Alcohol Use Disorder (AUD) is a debilitating disorder that manifests as problematic patterns of alcohol use. At the core of AUD's behavioral manifestations are the profound structural, physiological, cellular, and molecular effects of alcohol on the brain. While the field has made considerable progress in understanding the neuromolecular targets of alcohol we still lack a comprehensive understanding of alcohol's actions and effective treatment strategies. Drosophila melanogaster is a powerful model for investigating the neuromolecular targets of alcohol because flies model many of the core behavioral elements of AUD and offer a rich genetic toolkit to precisely reveal the in vivo molecular actions of alcohol. In this review, we focus on receptors and channels that are often targeted by alcohol within the brain. We discuss the general roles of these proteins, their role in alcohol-associated behaviors across species, and propose ways in which Drosophila models can help advance the field.
Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Journal of Experimental Neuroscience Volume 13: 1 © The Author(s) 2019 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/1 79069519829632
Brain development is highly demanding energetically, requiring neurons to have tightly regulated and highly dynamic metabolic machinery to achieve their ultimately complex cellular architecture. Mitochondria are the main source of neuronal adenosine 5′-triphosphate (ATP) and regulate critical neurodevelopmental processes including calcium signaling, iron homeostasis, oxidative stress, and apoptosis. Metabolic perturbations during critical neurodevelopmental windows impair neurological function not only acutely during the period of rapid growth/development, but also in adulthood long after the early-life insult has been rectified. Our laboratory uses iron deficiency (ID), the most common nutrient deficiency, as a model of early-life metabolic disruptions of neuronal metabolism because iron has a central role in mitochondrial function. Recently, we published that ID reduces hippocampal neuronal dendritic mitochondrial motility and size. In this commentary, we delve deeper into speculation about potential cellular mechanisms that drive the effects of neuronal ID on mitochondrial dynamics and quality control pathways. We propose that understanding the basic cellular biology of how mitochondria respond and adapt to ID and other metabolic perturbations during brain development may be a key factor in designing strategies to reduce the risk of later-life psychiatric, cognitive, and neurodegenerative disorders associated with early-life ID.
Considerably less attention has been paid to psychological and social sequelae of concussion in youth athletes compared with neurocognitive outcomes. This narrative review consolidates the literature on postconcussive emotional and psychosocial functioning in school-aged children and adolescents, highlighting athlete-specific findings. MEDLINE and PsycINFO databases were queried for pediatric concussion studies examining psychological and/or social outcomes, and 604 studies met search criteria (11 of those specific to sport). Results were organized into domains: emotional and social dysfunction, behavioral problems, academic difficulties, sleep disturbance, headache, and quality of life. The small body of literature regarding psychological and social issues following pediatric concussion suggests behavioral disturbances at least temporarily disrupt daily life. Extrapolation from samples of athletes and nonathletes indicates postconcussive anxiety and depressive symptoms appear, although levels may be subclinical. Social and academic findings were less clear. Future well-controlled and adequately powered research will be essential to anticipate concussed athletes’ psychosocial needs.
Changes in chromatin and epigenetic modifications have been associated with aging and aging-associated neurodegenerative diseases, although the causal relationship between these changes and disease-related pathology has been unclear. Recent studies have now made direct connections between neurodegeneration-associated proteins and derepression of repetitive element transcription due to changes in heterochromatin. We suggest that this derepression leads to an increased accumulation of intracellular double-stranded RNA (dsRNA), with an attendant induction of innate immune responses that contribute to the neuroinflammation found in essentially all age-associated neurodegenerative diseases.
There is growing public concern surrounding traumatic brain injury (TBI). TBI can cause significant morbidity, and the long-term sequelae are poorly understood. TBI diagnosis and management rely on patient-reported symptoms and subjective clinical assessment. There are no biologic tools to detect mild TBI or to track brain recovery. Emerging evidence suggests that microRNAs (miRNAs) may provide information about the injured brain. These tiny epigenetic molecules are expressed throughout the body. However, they are particularly important in neurons, can cross the blood-brain barrier, and are securely transported from cell to cell, where they regulate gene expression. miRNA levels may identify patients with TBI and predict symptom duration. This review synthesizes miRNA findings from 14 human studies. We distill more than 291 miRNAs to 17 biomarker candidates that overlap across multiple studies and multiple biofluids. The goal of this review is to establish a collective understanding of miRNA biology in TBI and identify clinical priorities for future investigations of this promising biomarker.
