Moderate maternal separation mitigates the altered synaptic transmission and neuronal activation in amygdala by chronic stress in adult mice

AbstractExposure to moderate level of stress during the perinatal period helps the organisms to cope well with stressful events in their later life, an effect known as stress inoculation. Amygdala is one of the kernel brain regions mediating stress-coping in the brain. However, little is known about whether early life stress may affect amygdala to have its inoculative effect. Here, we observed that moderate maternal separation (MS) from postnatal day 3 to day 21 (D3–21, 1 h per day) significantly alleviated the increased anxiety-like behavior induced by chronic social defeat stress (CSDS) in adulthood, suggesting an obvious inoculative effect of moderate MS. Further studies revealed that MS prevented CSDS-evoked augmentation of glutamatergic transmission onto principal neurons (PNs) in the basolateral amygdala (BLA) by inhibiting presynaptic glutamate release. By contrast, it did not affect GABAergic transmission in BLA PNs, as indicated by unaltered frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs). Moreover, the CSDS-induced increase of neuronal excitability was also mitigated by MS in BLA PNs. In conclusion, our results suggest that MS may have its inoculative effect through alleviating the influences of later life stress on the glutamatergic transmission and neuronal activity in amygdala neurons.

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Early-life stress and inflammation: A systematic review of a key experimental approach in rodents

Brain and Neuroscience Advances ◽

10.1177/2398212820978049 ◽

2020 ◽

Vol 4 ◽

pp. 239821282097804

Author(s):

Ethan G. Dutcher ◽

E.A. Claudia Pama ◽

Mary-Ellen Lynall ◽

Shahid Khan ◽

Menna R. Clatworthy ◽

...

Keyword(s):

Systematic Review ◽

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Early Life Stress ◽

Later Life ◽

Interleukin 10 ◽

Brain Regions ◽

Clinical Approach ◽

Necrosis Factor Alpha

Repeated maternal separation is the most widely used pre-clinical approach to investigate the relationship between early-life chronic stress and its neuropsychiatric and physical consequences. In this systematic review, we identified 46 studies that conducted repeated maternal separation or single-episode maternal separation and reported measurements of interleukin-1b, interleukin-6, interleukin-10, tumour necrosis factor-alpha, or microglia activation and density. We report that in the short-term and in the context of later-life stress, repeated maternal separation has pro-inflammatory immune consequences in diverse tissues. Repeated maternal separation animals exhibit greater microglial activation and elevated pro-inflammatory cytokine signalling in key brain regions implicated in human psychiatric disorders. Notably, repeated maternal separation generally has no long-term effect on cytokine expression in any tissue in the absence of later-life stress. These observations suggest that the elevated inflammatory signalling that has been reported in humans with a history of early-life stress may be the joint consequence of ongoing stressor exposure together with potentiated neural and/or immune responsiveness to stressors. Finally, our findings provide detailed guidance for future studies interrogating the causal roles of early-life stress and inflammation in disorders such as major depression.

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Chronic Alcohol Dysregulates Glutamatergic Function in the Basolateral Amygdala in a Projection- and Sex-Specific Manner

10.1101/2021.12.22.473716 ◽

2021 ◽

Author(s):

Michaela Price ◽

Brian McCool

Keyword(s):

