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Open accessJournal ArticleDOI: 10.1016/J.YNSTR.2021.100312

Synaptic and behavioral effects of chronic stress are linked to dynamic and sex-specific changes in microglia function and astrocyte dystrophy.

04 Mar 2021-Neurobiology of Stress (Elsevier)-Vol. 14, pp 100312-100312
Abstract: Emerging evidence indicates that males and females display different neurobiological responses to chronic stress which contribute to varied behavioral adaptations. In particular, pyramidal neurons undergo dendritic atrophy and synapse loss in the prefrontal cortex (PFC) of male, but not female, mice. Our recent work shows that chronic stress also provokes microglia-mediated neuronal remodeling, which contributes to synaptic deficits in the PFC and associated behavioral consequences in males. Separate studies indicate that chronic stress promotes astrocyte dystrophy in the PFC which is associated with behavioral despair. Notably, these prior reports focused primarily on stress effects in males. In the present studies, male and female mice were exposed to 14 or 28 days of chronic unpredictable stress (CUS) to assess molecular and cellular adaptations of microglia, astrocytes, and neurons in the medial PFC. Consistent with our recent work, male, but not female, mice displayed behavioral and cognitive deficits with corresponding perturbations of neuroimmune factors in the PFC after 14 days of CUS. Fluorescence-activated cell sorting and gene expression analyses revealed that CUS increased expression of select markers of phagocytosis in male PFC microglia. Confocal imaging in Thy1-GFP(M) mice showed that CUS reduced dendritic spine density, decreased GFAP immunolabeling, and increased microglia-mediated neuronal remodeling only in male mice. After 28 days of CUS, both male and female mice displayed behavioral and cognitive impairments. Interestingly, there were limited stress effects on neuroimmune factors and measures of microglial phagocytosis in the PFC of both sexes. Despite limited changes in neuroimmune function, reduced GFAP immunolabeling and dendritic spine deficits persisted in male mice. Further, GFAP immunolabeling and dendritic spine density remained unaltered in the PFC of females. These findings indicate that chronic stress causes sex-specific and temporally dynamic changes in microglial function which are associated with different neurobiological and behavioral adaptations. In all, these results suggest that microglia-mediated neuronal remodeling, astrocyte dystrophy, and synapse loss contribute to stress-induced PFC dysfunction and associated behavioral consequences in male mice.

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Topics: Chronic stress (54%), Dendritic spine (53%), Prefrontal cortex (50%)
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8 results found


Journal ArticleDOI: 10.1016/J.NEUBIOREV.2021.06.008
Abstract: Pain is a multidimensional experience comprising sensory-discriminative, affective-motivational, and cognitive-evaluative dimensions. Clinical and research findings have demonstrated a complex interplay between social burdens, individual coping strategies, mood states, psychological disorders, sleep disturbances, masticatory muscle tone, and orofacial musculoskeletal pain. Accordingly, current classification systems for orofacial pain require psychosocial assessments to be an integral part of the multidimensional diagnostic process. Here, we review evidence on how psychosocial and biological factors may generate and perpetuate musculoskeletal orofacial pain. Specifically, we discuss studies investigating a putative causal relationship between stress, bruxism, and pain in the masticatory system. We present findings that attribute brain structures various roles in modulating pain perception and pain-related behavior. We also examine studies investigating how the nervous and immune system on cellular and molecular levels may account for orofacial nociceptive signaling. Furthermore, we review evidence pointing towards associations between orofacial musculoskeletal pain and neuroendocrine imbalances, sleep disturbances, and alterations of the circadian timing system. We conclude with several proposals that may help to alleviate orofacial pain in the future.

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Topics: Orofacial pain (75%), Chronic pain (60%)

4 Citations


Journal ArticleDOI: 10.1016/J.NEUBIOREV.2021.09.023
Reza Rahimian1, Marina Wakid2, Marina Wakid1, Liam Anuj O’Leary2  +3 moreInstitutions (2)
Abstract: As the professional phagocytes of the brain, microglia orchestrate the immunological response and play an increasingly important role in maintaining homeostatic brain functions. Microglia are activated by pathological events or slight alterations in brain homeostasis. This activation is dependent on the context and type of stressor or pathology. Through secretion of cytokines, chemokines and growth factors, microglia can strongly influence the response to a stressor and can, therefore, determine the pathological outcome. Psychopathologies have repeatedly been associated with long-lasting priming and sensitization of cerebral microglia. This review focuses on the diversity of microglial phenotype and function in health and psychiatric disease. We first discuss the diverse homeostatic functions performed by microglia and then elaborate on context-specific spatial and temporal microglial heterogeneity. Subsequently, we summarize microglia involvement in psychopathologies, namely major depressive disorder, schizophrenia and bipolar disorder, with a particular focus on post-mortem studies. Finally, we postulate microglia as a promising novel therapeutic target in psychiatry through antidepressant and antipsychotic treatment.

