Showing papers in "Journal of Neuroscience Research in 2021"
TL;DR: Three factors that likely contribute to gender inequalities and women's departure from academic STEM fields are described, including numeric underrepresentation and stereotypes, a lack of supportive social networks, and chilly academic climates.
Abstract: Recently there is widespread interest in women's underrepresentation in science, technology, engineering, and mathematics (STEM); however, progress toward gender equality in these fields is slow. More alarmingly, these gender disparities worsen when examining women's representation within STEM departments in academia. While the number of women receiving postgraduate degrees has increased in recent years, the number of women in STEM faculty positions remains largely unchanged. One explanation for this lack of progress toward gender parity is negative and pervasive gender stereotypes, which may facilitate hiring discrimination and reduce opportunities for women's career advancement. Women in STEM also have lower social capital (e.g., support networks), limiting women's opportunities to earn tenure and learn about grant funding mechanisms. Women faculty in STEM may also perceive their academic climate as unwelcoming and threatening, and report hostility and uncomfortable tensions in their work environments, such as sexual harassment and discrimination. Merely the presence of gender-biased cues in physical spaces targeted toward men (e.g., "geeky" decor) can foster a sense of not belonging in STEM. We describe the following three factors that likely contribute to gender inequalities and women's departure from academic STEM fields: (a) numeric underrepresentation and stereotypes, (b) lack of supportive social networks, and (c) chilly academic climates. We discuss potential solutions for these problems, focusing on National Science Foundation-funded ADVANCE organizational change interventions that target (a) recruiting diverse applicants (e.g., training search committees), (b) mentoring, networking, and professional development (e.g., promoting women faculty networks); and (c) improving academic climate (e.g., educating male faculty on gender bias).
132 citations
TL;DR: ThePlacenta might provide a historical record of in utero threats the fetus confronted and a roadmap to understand how placenta responses to such encounters impacts the placental‐brain‐axis, and improved early diagnostic and preventative approaches may be designed to mitigate such placental disruptions.
Abstract: All mammalian species depend on the placenta, a transient organ, for exchange of gases, nutrients, and waste between the mother and conceptus. Besides serving as a conduit for such exchanges, the placenta produces hormones and other factors that influence maternal physiology and fetal development. To meet all of these adaptations, the placenta has evolved to become the most structurally diverse organ within all mammalian taxa. However, commonalities exist as to how placental responses promote survival against in utero threats and can alter the trajectory of fetal development, in particular the brain. Increasing evidence suggests that reactions of the placenta to various in utero stressors may lead to long-standing health outcomes, otherwise considered developmental origin of health and disease effects. Besides transferring nutrients and gases, the placenta produces neurotransmitters, including serotonin, dopamine, norepinephrine/epinephrine, that may circulate and influence brain development. Neurobehavioral disorders, such as autism spectrum disorders, likely trace their origins back to placental disturbances. This intimate relationship between the placenta and brain has led to coinage of the term, the placenta-brain-axis. This axis will be the focus herein, including how conceptus sex might influence it, and technologies employed to parse out the effects of placental-specific transcript expression changes on later neurobehavioral disorders. Ultimately, the placenta might provide a historical record of in utero threats the fetus confronted and a roadmap to understand how placenta responses to such encounters impacts the placental-brain-axis. Improved early diagnostic and preventative approaches may thereby be designed to mitigate such placental disruptions.
89 citations
TL;DR: Results support the notion of dedifferentiation processes, which refer to the decrease in functional selectivity of the brain regions, resulting in more diffuse and less specialized FC, associated with the disruption of cognitive functions with age.
Abstract: The dynamic of the temporal correlations between brain areas, called functional connectivity (FC), undergoes complex transformations through the life span. In this review, we aim to provide an overview of these changes in the nonpathological brain from fetal life to advanced age. After a brief description of the main methods, we propose that FC development can be divided into four main phases: first, before birth, a strong change in FC leads to the emergence of functional proto-networks, involving mainly within network short-range connections. Then, during the first years of life, there is a strong widespread organization of networks which starts with segregation processes followed by a continuous increase in integration. Thereafter, from adolescence to early adulthood, a refinement of existing networks in the brain occurs, characterized by an increase in integrative processes until about 40 years. Middle age constitutes a pivotal period associated with an inversion of the functional brain trajectories with a decrease in segregation process in conjunction to a large-scale reorganization of between network connections. Studies suggest that these processes are in line with the development of cognitive and sensory functions throughout life as well as their deterioration. During aging, results support the notion of dedifferentiation processes, which refer to the decrease in functional selectivity of the brain regions, resulting in more diffuse and less specialized FC, associated with the disruption of cognitive functions with age. The inversion of developmental processes during aging is in accordance with the developmental models of neuroanatomy for which the latest matured regions are the first to deteriorate.
42 citations
TL;DR: A review of the state of the art in microfluidic technologies for neurological disease research can be found in this paper, where the authors discuss the challenges and limitations while highlighting the benefits and potential of integrating technologies.