Alcohol Intake ◽

Basolateral Amygdala ◽

Glutamate Release ◽

Brain Regions ◽

Stria Terminalis ◽

Chronic Intermittent Ethanol ◽

External Capsule ◽

Specific Manner ◽

Insula Cortex ◽

Gabaergic Function

Chronic intermittent ethanol (CIE) produces alcohol dependence, facilitates anxiety-like behavior, and increases post-CIE alcohol intake. The basolateral amygdala (BLA) is one of several brain regions that regulates anxiety-like behavior and alcohol intake through downstream projections. The BLA receives information from two distinct input pathways. Afferents from medial structures like the thalamus and prefrontal cortex enter the BLA through the stria terminalis whereas lateral cortical structures like the anterior insula cortex enter the BLA through the external capsule. CIE induces input- and sex-specific adaptations to glutamatergic function in the BLA. Previous studies sampled neurons throughout the BLA, but did not distinguish between projection-specific populations. The current study investigated BLA neurons that project to the NAC (BLA-NAC neurons) or the BNST (BLA-BNST neurons) as representative "reward" and "aversion" BLA neurons, and showed that CIE alters glutamatergic function and excitability in a projection- and sex-specific manner. CIE increases glutamate release from stria terminalis inputs only onto BLA-BNST neurons. At external capsule synapses, CIE increases postsynaptic glutamatergic function in male BLA-NAC neurons and female BLA-BNST neurons. Subsequent experiments demonstrated that CIE enhanced the excitability of male BLA-NAC neurons and BLA-BNST neurons in both sexes when glutamatergic but not GABAergic function was intact. Thus, CIE-mediated increased glutamatergic function facilitates hyperexcitability in male BLA-NAC neurons and BLA-BNST neurons of both sexes.

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Long-Term Decreases in the Expression of Calcineurin and GABAA Receptors Induced by Early Maternal Separation Are Associated with Increased Anxiety-Like Behavior in Adult Male Rats

Developmental Neuroscience ◽

10.1159/000512221 ◽

2020 ◽

pp. 1-10

Author(s):

Maryam Mahmoodkhani ◽

Maedeh Ghasemi ◽

Leila Derafshpour ◽

Mohammad Amini ◽

Nasrin Mehranfard

Keyword(s):

Anxiety Disorders ◽

Glutamate Receptors ◽

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Central Area ◽

Early Life Stress ◽

Brain Regions ◽

Male Rats ◽

Lower Percentage

Introduction: Early life stress is a well-described risk factor of anxiety disorders in adulthood. Dysfunction in GABA/glutamate receptors and their functional regulator, calcineurin, is linked to anxiety disorders. Here, we investigated the effect of early life stress, such as repeated maternal separation (MS; 3 h per day from postnatal day [P] 2 to 11), on changes in the expression of calcineurin as well as the ionotropic glutamatergic and GABAergic receptors including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA) and GABAA receptors in the hippocampus and prefrontal cortex (PFC) of adolescent (P35) and adult (P62) male Wistar rats and their correlations with anxiety-like behavior in adulthood. Methods: The protein levels were assessed by Western blot analysis. Anxiety-like behavior was measured in the elevated plus maze (EPM) and open field (OF) tests. Results: MS induced a regional transient decrease of glutamate receptors expression at P35, with decreased NMDA and AMPA receptor levels, respectively, in the hippocampus and PFC, suggesting a possible decrease in excitatory synaptic strength. In contrast to glutamate receptors, MS had long-lasting influence on GABAA receptor and calcineurin levels, with reduced expression of GABAA receptor and calcineurin in both brain regions at P35 that continued into adulthood. These results were accompanied by increased anxiety behavior in adulthood, shown by lower percentage of number of total entries and time spent in the open arms of the EPM, and by lower time spent and number of entries in the OF central area. Conclusions: Together, our study suggests that GABAA receptors via calcineurin-dependent signaling pathways may play an important role in the expression of stress-induced anxiety-like behavior.

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GABAergic Transmission in the Basolateral Amygdala Differentially Modulates Plasticity in the Dentate Gyrus and the CA1 Areas

International Journal of Molecular Sciences ◽

10.3390/ijms21113786 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3786 ◽

Cited By ~ 1

Author(s):

Rose-Marie Vouimba ◽

Rachel Anunu ◽

Gal Richter-Levin

Keyword(s):