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Topics: Neuroinflammation (59%), Microglia (50%)

1 Citations


Open accessDOI: 10.1016/J.BBIH.2021.100378
06 Nov 2021-
Abstract: Major Depressive Disorder (MDD) is a common and debilitating mood disorder that is more prevalent in women than men. In humans, PET imaging of microglia activation is currently being explored as a potential biomarker of MDD and suicidal ideation. Stress is a trigger for many mood disorders, including MDD. Microglial changes in morphology and activation state in response to stress has been reported in various brain regions, but most studies only examined male subjects. Here we report changes in microglia morphology in the nucleus accumbens (NAc) and subregions of the hippocampus (HPC) in both male and female mice following variable stress of 6 or 28 days in duration. Our data demonstrate that after 6 days of stress, microglia in the female NAc and dentate gyrus have a reduction in homeostatic associated morphology and an increase in primed microglia. After 28 days some of these sex specific stress effects were still present in microglia within the NAc but not the dentate gyrus. There were no effects of stress in either sex at either timepoint in CA1. In female mice, anti-inflammatory activation of microglia using rosiglitazone promoted sociability behavior after 6 days of stress. Furthermore, both drug and stress have impact on microglia morphology and activation state in the NAc. These data suggest that microglia morphology and activation state are altered by 6 days of variable stress in a region-specific manner and may contribute to, or potentially compensate for, the onset of stress susceptibility rather than impacting long term exposure to stress.

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Topics: Dentate gyrus (53%), Hippocampus (51%)

Open accessJournal ArticleDOI: 10.3389/FNMOL.2021.749737
Abstract: The relationship between the central nervous system (CNS) and microglia is lifelong. Microglia originate in the embryonic yolk sac during development and populate the CNS before the blood-brain barrier forms. In the CNS, they constitute a self-renewing population. Although they represent up to 10% of all brain cells, we are only beginning to understand how much brain homeostasis relies on their physiological functions. Often compared to a double-edged sword, microglia hold the potential to exert neuroprotective roles that can also exacerbate neurodegeneration once compromised. Microglia can promote synaptic growth in addition to eliminating synapses that are less active. Synaptic loss, which is considered one of the best pathological correlates of cognitive decline, is a distinctive feature of major depressive disorder (MDD) and cognitive aging. Long-term psychological stress accelerates cellular aging and predisposes to various diseases, including MDD, and cognitive decline. Among the underlying mechanisms, stress-induced neuroinflammation alters microglial interactions with the surrounding parenchymal cells and exacerbates oxidative burden and cellular damage, hence inducing changes in microglia and neurons typical of cognitive aging. Focusing on microglial interactions with neurons and their synapses, this review discusses the disrupted communication between these cells, notably involving fractalkine signaling and the triggering receptor expressed on myeloid cells (TREM). Overall, chronic stress emerges as a key player in cellular aging by altering the microglial sensome, notably via fractalkine signaling deficiency. To study cellular aging, novel positron emission tomography radiotracers for TREM and the purinergic family of receptors show interest for human study.

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Topics: Neuroinflammation (60%), Cognitive decline (58%), Neuroprotection (54%) ... show more

Open accessJournal ArticleDOI: 10.1016/J.BBIH.2021.100320
Justin L. Bollinger1Institutions (1)
09 Aug 2021-
Abstract: Women suffer from major depressive disorder (MDD) more often than men and report greater MDD symptom severity. Mounting evidence suggests that sex differences in MDD may be driven, in part, by sex-specific neurobiological mechanisms. Chronic stress is a significant risk factor in MDD, and preclinical rodent models show differential patterns of stress-induced neural remodeling and cognitive-behavioral dysfunction in males and females. For instance, chronic stress leads to synapse loss in the medial prefrontal cortex in male rodents yet has either no effect on- or increases-synapse number in females. Recent reports have implicated microglia, the immune cells of the brain, in MDD, and findings demonstrate sex-specific microglial signatures in both preclinical stress models and MDD patients. Given that microglia can remodel neural architecture, modulate synaptic transmission, and affect subsequent changes in behavior, it is plausible that microglial pathways contribute to differential stress effects on neuroplasticity and function in males and females. As such, this review examines the evidence for sex-specific microglia-neuron interactions in preclinical stress models and in patients with MDD. Discoveries highlighted herein demonstrate divergent microglial contributions in males and females and suggest that future studies investigating stress-linked disorders should be guided by sex-dependent neurobiological and behavioral findings. Examining these pathways represents a clear avenue toward both a richer understanding of brain, behavior, and immunity, and innovative psychoneuroimmunology-based applications in personalized medicine.