Amyotrophic lateral sclerosis (ALS) is a devastating, motor neuron degenerative disease without any cure. About 95% of the ALS patients feature abnormalities in the RNA/DNA-binding protein, TDP-43, involving its nucleo-cytoplasmic mislocalization in spinal motor neurons. How TDP-43 pathology triggers neuronal apoptosis remains unclear. In a recent study, we reported for the first time that TDP-43 participates in the DNA damage response (DDR) in neurons, and its nuclear clearance in spinal motor neurons caused DNA double-strand break (DSB) repair defects in ALS. We documented that TDP-43 was a key component of the non-homologous end joining (NHEJ) pathway of DSB repair, which is likely the major pathway for repair of DSBs in post-mitotic neurons. We have also uncovered molecular insights into the role of TDP-43 in DSB repair and showed that TDP-43 acts as a scaffold in recruiting the XRCC4/DNA Ligase 4 complex at DSB damage sites and thus regulates a critical rate-limiting function in DSB repair. Significant DSB accumulation in the genomes of TDP-43-depleted, human neural stem cell-derived motor neurons as well as in ALS patient spinal cords with TDP-43 pathology, strongly supported a TDP-43 involvement in genome maintenance and toxicity-induced genome repair defects in ALS. In this commentary, we highlight our findings that have uncovered a link between TDP-43 pathology and impaired DNA repair and suggest potential possibilities for DNA repair-targeted therapies for TDP-43-ALS.
Traumatic brain injury (TBI) is a well-known consequence of participation in activities such as military combat or collision sports. But the wide variability in eliciting circumstances and injury severities makes the study of TBI as a uniform disease state impossible. Military Service members are under additional, unique threats such as exposure to explosive blast and its unique effects on the body. This review is aimed toward TBI researchers, as it covers important concepts and considerations for studying blast-induced head trauma. These include the comparability of blast-induced head trauma to other mechanisms of TBI, whether blast overpressure induces measureable biomarkers, and whether a biodosimeter can link blast exposure to health outcomes, using acute radiation exposure as a corollary. This examination is contextualized by the understanding of concussive events and their psychological effects throughout the past century’s wars, as well as the variables that predict sustaining a TBI and those that precipitate or exacerbate psychological conditions. Disclaimer: The views expressed in this article are solely the views of the authors and not those of the Department of Defense Blast Injury Research Coordinating Office, US Army Medical Research and Development Command, US Army Futures Command, US Army, or the Department of Defense.
Background: There is a significant number of military personnel with a history of mild traumatic brain injury (mTBI) who suffer from comorbid posttraumatic stress symptoms (PTS). Although there is evidence of disruptions of the default mode network (DMN) associated with PTS and mTBI, previous studies have only studied static connectivity while ignoring temporal variability of connectivity. Objective: To assess DMN disrupted or dysregulated neurocircuitry, cognitive functioning, and psychological health of active-duty military with mTBI and PTS. Method: U.S. Army soldiers with PTS (n = 14), mTBI + PTS (n = 25), and healthy controls (n = 21) voluntarily completed a cognitive and symptom battery. In addition, participants had magnetic resonance imaging (MRI) to assess both static functional connectivity (SFC) and variance of dynamic functional connectivity (vDFC) of the DMN. Results: Both the PTS and mTBI + PTS groups had significant symptoms, but only the comorbid group had significant decrements in cognitive functioning. Both groups showed less stable and disrupted neural signatures of the DMN, mainly constituting the cingulate-frontal-temporal-parietal attention network. Specifically, the PTS group showed a combination of both reduced contralateral strength and reduced unilateral variability of frontal- cingulate- temporal connectivities, as well as increased variability of frontal- parietal connectivities. The mTBI + PTS group had fewer abnormal connectives than the PTS group, all of which included reduced strength of frontal- temporal regions and reduced variability frontal- cingulate- temporal regions. Greater SFC and vDFC connectivity of the left dorsolateral prefrontal cortex (dlPFC) ↔ precuneus was associated with higher cognitive scores and lower symptom scores. Conclusions: Findings suggest that individuals with PTS and mTBI + PTS have a propensity for accentuated generation of thoughts, feelings, sensations, and/or images while in a resting state. Compared with controls, only the PTS group was associated with accentuated variability of the frontal- parietal attention network. While there were no significant differences in DMN connectivity strength between the mTBI + PTS and PTS groups, variability of connectivity was able to distinguish them.
Due to limitations of neuroimaging, such as the isodense appearance of blood to neuronal tissue in subacute hemorrhagic stroke, a body of studies have been performed to evaluate candidate biomarkers which may aid in accurate determination of cerebrovascular accident type. Beyond aiding in the delineation of stroke cause, biomarkers could also confer useful prognostic information to help clinicians plan use of resources. One of the candidate biomarkers studied for detection of cerebrovascular accident (CVA) includes a class of proteins called galectins. Galectins bind β-galactoside through a highly conserved carbohydrate recognition domain, endowing an ability to interact with carbohydrate moieties on glycoproteins, some of which are relevant to CVA response. Furthermore, galectins-1, -2, -3, -9, and -12 are expressed in tissues relevant to CVA, and some exhibit characteristics (eg, extracellular secretion) that could render feasible their detection in serum. Galectins-1 and -3 appear to have the largest amounts of preclinical evidence, consistently demonstrating increased activity and expression levels during CVA. However, a lack of standardization of biochemical assays across cohort studies limits further translation of these basic science studies. This review aims to increase awareness of the biochemical roles of galectins in CVA, while also highlighting challenges and remaining questions preventing the translation of basic science observations into a clinically useful test.