Dentate Gyrus ◽

Basolateral Amygdala ◽

Long Term Potentiation ◽

Brain Regions ◽

Stressful Events ◽

Perforant Path ◽

Tetanic Stimulation ◽

Gabaergic Neurotransmission ◽

Hippocampal Commissure ◽

Stimulation Of

The term “metaplasticity” is used to describe changes in synaptic plasticity sensitivity following an electrical, biochemical, or behavioral priming stimulus. For example, priming the basolateral amygdala (BLA) enhances long-term potentiation (LTP) in the dentate gyrus (DG) but decreases LTP in the CA1. However, the mechanisms underlying these metaplastic effects are only partly understood. Here, we examined whether the mechanism underlying these effects of BLA priming involves intra-BLA GABAergic neurotransmission. Low doses of muscimol, a GABAA receptor (GABAAR) agonist, were microinfused into the rat BLA before or after BLA priming. Our findings show that BLA GABAAR activation via muscimol mimicked the previously reported effects of electrical BLA priming on LTP in the perforant path and the ventral hippocampal commissure-CA1 pathways, decreasing CA1 LTP and increasing DG LTP. Furthermore, muscimol application before or after tetanic stimulation of the ventral hippocampal commissure-CA1 pathways attenuated the BLA priming-induced decrease in CA1 LTP. In contrast, muscimol application after tetanic stimulation of the perforant path attenuated the BLA priming-induced increase in DG LTP. The data indicate that GABAAR activation mediates metaplastic effects of the BLA on plasticity in the CA1 and the DG, but that the same GABAAR activation induces an intra-BLA form of metaplasticity, which alters the way BLA priming may modulate plasticity in other brain regions. These results emphasize the need for developing a dynamic model of BLA modulation of plasticity, a model that may better capture processes underlying memory alterations associated with emotional arousing or stressful events.

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Intermittent peripheral exposure to lipopolysaccharide induces exploratory behavior in mice and regulates brain glial activity in obese mice

10.21203/rs.2.22927/v2 ◽

2020 ◽

Author(s):

Hui-Ting Huang ◽

Po-See Chen ◽

Yu-Min Kuo ◽

Shun-Fen Tzeng

Keyword(s):

Exploratory Behavior ◽

Microglial Activation ◽

Basolateral Amygdala ◽

Later Life ◽

Brain Regions ◽

Anterior Cingulate ◽

Mrna Levels ◽

Morphological Examination ◽

Immune Challenges ◽

Hypothalamic Tissue

Abstract Background: Consecutive peripheral immune challenges can modulate the responses of brain resident microglia to stimuli. High-fat diet (HFD) intake has been reported to stimulate the activation of astrocytes and microglia in the arcuate nucleus (ARC) of the hypothalamus in obese rodents and humans. However, it is unknown whether intermittent exposure to additional peripheral immune challenge can modify HFD-induced hypothalamic glial activation in obese individuals. Methods: In this study, we administered 1 mg/kg LPS (or saline) by intraperitoneal (i.p.) injection to 8-week-old male mice after 1, 2, or 8 weeks of a regular diet (show) or HFD. The level of interleukin-1b (IL-1b) and tumor necrosis factor-a (TNF-a) expression in the plasma and hypothalamic tissue was analyzed 24 h after each LPS injection. The behaviors of the animals in the four groups (the chow-saline, chow-LPS, HFD-saline, and HFD-LPS groups) were examined 5 months after exposure to chow or a HFD. Morphological examination of microglia in related brain regions was also conducted. Results: The plasma levels and hypothalamic mRNA levels of IL-1b and TNF-a were significantly upregulated 24 h after the first injection of LPS but not after the second or third injection of LPS. Chow-LPS mice displayed increased exploratory behavior 5 months after feeding. However, this LPS-induced abnormal exploratory behavior was inhibited in HFD-fed mice. Chronic HFD feeding for 5 months induced apparent increases in the number and cell body size of microglia, mainly in the ARC, and also increased the size of microglia in the NAc and insula. Moreover, microglial activation in the nucleus accumbens (NAc), anterior cingulate cortex (ACC), insula, and basolateral amygdala (BLA) was observed in chow-LPS mice. However, microglial activation in the analyzed brain regions was suppressed in HFD-LPS mice.Conclusions: Altogether, the results indicate that intermittent peripheral challenge with LPS might prime microglia in the ARC and NAc to modify their response to chronic HFD feeding. Alternatively, chronic HFD feeding might mediate microglia in LPS-affected brain regions and subsequently suppress LPS-induced atypical exploratory behavior. Our findings suggest that the interaction of intermittent acute peripheral immune challenges with chronic HFD intake can drive microglia to amend the microenvironment and further modify animal behaviors in the later life.