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65 results found


Journal ArticleDOI: 10.1006/METH.2001.1262
01 Dec 2001-Methods
Abstract: The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data.

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Topics: MicroRNA 34a (52%), Cell wall organization (50%)

116,500 Citations


Open accessJournal ArticleDOI: 10.1016/S0092-8674(03)00035-7
24 Jan 2003-Cell
Abstract: Brain-derived neurotrophic factor (BDNF) modulates hippocampal plasticity and hippocampal-dependent memory in cell models and in animals. We examined the effects of a valine (val) to methionine (met) substitution in the 5' pro-region of the human BDNF protein. In human subjects, the met allele was associated with poorer episodic memory, abnormal hippocampal activation assayed with fMRI, and lower hippocampal n-acetyl aspartate (NAA), assayed with MRI spectroscopy. Neurons transfected with met-BDNF-GFP showed lower depolarization-induced secretion, while constitutive secretion was unchanged. Furthermore, met-BDNF-GFP failed to localize to secretory granules or synapses. These results demonstrate a role for BDNF and its val/met polymorphism in human memory and hippocampal function and suggest val/met exerts these effects by impacting intracellular trafficking and activity-dependent secretion of BDNF.

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Topics: rs6265 (57%), Hippocampal formation (54%)

3,366 Citations


Open accessJournal ArticleDOI: 10.1038/NATURE07455
15 Oct 2008-Nature
Abstract: Unravelling the pathophysiology of depression is a unique challenge. Not only are depressive syndromes heterogeneous and their aetiologies diverse, but symptoms such as guilt and suicidality are impossible to reproduce in animal models. Nevertheless, other symptoms have been accurately modelled, and these, together with clinical data, are providing insight into the neurobiology of depression. Recent studies combining behavioural, molecular and electrophysiological techniques reveal that certain aspects of depression result from maladaptive stress-induced neuroplastic changes in specific neural circuits. They also show that understanding the mechanisms of resilience to stress offers a crucial new dimension for the development of fundamentally novel antidepressant treatments.

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Topics: Poison control (50%)

2,248 Citations


Open accessJournal ArticleDOI: 10.1038/NRN2647
Abstract: The survival and well-being of all species requires appropriate physiological responses to environmental and homeostatic challenges. The re-establishment and maintenance of homeostasis entails the coordinated activation and control of neuroendocrine and autonomic stress systems. These collective stress responses are mediated by largely overlapping circuits in the limbic forebrain, the hypothalamus and the brainstem, so that the respective contributions of the neuroendocrine and autonomic systems are tuned in accordance with stressor modality and intensity. Limbic regions that are responsible for regulating stress responses intersect with circuits that are responsible for memory and reward, providing a means to tailor the stress response with respect to prior experience and anticipated outcomes.

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Topics: Limbic system (51%)

2,209 Citations


Journal ArticleDOI: 10.1176/AJP.156.6.837
Abstract: OBJECTIVE: Stressful life events are associated with the onset of episodes of major depression. However, exposure to stressful life events is influenced by genetic factors, and these factors are correlated with those that predispose to major depression. The aim of this study was to clarify the degree to which stressful life events cause major depression. METHOD: The authors assessed the occurrence of 15 classes of stressful life events and the onset of DSM-III-R major depression over a 1-year period in female twins ascertained from a population-based registry. The sample contained 24,648 person-months and 316 onsets of major depression. Stressful life events were individually rated on contextual threat and dependence (the degree to which the stressful life event could have resulted from the respondent’s behavior). The nature of the relationship between stressful life events and major depression was tested by 1) discrete-time survival analysis examining the relationship between dependence and the depressog...

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Topics: Population (51%)

2,060 Citations


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