Abstract: Neurological disorders are the leading cause of disability and the second largest cause of death worldwide. Despite significant research efforts, neurology remains one of the most failure-prone areas of drug development. The complexity of the human brain, boundaries to examining the brain directly in vivo, and the significant evolutionary gap between animal models and humans, all serve to hamper translational success. Recent advances in microfluidic in vitro models have provided new opportunities to study human cells with enhanced physiological relevance. The ability to precisely micro-engineer cell-scale architecture, tailoring form and function, has allowed for detailed dissection of cell biology using microphysiological systems (MPS) of varying complexities from single cell systems to "Organ-on-chip" models. Simplified neuronal networks have allowed for unique insights into neuronal transport and neurogenesis, while more complex 3D heterotypic cellular models such as neurovascular unit mimetics and "Organ-on-chip" systems have enabled new understanding of metabolic coupling and blood-brain barrier transport. These systems are now being developed beyond MPS toward disease specific micro-pathophysiological systems, moving from "Organ-on-chip" to "Disease-on-chip." This review gives an outline of current state of the art in microfluidic technologies for neurological disease research, discussing the challenges and limitations while highlighting the benefits and potential of integrating technologies. We provide examples of where such toolsets have enabled novel insights and how these technologies may empower future investigation into neurological diseases.
39 citations
TL;DR: The goal of this mini‐review was to discuss the evidence for the types of DNA damage that accumulates in PD, which has provided clues for which DNA repair pathways, such as DNA double‐strand break repair, are dysfunctional.
Abstract: Parkinson's disease (PD) is the most common movement neurodegenerative disorder. Although our understanding of the underlying mechanisms of pathogenesis in PD has greatly expanded, this knowledge thus far has failed to translate into disease-modifying therapies. Therefore, it is of the utmost urgency to interrogate further the multifactorial etiology of PD. DNA repair defects cause many neurodegenerative diseases. An exciting new PD research avenue is the role that DNA damage and repair may play in neuronal death. The goal of this mini-review was to discuss the evidence for the types of DNA damage that accumulates in PD, which has provided clues for which DNA repair pathways, such as DNA double-strand break repair, are dysfunctional. We further highlight compelling data for activation of the DNA damage response in familial and idiopathic PD. The significance of DNA damage and repair is emerging in the PD field and linking these insights to PD pathogenesis may provide new insights into PD pathophysiology and consequently lead to new therapies.
36 citations
TL;DR: Seven candidate routes, which the mature or immature SARS‐CoV‐2 components could use to reach the CNS and PNS, utilizing the within‐body cross talk between organs are enumerated.
Abstract: Without protective and/or therapeutic agents the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection known as coronavirus disease 2019 is quickly spreading worldwide. It has surprising transmissibility potential, since it could infect all ages, gender, and human sectors. It attacks respiratory, gastrointestinal, urinary, hepatic, and endovascular systems and can reach the peripheral nervous system (PNS) and central nervous system (CNS) through known and unknown mechanisms. The reports on the neurological manifestations and complications of the SARS-CoV-2 infection are increasing exponentially. Herein, we enumerate seven candidate routes, which the mature or immature SARS-CoV-2 components could use to reach the CNS and PNS, utilizing the within-body cross talk between organs. The majority of SARS-CoV-2-infected patients suffer from some neurological manifestations (e.g., confusion, anosmia, and ageusia). It seems that although the mature virus did not reach the CNS or PNS of the majority of patients, its unassembled components and/or the accompanying immune-mediated responses may be responsible for the observed neurological symptoms. The viral particles and/or its components have been specifically documented in endothelial cells of lung, kidney, skin, and CNS. This means that the blood-endothelial barrier may be considered as the main route for SARS-CoV-2 entry into the nervous system, with the barrier disruption being more logical than barrier permeability, as evidenced by postmortem analyses.
32 citations
TL;DR: In this article, a review of existing knowledge about various changes in and around mitochondria related to the pathogenesis of Alzheimer's disease, with particular emphasis on mitophagy and autophagy.
Abstract: Alzheimer's disease (AD) is the most common type of dementia and progressive neurodegenerative disease. The presence of β-amyloid (Aβ) plaques and phosphorylated Tau tangles are considered to be the two main hallmarks of AD. Recent findings have shown that different changes in the structure and dynamics of mitochondria play an important role in AD pathology progression. Mitochondrial changes in AD are expressed as enhanced mitochondrial fragmentation, altered mitochondrial dynamics, and changes in the expression of mitochondrial biogenesis genes in vitro and in vivo models. Therefore, targeting mitochondria and associated mitochondrial proteins seems to be a promising alternative instead of targeting Aβ and Tau in the prevention of Alzheimer's disease. The dynamin-related protein (Drp1) is one such protein that plays an important role in the regulation of mitochondrial division and maintenance of mitochondrial structures. Few researchers have shown that inhibition of Drp1 GTPase activity in neuronal cells rescues excessive mitochondrial fragmentation. In addition, the growing evidence revealed that Drp1 can interact with both Aβ and Tau protein in human brain tissues and mouse models. In this review, we would like to update existing knowledge about various changes in and around mitochondria related to the pathogenesis of Alzheimer's disease, with particular emphasis on mitophagy and autophagy.
28 citations
TL;DR: The literature on L‐VDCC expression and function in the CNS and on microglia in vitro and in vivo is reviewed and the therapeutic landscape of L-VDCC‐targeting agents at present and future challenges in the context of Alzheimer's disease, Parkinson’s disease, Huntington's Disease, neuropsychiatric diseases, and other CNS disorders are explored.
