scholarly journals Functional Dysregulations in CA1 Hippocampal Networks of a 3-Hit Mouse Model of Schizophrenia

2021 ◽  
Vol 22 (5) ◽  
pp. 2644
Author(s):  
Solenn Percelay ◽  
Jean-Marie Billard ◽  
Thomas Freret ◽  
Annie Andrieux ◽  
Michel Boulouard ◽  
...  
Keyword(s):  
Sexual Dimorphism ◽  
Mouse Model ◽  
Life Stress ◽  
Maternal Separation ◽  
Electrophysiological Study ◽  
Long Term Potentiation ◽  
Face Validity ◽  
Hippocampus Slice ◽  
Nmdar Activation ◽  
Hippocampal Networks

For a better translation from treatment designs of schizophrenia to clinical efficiency, there is a crucial need to refine preclinical animal models. In order to consider the multifactorial nature of the disorder, a new mouse model associating three factors (genetic susceptibility—partial deletion of the MAP6 gene, early-life stress—maternal separation, and pharmacological treatment—chronic Δ-9-tetrahydrocannabinol during adolescence) has recently been described. While this model depicts a schizophrenia-like phenotype, the neurobiological correlates remain unknown. Synaptic transmission and functional plasticity of the CA1 hippocampal region of male and female 3-hit mice were therefore investigated using electrophysiological recordings on the hippocampus slice. While basal excitatory transmission remained unaffected, NMDA receptor (NMDAr)-mediated long-term potentiation (LTP) triggered by theta-burst (TBS) but not by high-frequency (HFS) stimulation was impaired in 3-hit mice. Isolated NMDAr activation was not affected or even increased in female 3-hit mice, revealing a sexual dimorphism. Considering that the regulation of LTP is more prone to inhibitory tone if triggered by TBS than by HFS, the weaker potentiation in 3-hit mice suggests a deficiency of intrinsic GABA regulatory mechanisms. Indeed, NMDAr activation was increased by GABAA receptor blockade in wild-type but not in 3-hit mice. This electrophysiological study highlights dysregulations of functional properties and plasticity in hippocampal networks of 3-hit mice, one of the mechanisms suspected to contribute to the pathophysiology of schizophrenia. It also shows differences between males and females, supporting the sexual dimorphism observed in the disorder. Combined with the previously reported study, the present data reinforce the face validity of the 3-hit model that will help to consider new therapeutic strategies for psychosis.

Ferulic acid through mitigation of NMDA receptor pathway exerts anxiolytic-like effect in mouse model of maternal separation stress

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Zahra Lorigooini ◽  
Ali Nouri ◽  
Faezeh mottaghinia ◽  
Shima Balali-Dehkordi ◽  
Elham Bijad ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Mouse Model ◽  
Ferulic Acid ◽  
Nmda Receptors ◽  
Effective Dose ◽  
Life Stress ◽  
Receptor Agonist ◽  
Maternal Separation ◽  
Early Life Stress ◽  
Central Zone

AbstractBackgroundExperiencing early-life stress plays an important role in the pathophysiology of anxiety disorders. Ferulic acid is a phenolic compound found in some plants which has several pharmacological properties. N-methyl-D-aspartate (NMDA) receptors are involved in the pathophysiology of mood disorders. In this study we aimed to assess the anxiolytic-like effect of ferulic acid in a mouse model of maternal separation (MS) stress by focusing on the possible involvement of NMDA receptors.MethodsMice were treated with ferulic acid (5 and 40 mg/kg) alone and in combination with NMDA receptor agonist/antagonist. Valid behavioral tests were performed, including open field test (OFT) and elevated plus maze test (EPM), while quantitative real time polymerase chain reaction (qRT-PCR) was used to evaluate gene expression of NMDA subunits (GluN2A and GluN2B) in the hippocampus.ResultsFindings showed that treatment of MS mice with ferulic acid increased the time spent in the central zone of the OFT and increased both open arm time and the percent of open arm entries in the EPM. Ferulic acid reduced the expression of NMDA receptor subunit genes. We showed that administration of NMDA receptor agonist (NMDA) and antagonist (ketamine) exerted anxiogenic and anxiolytic-like effects, correspondingly. Results showed that co-administration of a sub-effective dose of ferulic acid plus ketamine potentiated the anxiolytic-like effect of ferulic acid. Furthermore, co-administration of an effective dose of ferulic acid plus NMDA receptor agonist (NMDA) attenuated the anxiolytic-like effect of ferulic acid.ConclusionsIn deduction, our findings showed that NMDA, partially at least, is involved in the anxiolytic-like effect of ferulic acid in the OFT and EPM tests.

scholarly journals Early life stress induces endothelial dysfunction in a mouse model of maternal separation