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Prenatal stress and risk of behavioral morbidity from age 2 to 14 years: The influence of the number, type, and timing of stressful life events

Development and Psychopathology ◽

10.1017/s0954579411000241 ◽

2011 ◽

Vol 23 (2) ◽

pp. 507-520 ◽

Cited By ~ 59

Author(s):

Monique Robinson ◽

Eugen Mattes ◽

Wendy H. Oddy ◽

Craig E. Pennell ◽

Anke van Eekelen ◽

...

Keyword(s):

Mental Health ◽

Behavioral Problems ◽

Prenatal Stress ◽

Life Stress ◽

Child Behavior Checklist ◽

Stressful Life Events ◽

Later Life ◽

Stressful Events ◽

Stress Exposure ◽

Maternal Experience

AbstractThe maternal experience of stressful events during pregnancy has been associated with a number of adverse consequences for behavioral development in offspring, but the measurement and interpretation of prenatal stress varies among reported studies. The Raine Study recruited 2900 pregnancies and recorded life stress events experienced by 18 and 34 weeks' gestation along with numerous sociodemographic data. The mother's exposure to life stress events was further documented when the children were followed-up in conjunction with behavioral assessments at ages 2, 5, 8, 10, and 14 years using the Child Behavior Checklist. The maternal experience of multiple stressful events during pregnancy was associated with subsequent behavioral problems for offspring. Independent (e.g., death of a relative, job loss) and dependent stress events (e.g., financial problems, marital problems) were both significantly associated with a greater incidence of mental health morbidity between age 2 and 14 years. Exposure to stressful events in the first 18 weeks of pregnancy showed similar associations with subsequent total and externalizing morbidity to events reported at 34 weeks of gestation. These results were independent of postnatal stress exposure. Improved support for women with chronic stress exposure during pregnancy may improve the mental health of their offspring in later life.

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Functional Interplay of Type-2 Corticotrophin Releasing Factor and Dopamine Receptors in the Basolateral Amygdala-Medial Prefrontal Cortex Circuitry

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyaa079 ◽

2020 ◽

Author(s):

H E Yarur ◽

J Zegers ◽

I Vega-Quiroga ◽

J Novoa ◽

F Ciruela ◽

...

Keyword(s):

Prefrontal Cortex ◽

Emotional Disorders ◽

Medial Prefrontal Cortex ◽

Stress Responses ◽

Basolateral Amygdala ◽

Stressful Events ◽

Glutamatergic Transmission ◽

Corticotrophin Releasing Factor ◽

Crf2 Receptor

Abstract Background Basolateral amygdala (BLA) excitatory projections to medial prefrontal cortex (PFC) play a key role controlling stress behavior, pain, and fear. Indeed, stressful events block synaptic plasticity at the BLA-PFC circuit. The stress responses involve the action of corticotrophin releasing factor (CRF) through type 1 and type 2 CRF receptors (CRF1 and CRF2). Interestingly, it has been described that dopamine receptor 1 (D1R) and CRF peptide have a modulatory role of BLA-PFC transmission. However, the participation of CRF1 and CRF2 receptors in BLA-PFC synaptic transmission still is unclear. Methods We used in vivo microdialysis to determine dopamine and glutamate (GLU) extracellular levels in PFC after BLA stimulation. Immunofluorescence anatomical studies in rat PFC synaptosomes devoid of postsynaptic elements were performed to determine the presence of D1R and CRF2 receptors in synaptical nerve endings. Results Here, we provide direct evidence of the opposite role that CRF receptors exert over dopamine extracellular levels in the PFC. We also show that D1R colocalizes with CRF2 receptors in PFC nerve terminals. Intra-PFC infusion of antisauvagine-30, a CRF2 receptor antagonist, increased PFC GLU extracellular levels induced by BLA activation. Interestingly, the increase in GLU release observed in the presence of antisauvagine-30 was significantly reduced by incubation with SCH23390, a D1R antagonist. Conclusion PFC CRF2 receptor unmasks D1R effect over glutamatergic transmission of the BLA-PFC circuit. Overall, CRF2 receptor emerges as a new modulator of BLA to PFC glutamatergic transmission, thus playing a potential role in emotional disorders.