Abstract: Calcium (Ca2+ ) is a ubiquitous mediator of a multitude of cellular functions in the central nervous system (CNS). Intracellular Ca2+ is tightly regulated by cells, including entry via plasma membrane Ca2+ permeable channels. Of specific interest for this review are L-type voltage-dependent Ca2+ channels (L-VDCCs), due to their pleiotropic role in several CNS disorders. Currently, there are numerous approved drugs that target L-VDCCs, including dihydropyridines. These drugs are safe and effective for the treatment of humans with cardiovascular disease and may also confer neuroprotection. Here, we review the potential of L-VDCCs as a target for the treatment of CNS disorders with a focus on microglia L-VDCCs. Microglia, the resident immune cells of the brain, have attracted recent attention for their emerging inflammatory role in several CNS diseases. Intracellular Ca2+ regulates microglia transition from a resting quiescent state to an "activated" immune-effector state and is thus a valuable target for manipulation of microglia phenotype. We will review the literature on L-VDCC expression and function in the CNS and on microglia in vitro and in vivo and explore the therapeutic landscape of L-VDCC-targeting agents at present and future challenges in the context of Alzheimer's disease, Parkinson's disease, Huntington's disease, neuropsychiatric diseases, and other CNS disorders.
27 citations
TL;DR: This narrative review aims to explore the recent neuroimaging literature on SG differences in brain function and structure as it pertains to alcohol across positron emission tomography, magnetic resonance imaging, and functional magnetic resonance Imaging modalities in humans and addresses SG disparities in the neuroim imaging of AUD.
Abstract: Over the last 10 years, rates of alcohol use disorder (AUD) have increased in women by 84% relative to a 35% increase in men. Rates of alcohol use and high-risk drinking have also increased in women by 16% and 58% relative to a 7% and 16% increase in men, respectively, over the last decade. This robust increase in drinking among women highlights the critical need to identify the underlying neural mechanisms that may contribute to problematic alcohol consumption across sex/gender (SG), especially given that many neuroimaging studies are underpowered to detect main or interactive effects of SG on imaging outcomes. This narrative review aims to explore the recent neuroimaging literature on SG differences in brain function and structure as it pertains to alcohol across positron emission tomography, magnetic resonance imaging, and functional magnetic resonance imaging modalities in humans. Additional work using magnetic resonance spectroscopy, diffusion tensor imaging, and event-related potentials to examine SG differences in AUD will be covered. Overall, current research on the neuroimaging of AUD, alcohol consumption, or risk of AUD is limited, and findings are mixed regarding the effect of SG on neurochemical, structural, and functional mechanisms associated with AUD. We address SG disparities in the neuroimaging of AUD and propose a call to action to include women in brain imaging research. Future studies are crucial to our understanding of the neurobiological underpinnings of AUD across neural systems and the vulnerability for AUD among women and men.
26 citations
TL;DR: This paper investigated the role of extracellular vesicles (MVs) in pro-inflammatory and microglial functional gene expression using primary organotypic brain slice culture (OBSC).
Abstract: Alcohol use disorder (AUD) pathology features pro-inflammatory gene induction and microglial activation. The underlying cellular processes that promote this activation remain unclear. Previously considered cellular debris, extracellular vesicles (EVs) have emerged as mediators of inflammatory signaling in several disease states. We investigated the role of microvesicles (MVs, 50 nm-100 µm diameter EVs) in pro-inflammatory and microglial functional gene expression using primary organotypic brain slice culture (OBSC). Ethanol caused a unique immune gene signature that featured: temporal induction of pro-inflammatory TNF-α and IL-1β, reduction of homeostatic microglia state gene Tmem119, progressive increases in purinergic receptor P2RY12 and the microglial inhibitory fractalkine receptor CX3CR1, an increase in the microglial presynaptic gene C1q, and a reduction in the phagocytic gene TREM2. MV signaling was implicated in this response as reduction of MV secretion by imipramine blocked pro-inflammatory TNF-α and IL-1β induction by ethanol, and ethanol-conditioned MVs (EtOH-MVs) reproduced the ethanol-associated immune gene signature in naive OBSC slices. Depletion of microglia prior to ethanol treatment prevented pro-inflammatory activity of EtOH-MVs, as did incubation of EtOH-MVs with the HMGB1 inhibitor glycyrrhizin. Ethanol caused HMGB1 secretion from cultured BV2 microglia in MVs through activation of PI3 kinase. In summary, these studies find MVs modulate pro-inflammatory gene induction and microglial activation changes associated with ethanol. Thus, MVs may represent a novel therapeutic target to reduce neuroinflammation in the setting of alcohol abuse or other diseases that feature a neuroimmune component. [Correction added on 5 April 2021, after first online publication: The copyright line was changed.].
26 citations
TL;DR: The survey of the literature indicates that maternal diet influences early postnatal microbiota development, which in turn may serve as a mechanism through which maternal diet impacts neurodevelopment.
Abstract: In offspring, an adequate maternal diet is important for neurodevelopment. One mechanism by which maternal diet impacts neurodevelopment is through its dynamic role in the development of the gut microbiota. Communication between the gut, and its associated microbiota, and the brain is facilitated by the vagus nerve, in addition to other routes. Currently, the mechanisms through which maternal diet impacts offspring microbiota development are not well-defined. Therefore, this review aims to investigate the relationship between maternal diet during pregnancy and offspring microbiota development and its impact on neurodevelopment. Both human and animal model studies were reviewed to understand the impact of maternal diet on offspring microbiota development and potential consequences on neurodevelopment. In the period after birth, as reported in both human and model system studies, maternal diet impacts offspring bacterial colonization (e.g., decreased presence of Lactobacillus reuteri as a result of a high-fat maternal diet). It remains unknown whether these changes persist into adulthood and whether they impact vulnerability to disease. Therefore, further long-term studies are required in both human and model systems to study these changes. Our survey of the literature indicates that maternal diet influences early postnatal microbiota development, which in turn, may serve as a mechanism through which maternal diet impacts neurodevelopment.
