful situations include social isolation in early postnatal ontogenesis. Behavioral and cognitive impairments associated with neuroplastic changes in brain structures. We have found that after ten weeks of social isolation, male Wistar rats show behavioral abnormalities and cognitive deficit, accompanied by an increase in the relative expression of gene encoding serine protease prolyl endopeptidase (PREP, EC 3.4.21.26) in the brain frontal cortex. The present study aimed to assess synaptophysin (SYP), brain-derived neurotrophic factor precursor (proBDNF), and PREP expression using Western blot in the brain structures – the hippocampus, frontal cortex, and striatum of the rats subjected to prolonged social isolation compared with group-housed animals. Twenty Wistar rats were used for this study (10 males and 10 females). Experimental animals (5 males and 5 females) were kept one per cage for nine months, starting from the age of one month. Ten-month-old socially isolated rats showed memory deficit in passive avoidance paradigm and Morris Water Maze and reactivity to novelty reduction. We used monoclonal antibodies for the Western blot analysis of the expression of SYP, proBDNF, and PREP in the rat brain structures. Social isolation caused a proBDNF expression reduction in the frontal cortex in females and a reduction in PREP expression in the striatum in males. These data suppose that neurotrophic factors and PREP are involved in the mechanisms of behavioral and cognitive impairments observed in the rats subjected to prolonged social isolation with an early life onset.

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

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.

scholarly journals Lasting Differential Effects on Plasticity Induced by Prenatal Stress in Dorsal and Ventral Hippocampus

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Gayane Grigoryan ◽  
Menahem Segal
Keyword(s):  
Prenatal Stress ◽  
Life Stress ◽  
Early Life ◽  
Early Life Stress ◽  
Brain Structures ◽  
Traumatic Experience ◽  
Stressful Stimulation ◽  
The Brain ◽  
Two Sectors ◽  
Structure And Functions

Early life adversaries have a profound impact on the developing brain structure and functions that persist long after the original traumatic experience has vanished. One of the extensively studied brain structures in relation to early life stress has been the hippocampus because of its unique association with cognitive processes of the brain. While the entire hippocampus shares the same intrinsic organization, it assumes different functions in its dorsal and ventral sectors (DH and VH, resp.), based on different connectivity with other brain structures. In the present review, we summarize the differences between DH and VH and discuss functional and structural effects of prenatal stress in the two sectors, with the realization that much is yet to be explored in understanding the opposite reactivity of the DH and VH to stressful stimulation.

Central monoaminergic systems sensitivity to acute hypoxia with hypercapnia changes after the maintenance under the long-term social isolation

2018 ◽  
Vol 64 (6) ◽  
pp. 511-516 ◽  
Author(s):  
I.V. Karpova ◽  
V.V. Mikheev ◽  
V.V. Marysheva ◽  
N.A. Kuritcyna ◽  
E.R. Bychkov ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Social Isolation ◽  
Acute Hypoxia ◽  
Brain Structures ◽  
Hypoxia With Hypercapnia ◽  
Long Time ◽  
The Right ◽  
The Brain ◽  
Monoamines And Their Metabolites

The experiments were performed in male albino outbred mice kept in a group and under the conditions of long-term social isolation. The changes in the monoaminergic systems of the left and right hemispheres of the brain after acute hypoxia with hypercapnia have been studied. The levels of dopamine (DA), serotonin (5-HT) and their metabolites – dioxyphenylacetic (DOPAC), homovanillic (HVA), and 5-hydroxyindoleacetic (5-HIAA) acids – were determined by HPLC in the cerebral cortex, hippocampus and striatum of the right and left sides of the brain. In the control mice kept both in the group and under the conditions of social isolation, a higher content of DA in the cortex of the left hemisphere has been found. In the other brain structures the monoamine content was symmetric. In the cerebral cortex of the mice in the group, acute hypoxia with hypercapnia led to a right-sided increase in the DA and 5HT levels. At the same time, the DOPAC content decreased in the left cortex. In mice in the group, under the hypoxia with hypercapnia conditions, the DA level in the left hippocampus increased. In the striatum, the content of monoamines and their metabolites did not change significantly. In animals kept for a long time under the conditions of social isolation, hypoxia with hypercapnia no statistically significant changes in the monoamines and their metabolites levels were found. It has been concluded that the preliminary maintenance under the conditions of prolonged social isolation changes the reaction of central monoaminergic systems to acute hypoxia with hypercapnia.

scholarly journals Asymmetry in the content of brain monoamines of BALB/c mice reared in social isolation conditions

2012 ◽  
Vol 10 (4) ◽  
pp. 42-48 ◽  
Author(s):  
Inessa Vladimirovna Karpova ◽  
Vladimir Vladimirovich Mikheyev ◽  
Yevgeniy Rudolfovich Bychkov ◽  
Andrey Andreyevich Lebedev ◽  
Petr Dmitriyevich Shabanov
Keyword(s):  
Social Isolation ◽  
Elevated Level ◽  
Right Hemisphere ◽  
Brain Structures ◽  
Brain Monoamines ◽  
Left Hippocampus ◽  
The Right ◽  
High Level ◽  
The Brain