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Early-life short-term environmental enrichment counteracts the effects of stress on anxiety-like behavior, brain-derived neurotrophic factor and nuclear translocation of glucocorticoid receptors in the basolateral amygdala

Scientific Reports ◽

10.1038/s41598-020-70875-5 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Akshaya Hegde ◽

Shruti Suresh ◽

Rupshi Mitra

Keyword(s):

Neurotrophic Factor ◽

Life Stress ◽

Early Life ◽

Environmental Enrichment ◽

Glucocorticoid Receptors ◽

Basolateral Amygdala ◽

Maternal Separation ◽

Nuclear Translocation ◽

Brain Derived Neurotrophic Factor ◽

Spine Density

Abstract Early life is a decisive stage for the development of physiological and psychological characteristics of an individual. Any stress or disruption of healthy development at this stage has serious long-lasting consequences for the remaining life. Unfortunately, early life stress is a common occurrence in humans and other animals. In this context, we investigated if the provision of environmental enrichment during the pre-weaning phase of rat pups and dams could alter the consequences of early-life maternal-separation stress. Pre-weaning enrichment rescued the effects of maternal separation on the excess secretion of adrenal stress hormones and anxiety-like behavior during adulthood. Enrichment also reduced the effect of stress on the spine density of basolateral amygdala neurons, a brain region critical for stress-induced facilitation of emotional behaviors. Pre-weaning enrichment, provided during early-life, blunted the effects of maternal separation stress on decreased intra-nuclear translocation of glucocorticoid receptors within the amygdala neurons when tested later in adulthood. Early-life, pre-weaning environmental enrichment also increased the amount of brain-derived neurotrophic factor within adult basolateral amygdala. Our observations showed that environmental manipulation during early formative years could be utilized to build lifelong resilience to stress. Complex naturalistic housing and sensory enrichment is, thus, an useful buffer against an impoverished and stressful childhood.

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

Journal of Basic and Clinical Physiology and Pharmacology ◽

10.1515/jbcpp-2019-0263 ◽

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.

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The G Protein-Coupled Glutamate Receptors as Novel Molecular Targets in Schizophrenia Treatment—A Narrative Review

Journal of Clinical Medicine ◽

10.3390/jcm10071475 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1475

Author(s):

Waldemar Kryszkowski ◽

Tomasz Boczek

Keyword(s):

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Glutamate Release ◽

Molecular Targets ◽

Brain Regions ◽

Psychotic Symptoms ◽

Unknown Etiology ◽

Metabotropic Glutamate ◽

G Protein Coupled

Schizophrenia is a severe neuropsychiatric disease with an unknown etiology. The research into the neurobiology of this disease led to several models aimed at explaining the link between perturbations in brain function and the manifestation of psychotic symptoms. The glutamatergic hypothesis postulates that disrupted glutamate neurotransmission may mediate cognitive and psychosocial impairments by affecting the connections between the cortex and the thalamus. In this regard, the greatest attention has been given to ionotropic NMDA receptor hypofunction. However, converging data indicates metabotropic glutamate receptors as crucial for cognitive and psychomotor function. The distribution of these receptors in the brain regions related to schizophrenia and their regulatory role in glutamate release make them promising molecular targets for novel antipsychotics. This article reviews the progress in the research on the role of metabotropic glutamate receptors in schizophrenia etiopathology.

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