TL;DR: The role of mitogen-activated protein kinase (MAPK) pathway signaling in regulating microglia-mediated neuroinflammation in Alzheimer's disease (AD) remains unclear.
Abstract: The importance of mitogen-activated protein kinase (MAPK) pathway signaling in regulating microglia-mediated neuroinflammation in Alzheimer's disease (AD) remains unclear. We examined the role of MAPK signaling in microglia using a preclinical model of AD pathology and quantitative proteomics studies of postmortem human brains. In multiplex immunoassay analyses of MAPK phosphoproteins in acutely isolated microglia and brain tissue from 5xFAD mice, we found phosphorylated extracellular signal-regulated kinase (ERK) was the most strongly upregulated phosphoprotein within the MAPK pathway in acutely isolated microglia, but not whole-brain tissue from 5xFAD mice. The importance of ERK signaling in primary microglia cultures was next investigated using transcriptomic profiling and functional assays of amyloid-β and neuronal phagocytosis, which confirmed that ERK is a critical regulator of IFNγ-mediated pro-inflammatory activation of microglia, although it was also partly important for constitutive microglial functions. Phospho-ERK was an upstream regulator of disease-associated microglial gene expression (Trem2, Tyrobp), as well as several human AD risk genes (Bin1, Cd33, Trem2, Cnn2), indicative of the importance of microglial ERK signaling in AD pathology. Quantitative proteomic analyses of postmortem human brain showed that ERK1 and ERK2 were the only MAPK proteins with increased protein expression and positive associations with neuropathological grade. In a human brain phosphoproteomic study, we found evidence for increased flux through the ERK signaling pathway in AD. Overall, our analyses strongly suggest that ERK phosphorylation, particularly in microglia in mouse models, is a regulator of pro-inflammatory immune responses in AD pathogenesis.
TL;DR: In vitro human neuronal systems that employ stem cell and reprogramming technology and their application to a range of neurodegenerative diseases are reviewed, including human‐induced pluripotent stem cell‐derived neurons to directly converted, or transdifferentiated, induced neurons.
Abstract: The development of safe and effective treatments for age-associated neurodegenerative disorders is an on-going challenge faced by the scientific field. Key to the development of such therapies is the appropriate selection of modeling systems in which to investigate disease mechanisms and to test candidate interventions. There are unique challenges in the development of representative laboratory models of neurodegenerative diseases, including the complexity of the human brain, the cumulative and variable contributions of genetic and environmental factors over the course of a lifetime, inability to culture human primary neurons, and critical central nervous system differences between small animal models and humans. While traditional rodent models have advanced our understanding of neurodegenerative disease mechanisms, key divergences such as the species-specific genetic background can limit the application of animal models in many cases. Here we review in vitro human neuronal systems that employ stem cell and reprogramming technology and their application to a range of neurodegenerative diseases. Specifically, we compare human-induced pluripotent stem cell-derived neurons to directly converted, or transdifferentiated, induced neurons, as both model systems can take advantage of patient-derived human tissue to produce neurons in culture. We present recent technical developments using these two modeling systems, as well as current limitations to these systems, with the aim of advancing investigation of neuropathogenic mechanisms using these models.
TL;DR: Findings indicate higher levels of resilience associate with lower levels of clinical pain and functional limitations, and provide compelling evidence that in order to decipher the neurobiological code of chronic pain and related protective factors, it will be important to improve how chronic pain is phenotyped.
Abstract: Chronic musculoskeletal (MSK) pain is disabling to individuals and burdensome to society. A relationship between telomere length and resilience was reported in individuals with consideration for chronic pain intensity. While chronic pain associates with brain changes, little is known regarding the neurobiological interface of resilience. In a group of individuals with chronic MSK pain, we examined the relationships between a previously investigated resilience index, clinical pain and functioning measures, and pain-related brain structures, with consideration for sex and ethnicity/race. A cross-sectional analysis of 166 non-Hispanic Black and non-Hispanic White adults, 45-85 years of age with pain ≥ 1 body site (s) over the past 3 months was completed. Measures of clinical pain and functioning, biobehavioral and psychosocial resilience, and structural MRI were completed. Our findings indicate higher levels of resilience associate with lower levels of clinical pain and functional limitations. Significant associations between resilience, ethnicity/race, and/or sex, and pain-related brain gray matter structure were demonstrated in the right amygdaloid complex, bilateral thalamus, and postcentral gyrus. Our findings provide compelling evidence that in order to decipher the neurobiological code of chronic pain and related protective factors, it will be important to improve how chronic pain is phenotyped; to include an equal representation of females in studies including analyses stratifying by sex, and to consider other sociodemographic factors.
TL;DR: M6A RNA methylation is dynamic and conserved following SCI and may contribute to spinal cord regeneration, and the expression of METTL3 is increased in both astrocytes and neural stem cells.
Abstract: RNA methylation is involved in multiple physiological and pathological processes. However, the role of RNA methylation in spinal cord regeneration has not been reported. In this study, we find an altered m6A (N6-methyladenosine) RNA methylation profiling following zebrafish spinal cord injury (SCI), in line with an altered transcription level of the m6A methylase Mettl3. Interestingly, many of the differential m6A-tagged genes associated with neural regeneration are hypomethylated, but their transcription levels are upregulated in SCI. Moreover, we find that METTL3 may be important for spinal cord regeneration. We also show a conserved feature of METTL3 changes in mouse SCI model, in which the expression of METTL3 is increased in both astrocytes and neural stem cells. Together, our results indicate that m6A RNA methylation is dynamic and conserved following SCI and may contribute to spinal cord regeneration.