The effects of long-term social isolation on the content and metabolism of dopamine and serotonin systems were studied in symmetrical brain structures of BALB/c male mice. With HPLC the contents of dopamine (DA), serotonin (5-HT) and their metabolites dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindolacetic acid (5-HIAA) were measured in the cortex, hippocampus and striatum of both the right and the left hemispheres of the brain in mice reared in groups and social isolation. The isolated mice were characterized by reduced level of DA in the left striatum and elevated level of 5-HIAA and ratio 5-HIAA/5-HT in the right striatum. In the hippocampus of isolated mice, the activation of both DA-ergic and 5-HT-ergic systems was observed, that is the high level of DA and DOPAC in the left hippocampus and the elevated level of 5-HT in both hemispheres and of 5-HIAA in the right hippocampus were registered. On the other hand, the reduction of both DA-ergic and 5-HT-ergic systems activity was shown to be in the right hemisphere. The decreased concentration of DOPAC and ratio DOPAC/DA in the right cortex were observed as well. As to 5-HT-ergic system, the reduced level of 5-HT in the both cortex of the hemispheres as well as 5-HIAA in the right hemisphere of isolated mice was determined. The phenomenon of interhemispheric asymmetry was revealed in the hippocampus only, which was characterized by the increased DA-ergic activity in the left hippocampus but not in the striatum and the cortex.

Regulation of metallothionein concentrations in rat brain: effect of glucocorticoids, zinc, copper, and endotoxin

1994 ◽  
Vol 266 (5) ◽  
pp. E760-E767 ◽  
Author(s):  
T. Gasull ◽  
M. Giralt ◽  
J. Hernandez ◽  
P. Martinez ◽  
I. Bremner ◽  
...  
Keyword(s):  
Frontal Cortex ◽  
Rat Brain ◽  
Medulla Oblongata ◽  
Adrenocorticotropic Hormone ◽  
Brain Areas ◽  
Deficient Diet ◽  
Zinc Deficient Diet ◽  
The Brain

The effects of known inducers of liver metallothionein (MT) synthesis on MT concentrations in the rat brain have been determined using antibodies that are specific for MT I and II and do not cross-react with MT III. There were substantial differences in the MT concentrations in different areas of the brain. Dexamethasone increased MT levels after 24 h in the frontal cortex, cortex, medulla oblongata plus pons, midbrain, striatum, hippocampus, and cerebellum but not in the hypothalamus. Corticosterone produced similar results except in the hippocampus. Long-lasting adrenocorticotropic hormone increased MT concentrations after 12 h in midbrain and striatum but not in the liver. Adrenalectomy decreased MT concentrations after 6 days in the medulla oblongata plus pons, striatum, hippocampus, and hypothalamus but increased concentrations in the liver and kidneys; these effects were reversed by corticosterone. The role of glucocorticoids in the regulation of MT levels therefore differs between tissues and within specific areas of the brain. Injection of zinc or copper intracerebroventricularly and the use of a zinc-deficient diet increased and decreased MT levels, respectively, in some but not all brain areas. Endotoxin increased liver MT but not brain MT I levels after 8 h.

The Levels of Monoamines and Their Metabolites in the Brain Structures of Rats Subjected to Two- and Three-Month-Long Social Isolation

2020 ◽  
Vol 168 (5) ◽  
pp. 605-609 ◽  
Author(s):  
N. A. Krupina ◽  
N. N. Khlebnikova ◽  
V. B. Narkevich ◽  
P. L. Naplekova ◽  
V. S. Kudrin
Keyword(s):  
Social Isolation ◽  
Brain Structures ◽  
The Brain ◽  
Monoamines And Their Metabolites

scholarly journals Expression of somatostatine in ischemia of rat brain

2013 ◽  
Vol 66 (11-12) ◽  
pp. 476-482
Author(s):  
Sinisa Babovic ◽  
Biljana Srdic-Galic ◽  
Branislava Soldatovic-Stajic ◽  
Mina Cvjetkovic-Bosnjak ◽  
Bojana Krstonosic ◽  
...  
Keyword(s):  
Rat Brain ◽  
Pyramidal Cells ◽  
Brain Structures ◽  
Immunohistochemical Method ◽  
Protein Distribution ◽  
Cortex Area ◽  
Histological Data ◽  
Bipolar Type ◽  
Ischemic Attack ◽  
The Brain