Several studies have noted a correlation between retinal degeneration and traumatic encephalopathy (TE) making the retina a leading candidate for detection and assessment. Scattering-angle-resolved optical coherence tomography (SAR-OCT) is a candidate imaging modality to detect sub-resolution changes in retinal microstructure. SAR-OCT images of murine retinas that experience a hypoxic insult—euthanasia by isoflurane overdose—are presented. A total of 4 SAR-OCT measurement parameters are reported in 6 longitudinal experiments: blood flow volume fraction, total retinal thickness, reflectance index, and scattering angle. As each mouse expires, blood flow volume fraction decreases, total retinal thickness increases, reflectance index decreases, and scattering angle diversity increases. Contribution of the retinal vasculature to scattering angle diversity is discussed. Results of this study suggest the utility of SAR-OCT to measure TE using scattering angle diversity contrast in the retina.
The primate cerebral cortex is broadly organized along hierarchical processing streams underpinned by corresponding variation in the brain's microstructure and interareal connectivity patterns. Fulcher et al. recently demonstrated that a similar organization exists in the mouse cortex by combining independent datasets of cytoarchitecture, gene expression, cell densities, and long-range axonal connectivity. Using the T1w:T2w magnetic resonance imaging map as a common spatial reference for data-driven comparison of cortical gradients between mouse and human, we highlighted a common hierarchical expression pattern of numerous brain-related genes, providing new understanding of how systematic structural variation shapes functional specialization in mammalian brains. Reflecting on these findings, here we discuss how open neuroscience datasets, combined with advanced neuroinformatics approaches, will be crucial in the ongoing search for organization principles of brain structure. We explore the promises and challenges of integrative studies and argue that a tighter collaboration between experimental, statistical, and theoretical neuroscientists is needed to drive progress further.
A hallmark of many neuromuscular diseases including Alzheimer disease, inclusion body myositis, amyotrophic lateral sclerosis, frontotemporal lobar dementia, and ocular pharyngeal muscular dystrophy is large cytoplasmic aggregates containing the RNA-binding protein, TDP-43. Despite acceptance that cytoplasmic TDP-43 aggregation is pathological, cytoplasmic TDP-43 assemblies form in healthy regenerating muscle. These recently discovered ribonucleoprotein assemblies, termed myo-granules, form in healthy muscle following injury and are readily cleared as the myofibers mature. The formation and dissolution of myo-granules during normal muscle regeneration suggests that these amyloid-like oligomers may be functional and that perturbations in myo-granule kinetics or composition may promote pathological aggregation.
Background/main objectives: No effective strategy exists to treat the well-recognized, devastating impact of traumatic brain injury (TBI) and chronic traumatic encephalopathy (CTE), which is the brain degeneration likely caused by repeated head trauma. The goals of this project were (1) to study the effects of single and recurrent TBI (rTBI) on Drosophila melanogaster’s (a) life span, (b) response to sedatives, and (c) behavioral responses to light and gravity and (2) to determine whether therapeutic hypothermia can mitigate the deleterious effects of TBI. Methods: Five experimental groups were created: (1) control, (2) single TBI or concussion; (3) concussion + hypothermia, (4) rTBI, and (5) rTBI + hypothermia. A “high-impact trauma” (HIT) device was built, which used a spring-based mechanism to propel flies against the wall of a vial, causing mechanical damage to the brain. Hypothermia groups were cooled to 15°C for 3 minutes. Group differences were analyzed with chi-square tests for the categorical variables and with ANOVA tests for the continuous variables. Results: Survival curve analysis showed that rTBI can decrease Drosophila lifespan and hypothermia diminished this impact. Average sedation time for control vs concussion vs concussion + hypothermia was 78 vs 52 vs 61 seconds ( P < .0001). Similarly, rTBI vs rTBI/hypothermia groups took 43 vs 59 seconds ( P < .0001). Concussed flies preferred dark environments compared with control flies (risk ratio 3.3, P < .01) while flies who were concussed and cooled had a risk ratio of 2.7 ( P < .01). Flies with rTBI were almost 4 times likely to prefer the dark environment but only 3 times as likely if they were cooled, compared with controls. Geotaxis was significantly affected by rTBI only and yet less so if rTBI flies were cooled. Conclusions: Hypothermia successfully mitigated many deleterious effects of single TBI and rTBI in Drosophila and may represent a promising breakthrough in the treatment of human TBI.