TL;DR: Increasing evidence suggests that oral dysfunction is not only a result of dementia in the elderly people, but could also be a causative factor for the onset of dementia.
Abstract: With global increases in the aging population, the number of patients with dementia is greatly increasing, which has become a big social problem. Many studies have shown strong associations between oral disorders and systemic disorders, such as diabetes, arthritis, sepsis, aspiration pneumonia, arteriosclerosis, bacterial endocarditis, and other cardiovascular diseases. Similarly, numerous cross-sectional studies showed that patients with dementia usually have poor oral conditions and tooth loss. These have long been considered as a result of difficulty with oral care due to impaired cognitive function, memory, and physical ability in patients with dementia. Indeed, even in patients with mild cognitive impairment, oral care becomes insufficient owing to decreases in spontaneity of grooming and finger dexterity. However, recent studies have shown that tooth loss and occlusal dysfunction may affect brain function and trigger the onset of dementia found in neurodegenerative diseases including Alzheimer's disease. In this review, we highlight the relationships among aging, oral dysfunction, and the development of dementia. Increasing evidence suggests that oral dysfunction is not only a result of dementia in the elderly people, but could also be a causative factor for the onset of dementia.
TL;DR: In this paper, the authors summarized the evidence that supports the involvement of COX-1 in the brain during neuroinflammation and found that COX1 can also be upregulated.
Abstract: Purpose Reactive microglia are an important hallmark of neuroinflammation. Reactive microglia release various inflammatory mediators, such as cytokines, chemokines, and prostaglandins, which are produced by enzymes like cyclooxygenases (COX). The inducible COX-2 subtype has been associated with inflammation, whereas the constitutively expressed COX-1 subtype is generally considered as a housekeeping enzyme. However, recent evidence suggests that COX-1 can also be upregulated and may play a prominent role in the brain during neuroinflammation. In this review, we summarize the evidence that supports this involvement of COX-1. Methods Five databases were used to retrieve relevant studies that addressed COX-1 in the context of neuroinflammation. The search resulted in 32 articles, describing in vitro, in vivo, post mortem, and in vivo imaging studies that specifically investigated the COX-1 isoform under such conditions. Results Reviewed literature generally indicated that the overexpression of COX-1 was induced by an inflammatory stimulus, which resulted in an increased production of prostaglandin E2. The pharmacological inhibition of COX-1 was shown to suppress the induction of inflammatory mediators like prostaglandin E2. Positron emission tomography (PET) imaging studies in animal models confirmed the overexpression of COX-1 during neuroinflammation. The same imaging method, however, could not detect any upregulation of COX-1 in patients with Alzheimer's disease. Conclusion Taken together, studies in cultured cells and living rodents suggest that COX-1 is involved in neuroinflammation. Most postmortem studies on human brains indicate that the concentration of COX-1-expressing microglial cells is increased near sites of inflammation. However, evidence for the involvement of COX-1 in neuroinflammation in the living human brain is still largely lacking.
TL;DR: Ethanol exposure to the fetus during pregnancy can result in fetal alcohol spectrum disorders (FASD) and the activation of glia and neuroinflammation, which may contribute to the pathology associated with FASD, suggesting that anti‐inflammatory agents may be effective in the treatment of FASd.
Abstract: Ethanol exposure to the fetus during pregnancy can result in fetal alcohol spectrum disorders (FASD). These disorders vary in severity, can affect multiple organ systems, and can lead to lifelong disabilities. Damage to the central nervous system (CNS) is common in FASD, and can result in altered behavior and cognition. The incidence of FASD is alarmingly high, resulting in significant personal and societal costs. There are no cures for FASD. Alcohol can directly alter the function of neurons in the developing CNS. In addition, ethanol can alter the function of CNS glial cells including microglia and astrocytes which normally maintain homeostasis in the CNS. These glial cells can function as resident immune cells in the CNS to protect against pathogens and other insults. However, activation of glia can also damage CNS cells and lead to aberrant CNS function. Ethanol exposure to the developing brain can result in the activation of glia and neuroinflammation, which may contribute to the pathology associated with FASD. This suggests that anti-inflammatory agents may be effective in the treatment of FASD.
TL;DR: In this paper, the effects of α-syn on MAMs and Ca2+ transfer from the ER to mitochondria in WT- and A30P αsyn-overexpressing SH-SY5Y or HEK293 cells were investigated.
Abstract: Mitochondria-associated ER membranes (MAMs) are formed by close and specific components in the contact sites between the endoplasmic reticulum (ER) and mitochondria, which participate in several cell functions, including lipid metabolism, autophagy, and Ca2+ signaling. Particularly, the presence of α-synuclein (α-syn) in MAMs was previously demonstrated, indicating a physical interaction among some proteins in this region and a potential involvement in cell dysfunctions. MAMs alterations are associated with neurodegenerative diseases such as Parkinson's disease (PD) and contribute to the pathogenesis features. Here, we investigated the effects of α-syn on MAMs and Ca2+ transfer from the ER to mitochondria in WT- and A30P α-syn-overexpressing SH-SY5Y or HEK293 cells. We observed that α-syn potentiates the mitochondrial membrane potential (Δψm ) loss induced by rotenone, increases mitophagy and mitochondrial Ca2+ overload. Additionally, in α-syn-overexpressing cells, we found a reduction in ER-mitochondria contact sites through the impairment of the GRP75-IP3R interaction, however, with no alteration in VDAC1-GRP75 interaction. Consequently, after Ca2+ release from the ER, α-syn-overexpressing cells demonstrated a reduction in Ca2+ buffering by mitochondria, suggesting a deregulation in MAM activity. Taken together, our data highlight the importance of the α-syn/MAMs/Ca2+ axis that potentially affects cell functions in PD.