Introduction. This study used the immunohistochemical method to follow the expression of cytoplasmatic protein somatostanin in the course of ischemia of rat brain. The aim of the study was to define all the areas of expression of somatostain and to show the protein distribution on the map. Material and Methods. All the sections of telencephalon, diencephalon and midbrain were studied in resistant, and transitory ischemia, which enabled us to observe the reaction of neurons to an ischemic attack or to repeated attacks. Results and Discussion. The results of this study show that there is a difference in the reaction between the resistant and transitory ischemia groups of rats, especially in the parietofrontal cortex, area amygdaloidea anterior, clastrum, nc. reuniens and nc. suprachiasmaticus. The mapping shows the reaction in the structures of motor, sensitive and sensory cortex, mostly in the laminae II/III and V/VI, hippocampus - gyrus dentatus and CA1, CA2, CA3, endopiriform nucleus, paraventricular and periventricular nucleus of hypothalamus, corpus amygdaloideum, claustrum and caudoputamen. The more primitive sections of the brain - rhinencephalon, also showed a reaction, which led us to conclude that both newer and older brain structures reacted immunohistochemically. Histological data showed that small neurons are most commonly found while the second most common are big pyramidal cells of multipolar and bipolar type, with the different body shape. Conclusion. Our findings have confirmed the results of rare studies that dealt with these issues, and offered a precise and detailed map of cells expressing somatostanin in the rat brain following ischemic attack.

scholarly journals Effects of social isolation and re-socialization on cognition and ADAR1 (p110) expression in mice

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2306 ◽  
Author(s):  
Wei Chen ◽  
Dong An ◽  
Hong Xu ◽  
Xiaoxin Cheng ◽  
Shiwei Wang ◽  
...  
Keyword(s):  
Protein Expression ◽  
Frontal Cortex ◽  
Social Isolation ◽  
Cognitive Deficit ◽  
Close Relation ◽  
Rodent Models ◽  
Isolation Stress ◽  
Social Isolation Stress ◽  
Key Factor ◽  
The Brain

It has been reported that social isolation stress could be a key factor that leads to cognitive deficit for both humans and rodent models. However, detailed mechanisms are not yet clear. ADAR1 (Adenosine deaminase acting on RNA) is an enzyme involved in RNA editing that has a close relation to cognitive function. We have hypothesized that social isolation stress may impact the expression of ADAR1 in the brain of mice with cognitive deficit. To test our hypothesis, we evaluated the cognition ability of mice isolated for different durations (2, 4, and 8 weeks) using object recognition and object location tests; we also measured ADAR1 expression in hippocampus and cortex using immunohistochemistry and western blot. Our study showed that social isolation stress induced spatial and non-spatial cognition deficits of the tested mice. In addition, social isolation significantly increased both the immunoreactivity and protein expression of ADAR1 (p110) in the hippocampus and frontal cortex. Furthermore, re-socialization could not only recover the cognition deficits, but also bring ADAR1 (p110) immunoreactivity of hippocampus and frontal cortex, as well as ADAR1 (p110) protein expression of hippocampus back to the normal level for the isolated mice in adolescence. In conclusion, social isolation stress significantly increases ADAR1 (p110) expression in the hippocampus and frontal cortex of the mice with cognitive deficit. This finding may open a window to better understand the reasons (e.g., epigenetic change) that are responsible for social isolation-induced cognitive deficit and help the development of novel therapies for the resulted diseases.

scholarly journals Altered ADAR1 in mice affected by social isolation stress-induced cognitive deficits

2016 ◽  
Author(s):  
Wei Chen ◽  
Dong An ◽  
Hong Xu ◽  
Xiaoxin Cheng ◽  
Shiwei Wang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Protein Expression ◽  
Western Blot ◽  
Frontal Cortex ◽  
Adenosine Deaminase ◽  
Social Isolation ◽  
Cognitive Deficits ◽  
Isolation Stress ◽  
Social Isolation Stress ◽  
Set Up

Adenosine deaminase acting on RNA (ADAR) activity increases in response to inflammation. Social isolation stress is related to neuroinflammation; however, it remains unclear whether ADAR1 is altered in response to social isolation stress-induced cognitive deficits. To investigate our hypothesis that ADAR1 displayed patterns of change in response to social isolation stress, we addressed this issue systemically by isolating Kunming mice for 2, 4 and 8 weeks individually since postnatal 21 days to set up isolation mouse model. Furthermore, we arranged re-socialization group to evaluate the alterations of ADAR1 in the cognitive deficits recovery. The results of behavior tests showed that social isolation stress resulted in cognitive dysfunction, which was recovered by re-socialization in re-gregarious rearing group. Furthermore, the immunohistochemistry and western blot results displayed that both the immunoreactivity and protein expression of ADAR1 in the hippocampus and frontal cortex increased obviously as compared to the same age mice without isolation. The above abnormal alterations of ADAR1 were recovered by re-socialization in re-gregarious rearing group. Our study supports the hypothesis that ADAR1 is altered in mice affected by social isolation stress-induced cognitive deficits.

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