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Dao H. Ho ◽  
Megan L. Yu ◽  
Catalina Bazacliu ◽  
Jennifer S. Pollock
Keyword(s):  
Endothelial Dysfunction ◽  
Mouse Model ◽  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Early Life Stress

scholarly journals Torpor enhances synaptic strength and restores memory performance in a mouse model of Alzheimer’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Christina F. de Veij Mestdagh ◽  
Jaap A. Timmerman ◽  
Frank Koopmans ◽  
Iryna Paliukhovich ◽  
Suzanne S. M. Miedema ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Memory Performance ◽  
Long Term Potentiation ◽  
Fear Memory ◽  
Contextual Fear ◽  
Contextual Fear Memory ◽  
Model Of Alzheimer’S Disease ◽  
Term Potentiation

AbstractHibernation induces neurodegeneration-like changes in the brain, which are completely reversed upon arousal. Hibernation-induced plasticity may therefore be of great relevance for the treatment of neurodegenerative diseases, but remains largely unexplored. Here we show that a single torpor and arousal sequence in mice does not induce dendrite retraction and synapse loss as observed in seasonal hibernators. Instead, it increases hippocampal long-term potentiation and contextual fear memory. This is accompanied by increased levels of key postsynaptic proteins and mitochondrial complex I and IV proteins, indicating mitochondrial reactivation and enhanced synaptic plasticity upon arousal. Interestingly, a single torpor and arousal sequence was also sufficient to restore contextual fear memory in an APP/PS1 mouse model of Alzheimer’s disease. Our study demonstrates that torpor in mice evokes an exceptional state of hippocampal plasticity and that naturally occurring plasticity mechanisms during torpor provide an opportunity to identify unique druggable targets for the treatment of cognitive impairment.

scholarly journals Early-Life Stress Modulates Gut Microbiota and Peripheral and Central Inflammation in a Sex-Dependent Manner

2021 ◽  
Vol 22 (4) ◽  
pp. 1899 ◽  
Author(s):  
Hae Jeong Park ◽  
Sang A. Kim ◽  
Won Sub Kang ◽  
Jong Woo Kim
Keyword(s):  
Gut Microbiota ◽  
Relative Abundance ◽  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Early Life Stress ◽  
Female Rats ◽  
Rrna Gene ◽  
Dependent Manner ◽  
Male And Female Rats

Recent studies have reported that changes in gut microbiota composition could induce neuropsychiatric problems. In this study, we investigated alterations in gut microbiota induced by early-life stress (ELS) in rats subjected to maternal separation (MS; 6 h a day, postnatal days (PNDs) 1–21), along with changes in inflammatory cytokines and tryptophan-kynurenine (TRP-KYN) metabolism, and assessed the differences between sexes. High-throughput sequencing of the bacterial 16S rRNA gene showed that the relative abundance of the Bacteroides genus was increased and that of the Lachnospiraceae family was decreased in the feces of MS rats of both sexes (PND 56). By comparison, MS increased the relative abundance of the Streptococcus genus and decreased that of the Staphylococcus genus only in males, whereas the abundance of the Sporobacter genus was enhanced and that of the Mucispirillum genus was reduced by MS only in females. In addition, the levels of proinflammatory cytokines were increased in the colons (IFN-γ and IL-6) and sera (IL-1β) of the male MS rats, together with the elevation of the KYN/TRP ratio in the sera, but not in females. In the hippocampus, MS elevated the level of IL-1β and the KYN/TRP ratio in both male and female rats. These results indicate that MS induces peripheral and central inflammation and TRP-KYN metabolism in a sex-dependent manner, together with sex-specific changes in gut microbes.

The timing of maternal separation affects morris water maze performance and long-term potentiation in male rats

2013 ◽  
Vol 56 (5) ◽  
pp. 1102-1109 ◽  
Author(s):  
Xiujing Cao ◽  
Shenghai Huang ◽  
Jiejie Cao ◽  
Tingting Chen ◽  
Ping Zhu ◽  
...  
Keyword(s):  
Morris Water Maze ◽  
Water Maze ◽  
Maternal Separation ◽  
Long Term Potentiation ◽  
Male Rats ◽  
Maze Performance ◽  
Term Potentiation

scholarly journals Maternal Separation as Early-Life Stress Causes Enhanced Allergic Airway Responses by Inhibiting Respiratory Tolerance in Mice

2018 ◽  
Vol 246 (3) ◽  
pp. 155-165 ◽  
Author(s):  
Ryusuke Ouchi ◽  
Tasuku Kawano ◽  
Hitomi Yoshida ◽  
Masato Ishii ◽  
Tomomitsu Miyasaka ◽  
...  
Keyword(s):  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Early Life Stress ◽  
Airway Responses

scholarly journals A Novel Mouse Model for Acute and Long-Lasting Consequences of Early Life Stress

Endocrinology ◽  
2008 ◽  
Vol 149 (10) ◽  
pp. 4892-4900 ◽  
Author(s):  
Courtney J. Rice ◽  
Curt A. Sandman ◽  
Mohammed R. Lenjavi ◽  
Tallie Z. Baram
Keyword(s):  
Mouse Model ◽  
Paraventricular Nucleus ◽  
Life Stress ◽  
Early Life ◽  
Molecular Mechanisms ◽  
Early Life Stress ◽  
Plasma Corticosterone ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Basal Plasma