TL;DR: In commonly used models, the female depressive‐like phenotype in rodents seems significantly less dependent on the stress hormone cortic testosterone, whereas the male behavioral response is more evident and associates with variations of corticosterone.
Abstract: Dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is often linked to the neurobiology of depression, though the presence and type of this dysregulation is not a consistent finding. Meanwhile, significant sex differences exist regarding depression and the HPA axis. Animal models of depression simulate certain aspects of the human disease and aim to advance our knowledge regarding its neurobiology and discover new antidepressant treatments. Most animal models of depression induce a depressive-like phenotype taking advantage of stressful experimental conditions, that also increase corticosterone, the main stress hormone in rodents. In this review we present inconsistent results in male and female rodents regarding the interaction between the depressive-like behavioral phenotype and corticosterone. In commonly used models, the female depressive-like phenotype in rodents seems significantly less dependent on the stress hormone corticosterone, whereas the male behavioral response is more evident and associates with variations of corticosterone. Further research and clarification of this sex-dependent interaction will have significant ramifications on the improvement of the validity of animal models of depression.
TL;DR: A review of recent advancements in knowledge regarding the development and role of astrocytes in the healthy and pathological central nervous system (CNS) can be found in this paper.
Abstract: Astrocytes play essential roles in development, homeostasis, injury, and repair of the central nervous system (CNS). Their development is tightly regulated by distinct spatial and temporal cues during embryogenesis and into adulthood throughout the CNS. Astrocytes have several important responsibilities such as regulating blood flow and permeability of the blood-CNS barrier, glucose metabolism and storage, synapse formation and function, and axon myelination. In CNS pathologies, astrocytes also play critical parts in both injury and repair mechanisms. Upon injury, they undergo a robust phenotypic shift known as "reactive astrogliosis," which results in both constructive and deleterious outcomes. Astrocyte activation and migration at the site of injury provides an early defense mechanism to minimize the extent of injury by enveloping the lesion area. However, astrogliosis also contributes to the inhibitory microenvironment of CNS injury and potentiate secondary injury mechanisms, such as inflammation, oxidative stress, and glutamate excitotoxicity, which facilitate neurodegeneration in CNS pathologies. Intriguingly, reactive astrocytes are increasingly a focus in current therapeutic strategies as their activation can be modulated toward a neuroprotective and reparative phenotype. This review will discuss recent advancements in knowledge regarding the development and role of astrocytes in the healthy and pathological CNS. We will also review how astrocytes have been genetically modified to optimize their reparative potential after injury, and how they may be transdifferentiated into neurons and oligodendrocytes to promote repair after CNS injury and neurodegeneration.
TL;DR: This work reviews examples of rodent models of NDDs in which sex‐specific deficits were identified in molecular, physiological, and/or behavioral responses, showing sex differences in susceptibility to disruption of genes mutated in N DDs and proposes a framework to approach the study of sex-specific deficits possibly leading to sex bias in NDS.
Abstract: Neurodevelopmental disorders (NDDs) such as intellectual disability and autism spectrum disorder consistently show a male bias in prevalence, but it remains unclear why males and females are affected with different frequency. While many behavioral studies of transgenic NDD models have focused only on males, the requirement by the National Institutes of Health to consider sex as a biological variable has promoted the comparison of male and female performance in wild-type and mutant animals. Here, we review examples of rodent models of NDDs in which sex-specific deficits were identified in molecular, physiological, and/or behavioral responses, showing sex differences in susceptibility to disruption of genes mutated in NDDs. Haploinsufficiency in genes involved in mechanisms such as synaptic function (GABRB3 and NRXN1), chromatin remodeling (CHD8, EMHT1, and ADNP), and intracellular signaling (CC2D1A and ERK1) lead to more severe behavioral outcomes in males. However, in the absence of behavioral deficits, females can still present with cellular and electrophysiological changes that could be due to compensatory mechanisms or differential allocation of molecular and cellular functions in the two sexes. By contrasting these findings with mouse models where females are more severely affected (MTHFR and AMBRA1), we propose a framework to approach the study of sex-specific deficits possibly leading to sex bias in NDDs.
TL;DR: A comprehensive overview of the use of adipose tissue stem cells in peripheral nerve regeneration and peripheral nerve tissue engineering both in vitro and in vivo is given.
Abstract: After peripheral nerve injury, Schwann cells (SCs) are crucially involved in several steps of the subsequent regenerative processes, such as the Wallerian degeneration. They promote lysis and phagocytosis of myelin, secrete numbers of neurotrophic factors and cytokines, and recruit macrophages for a biological debridement. However, nerve injuries with a defect size of >1 cm do not show proper tissue regeneration and require a surgical nerve gap reconstruction. To find a sufficient alternative to the current gold standard-the autologous nerve transplant-several cell-based therapies have been developed and were experimentally investigated. One approach aims on the use of adipose tissue stem cells (ASCs). These are multipotent mesenchymal stromal cells that can differentiate into multiple phenotypes along the mesodermal lineage, such as osteoblasts, chondrocytes, and myocytes. Furthermore, ASCs also possess neurotrophic features, that is, they secrete neurotrophic factors like the nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, ciliary neurotrophic factor, glial cell-derived neurotrophic factor, and artemin. They can also differentiate into the so-called Schwann cell-like cells (SCLCs). These cells share features with naturally occurring SCs, as they also promote nerve regeneration in the periphery. This review gives a comprehensive overview of the use of ASCs in peripheral nerve regeneration and peripheral nerve tissue engineering both in vitro and in vivo. While the sustainability of differentiation of ASCs to SCLCs in vivo is still questionable, ASCs used with different nerve conduits, such as hydrogels or silk fibers, have been shown to promote nerve regeneration.
TL;DR: The main advances of PDT for GBM management are revisited and also, the recent mechanistic insights about cellular and molecular aspects related to tumoral resistance to PDT of GBM are reviewed.
Abstract: Photodynamic therapy (PDT) has recently gained attention as an alternative treatment of malignant gliomas. Glioblastoma (GBM) is the most prevalent within tumors of the central nervous system (CNS). Conventional treatments for this CNS tumor include surgery, radiation, and chemotherapy. Surgery is still being considered as the treatment of choice. Even so, the poor prognosis and/or recurrence of the disease after applying any of these treatments highlight the urgency of exploring new therapies and/or improving existing ones to achieve the definitive eradication of tumor masses and remaining cells. PDT is a therapeutic modality that involves the destruction of tumor cells by reactive oxygen species induced by light, which were previously treated with a photosensitizing agent. However, in recent years, its experimental application has expanded to other effects that could improve overall performance against GBM. In the current review, we revisit the main advances of PDT for GBM management and also, the recent mechanistic insights about cellular and molecular aspects related to tumoral resistance to PDT of GBM.
TL;DR: Age‐related changes in brain SC are shown, characterized by both decreases and increases in connectivity weight, confirming that aging triggers a reorganization of the brain structural network.
Abstract: Normal aging is characterized by structural and functional changes in the brain contributing to cognitive decline Structural connectivity (SC) describes the anatomical backbone linking distinct functional subunits of the brain and disruption of this communication is thought to be one of the potential contributors for the age-related deterioration observed in cognition Several studies already explored brain network's reorganization during aging, but most focused on average connectivity of the whole-brain or in specific networks, such as the resting-state networks Here, we aimed to characterize longitudinal changes of white matter (WM) structural brain networks, through the identification of sub-networks with significantly altered connectivity along time Then, we tested associations between longitudinal changes in network connectivity and cognition We also assessed longitudinal changes in topological properties of the networks For this, older adults were evaluated at two timepoints, with a mean interval time of 528 months (SD = 724) WM structural networks were derived from diffusion magnetic resonance imaging, and cognitive status from neurocognitive testing Our results show age-related changes in brain SC, characterized by both decreases and increases in connectivity weight Interestingly, decreases occur in intra-hemispheric connections formed mainly by association fibers, while increases occur mostly in inter-hemispheric connections and involve association, commissural, and projection fibers, supporting the last-in-first-out hypothesis Regarding topology, two hubs were lost, alongside with a decrease in connector-hub inter-modular connectivity, reflecting reduced integration Simultaneously, there was an increase in the number of provincial hubs, suggesting increased segregation Overall, these results confirm that aging triggers a reorganization of the brain structural network
TL;DR: In this article, several lines of empirical evidences about sex differences in functions and anatomy of social brain are discussed and the most relevant differences involve face processing, facial expression recognition, response to baby schema, ability to see faces in things, the processing of social interactions, the response to the others' pain, interest in social information, processing of gestures and actions, biological motion, erotic, and affective stimuli.
Abstract: Many studies have reported sex differences in empathy and social skills. In this review, several lines of empirical evidences about sex differences in functions and anatomy of social brain are discussed. The most relevant differences involve face processing, facial expression recognition, response to baby schema, the ability to see faces in things, the processing of social interactions, the response to the others' pain, interest in social information, processing of gestures and actions, biological motion, erotic, and affective stimuli. Sex differences in oxytocin-based parental response are also reported. In conclusion, the female and male brains show several neuro-functional differences in various aspects of social cognition, and especially in emotional coding, face processing, and response to baby schema. An interpretation of this sexual dimorphism is provided in the view of evolutionary psychobiology.
TL;DR: Female animals expressed lower levels of GLT‐1 in the DH and greater levels of ephrin receptor B6 (EphB6) in the VH, in the absence of AIE effects, which support the growing literature indicating that adolescent alcohol exposure produces long‐lasting effects on astrocyte function and astroCyte‐neuronal interactions.
Abstract: Adolescent alcohol drinking is widely recognized as a significant public health problem, and evidence is accumulating that sufficient levels of consumption during this critical period of brain development have an enduring impact on neural and behavioral function. Recent studies have indicated that adolescent intermittent ethanol (AIE) exposure alters astrocyte function, astrocyte-neuronal interactions, and related synaptic regulation and activity. However, few of those studies have included female animals, and a broader assessment of AIE effects on the proteins mediating astrocyte-mediated glutamate dynamics and synaptic function is needed. We measured synaptic membrane expression of several such proteins in the dorsal and ventral regions of the hippocampal formation (DH, VH) from male and female rats exposed to AIE or adolescent intermittent water. In the DH, AIE caused elevated expression of glutamate transporter 1 (GLT-1) in both males and females, elevated postsynaptic density 95 expression in females only, and diminished NMDA receptor subunit 2A expression in males only. AIE and sex interactively altered ephrin receptor A4 (EphA4) expression in the DH. In the VH, AIE elevated expression of the cystine/glutamate antiporter and the glutamate aspartate transporter 1 (GLAST) in males only. Compared to males, female animals expressed lower levels of GLT-1 in the DH and greater levels of ephrin receptor B6 (EphB6) in the VH, in the absence of AIE effects. These results support the growing literature indicating that adolescent alcohol exposure produces long-lasting effects on astrocyte function and astrocyte-neuronal interactions. The sex and subregion specificity of these effects have mechanistic implications for our understanding of AIE effects generally.