Chronic early-life stress (ES) exerts profound acute and long-lasting effects on the hypothalamic-pituitary-adrenal system, with relevance to cognitive function and affective disorders. Our ability to determine the molecular mechanisms underlying these effects should benefit greatly from appropriate mouse models because these would enable use of powerful transgenic methods. Therefore, we have characterized a mouse model of chronic ES, which was provoked in mouse pups by abnormal, fragmented interactions with the dam. Dam-pup interaction was disrupted by limiting the nesting and bedding material in the cages, a manipulation that affected this parameter in a dose-dependent manner. At the end of their week-long rearing in the limited-nesting cages, mouse pups were stressed, as apparent from elevated basal plasma corticosterone levels. In addition, steady-state mRNA levels of CRH in the hypothalamic paraventricular nucleus of ES-experiencing pups were reduced, without significant change in mRNA levels of arginine vasopressin. Rearing mouse pups in this stress-provoking cage environment resulted in enduring effects: basal plasma corticosterone levels were still increased, and CRH mRNA levels in paraventricular nucleus remained reduced in adult ES mice, compared with those of controls. In addition, hippocampus-dependent learning and memory functions were impaired in 4- to 8-month-old ES mice. In summary, this novel, robust model of chronic early life stress in the mouse results in acute and enduring neuroendocrine and cognitive abnormalities. This model should facilitate the examination of the specific genes and molecules involved in the generation of this stress as well as in its consequences.

scholarly journals Maternal separation in rodents: a journey from gut to brain and nutritional perspectives

2019 ◽  
Vol 79 (1) ◽  
pp. 113-132 ◽  
Author(s):  
Marion Rincel ◽  
Muriel Darnaudéry
Keyword(s):  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Human Subjects ◽  
Early Life Stress ◽  
Long Term Effects ◽  
Early Life Adversity ◽  
Critical Window ◽  
Beneficial Impact ◽  
The Impact

The developmental period constitutes a critical window of sensitivity to stress. Indeed, early-life adversity increases the risk to develop psychiatric diseases, but also gastrointestinal disorders such as the irritable bowel syndrome at adulthood. In the past decade, there has been huge interest in the gut–brain axis, especially as regards stress-related emotional behaviours. Animal models of early-life adversity, in particular, maternal separation (MS) in rodents, demonstrate lasting deleterious effects on both the gut and the brain. Here, we review the effects of MS on both systems with a focus on stress-related behaviours. In addition, we discuss more recent findings showing the impact of gut-directed interventions, including nutrition with pre- and probiotics, illustrating the role played by gut microbiota in mediating the long-term effects of MS. Overall, preclinical studies suggest that nutritional approaches with pro- and prebiotics may constitute safe and efficient strategies to attenuate the effects of early-life stress on the gut–brain axis. Further research is required to understand the complex mechanisms underlying gut–brain interaction dysfunctions after early-life stress as well as to determine the beneficial impact of gut-directed strategies in a context of early-life adversity in human subjects.

scholarly journals Downregulation of kainate receptors regulating GABAergic transmission in amygdala after early life stress is associated with anxiety-like behavior in rodents

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jonas Englund ◽  
Joni Haikonen ◽  
Vasilii Shteinikov ◽  
Shyrley Paola Amarilla ◽  
Tsvetomira Atanasova ◽  
...  
Keyword(s):  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Early Life Stress ◽  
Kainate Receptors ◽  
Gabaergic Transmission ◽  
Cortical Afferents ◽  
Functional Modulation ◽  
Endogenous Activity ◽  
Dependent Mechanism

AbstractEarly life stress (ELS) is a well-characterized risk factor for mood and anxiety disorders. GABAergic microcircuits in the amygdala are critically implicated in anxiety; however, whether their function is altered after ELS is not known. Here we identify a novel mechanism by which kainate receptors (KARs) modulate feedforward inhibition in the lateral amygdala (LA) and show that this mechanism is downregulated after ELS induced by maternal separation (MS). Specifically, we show that in control rats but not after MS, endogenous activity of GluK1 subunit containing KARs disinhibit LA principal neurons during activation of cortical afferents. GluK1 antagonism attenuated excitability of parvalbumin (PV)-expressing interneurons, resulting in loss of PV-dependent inhibitory control and an increase in firing of somatostatin-expressing interneurons. Inactivation of Grik1 expression locally in the adult amygdala reduced ongoing GABAergic transmission and was sufficient to produce a mild anxiety-like behavioral phenotype. Interestingly, MS and GluK1-dependent phenotypes showed similar gender specificity, being detectable in male but not female rodents. Our data identify a novel KAR-dependent mechanism for cell-type and projection-specific functional modulation of the LA GABAergic microcircuit and suggest that the loss of GluK1 KAR function contributes to anxiogenesis after ELS.

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