TL;DR: In this paper, the authors examined the effects of alcohol consumption on the astrocytic response in the central amygdala and basolateral amygdala (BLA) in a non-dependent model.
Abstract: Binge drinking is a common occurrence in the United States, but a high concentration of alcohol in the blood has been shown to have reinforcing and reciprocal effects on the neuroimmune system in both dependent and non-dependent scenarios. The first part of this study examined alcohol's effects on the astrocytic response in the central amygdala and basolateral amygdala (BLA) in a non-dependent model. C57BL/6J mice were given access to either ethanol, water, or sucrose during a "drinking in the dark" paradigm, and astrocyte number and astrogliosis were measured using immunohistochemistry. Results indicate that non-dependent consumption increased glial fibrillary acidic protein (GFAP) density but not the number of GFAP+ cells, suggesting that non-dependent ethanol is sufficient to elicit astrocyte activation. The second part of this study examined how astrocytes impacted behaviors and the neurochemistry related to alcohol using the chemogenetic tool, DREADDs (designer receptors exclusively activated by designer drugs). Transgenic GFAP-hM3Dq mice were administered clozapine N-oxide both peripherally, affecting the entire central nervous system (CNS), or directly into the BLA. In both instances, GFAP-Gq-signaling activation significantly reduced ethanol consumption and correlating blood ethanol concentrations. However, GFAP-Gq-DREADD activation throughout the CNS had more broad effects resulting in decreased locomotor activity and sucrose consumption. More targeted GFAP-Gq-signaling activation in the BLA only impacted ethanol consumption. Finally, a glutamate assay revealed that after GFAP-Gq-signaling activation glutamate concentrations in the amygdala were partially normalized to control levels. Altogether, these studies support the theory that astrocytes represent a viable target for alcohol use disorder therapies.
TL;DR: The authors showed that α-synuclein species isolated from human PD patient brain and recombinant α-Synuclein oligomers caused similar deficits in lipid vesicle trafficking rates in cultured rat neurons and glia.
Abstract: α-Synuclein oligomers are thought to have a pivotal role in sporadic and familial Parkinson's disease (PD) and related α-synucleinopathies, causing dysregulation of protein trafficking, autophagy/lysosomal function, and protein clearance, as well as synaptic function impairment underlying motor and cognitive symptoms of PD. Moreover, trans-synaptic spread of α-synuclein oligomers is hypothesized to mediate disease progression. Therapeutic approaches that effectively block α-synuclein oligomer-induced pathogenesis are urgently needed. Here, we show for the first time that α-synuclein species isolated from human PD patient brain and recombinant α-synuclein oligomers caused similar deficits in lipid vesicle trafficking rates in cultured rat neurons and glia, while α-synuclein species isolated from non-PD human control brain samples did not. Recombinant α-synuclein oligomers also increased neuronal expression of lysosomal-associated membrane protein-2A (LAMP-2A), the lysosomal receptor that has a critical role in chaperone-mediated autophagy. Unbiased screening of several small molecule libraries (including the NIH Clinical Collection) identified sigma-2 receptor antagonists as the most effective at blocking α-synuclein oligomer-induced trafficking deficits and LAMP-2A upregulation in a dose-dependent manner. These results indicate that antagonists of the sigma-2 receptor complex may alleviate α-synuclein oligomer-induced neurotoxicity and are a novel therapeutic approach for disease modification in PD and related α-synucleinopathies.
TL;DR: The bed nucleus of the stria terminalis (BNST) encodes aspects of anxiety‐like and social behaviors, and also undergoes developmental maturation during the early postnatal period, rendering it vulnerable to effects of ELS.
Abstract: Trauma during critical periods of development can induce long-lasting adverse effects. To study neural aberrations resulting from early life stress (ELS), many studies utilize rodent maternal separation, whereby pups are intermittently deprived of maternal care necessary for proper development. This can produce adulthood behavioral deficits related to anxiety, reward, and social behavior. The bed nucleus of the stria terminalis (BNST) encodes aspects of anxiety-like and social behaviors, and also undergoes developmental maturation during the early postnatal period, rendering it vulnerable to effects of ELS. Mice underwent maternal separation (separation 4 hr/day during postnatal day (PD)2-5 and 8 hr/day on PD6-16) with early weaning on PD17, which induced behavioral deficits in adulthood performance on two-part social interaction task designed to test social motivation (choice between a same-sex novel conspecific or an empty cup) and social novelty preference (choice between the original-novel conspecific vs. a new-novel conspecific). We used chemogenetics to non-selectively silence or activate neurons in the BNST to examine its role in social motivation and social novelty preference, in mice with or without the history of ELS. Manipulation of BNST produced differing social behavior effects in non-stressed versus ELS mice; social motivation was decreased in non-stressed mice following BNST activation, but unchanged following BNST silencing, while ELS mice showed no change in social behavior after BNST activation, but exhibited enhancement of social motivation-for which they were deficient prior-following BNST silencing. Findings emphasize the BNST as a potential therapeutic target for social anxiety disorders instigated by childhood trauma.