The neuroplasticity hypothesis of depression proposes that major depressive disorders are related to decreased hippocampal and cortical neural plasticity, which is reversed by antidepressant treatment. Astroglial cells have emerged as key mediators of neural plasticity and are involved in the cause and treatment of depression and anxiety-like behaviors. One of the ways that astroglia modulate neuroplasticity is through the formation and maintenance of perineuronal nets (PNNs). Perineuronal nets are important extracellular matrix components that respond to stress and are implicated in anxiety-like behaviors. Normally, astroglial cells continuously turnover PNNs by degrading and donating PNN proteins; however, chronic stress slows PNN protein degradation and increases cortical PNN expression overall. In this report, we used weighted gene co-expression network analysis and eigengene analysis to further delineate the pathways and key regulators involved in the astroglial-PNN relationship following chronic stress. Our analyses indicate that chronic variable stress induces the expression of PNNs through inhibition of trophic pathways and key transcription factors in astroglial cells. These data further support the integral role of astroglial cells in the neuroplasticity hypothesis of depression through their modulation of anxiety-like behaviors and PNNs.
Mild traumatic brain injury (mTBI), also known as concussion, is a serious public health challenge. Although most patients recover. a substantial minority suffers chronic disability. The mechanisms underlying mTBI-related detrimental effects remain poorly understood. Although animal models contribute valuable preclinical information and improve our understanding of the underlying mechanisms following mTBI, only few studies have used diffusion tensor imaging (DTI) to study the evolution of axonal injury following mTBI in rodents. It is known that DTI shows changes after human concussion and the role of delineating imaging findings in animals is therefore to facilitate understanding of related mechanisms. In this work, we used a rodent model of mTBI to investigate longitudinal indices of axonal injury. We present the results of 45 animals that received magnetic resonance imaging (MRI) at multiple time points over a 2-week period following concussive or sham injury yielding 109 serial observations. Overall, the evolution of DTI metrics following concussive or sham injury differed by group. Diffusion tensor imaging changes within the white matter were most noticeable 1 week following injury and returned to baseline values after 2 weeks. More specifically, we observed increased fractional anisotropy in combination with decreased radial diffusivity and mean diffusivity, in the absence of changes in axial diffusivity, within the white matter of the genu corpus callosum at 1 week post-injury. Our study shows that DTI can detect microstructural white matter changes in the absence of gross abnormalities as indicated by visual screening of anatomical MRI and hematoxylin and eosin (H&E)-stained sections in a clinically relevant animal model of mTBI. Whereas additional histopathologic characterization is required to better understand the neurobiological correlates of DTI measures. our findings highlight the evolving nature of the brain's response to injury following concussion.
Traumatic brain injury (TBI) is highly prevalent and there is currently no adequate treatment. Understanding the underlying mechanisms governing TBI and recovery remains an elusive goal. The heterogeneous nature of injury and individual's response to injury have made understanding risk and susceptibility to TBI of great importance. Epidemiologic studies have provided evidence of sex-dependent differences following TBI. However, preclinical models of injury have largely focused on adult male animals. Here, we review 50 studies that have investigated TBI in both sexes using animal models. Results from these studies are highly variable and model dependent. but largely show females to have a protective advantage in behavioral outcomes and pathology following TBI. Further research of both sexes using newer models that better recapitulate mild and repetitive TBI is needed to characterize the nature of sex-dependent injury and recovery, and ultimately identifies targets for enhanced recovery.
The cerebellum integrates sensory information and motor actions. Increasing experimental evidence has revealed that these functions as well as the cerebellar cytoarchitecture are highly conserved in zebrafish compared with mammals. However, the potential of zebrafish for modelling human cerebellar diseases remains to be addressed. Spinocerebellar ataxias (SCAs) represent a group of genetically inherited cerebellar diseases leading to motor discoordination that is most often caused by affected cerebellar Purkinje cells (PCs). Towards modelling SCAs in zebrafish we identified a small-sized PC-specific regulatory element that was used to develop coexpression vectors with tunable expression strength. These vectors allow for in vivo imaging of SCA-affected PCs by high-resolution fluorescence imaging. Next, zebrafish with SCA type 13 (SCA13) transgene expression were established, revealing that SCA13-induced cell-autonomous PC degeneration results in eye movement deficits. Thus, SCA13 zebrafish mimic the neuropathology of an SCA-affected brain as well as the involved loss of motor control and hence provide a powerful approach to unravel SCA13-induced cell biological pathogenic and cytotoxic mechanisms.
In recent years, research examining the neurocognitive effects of bilingualism has undergone a shift in focus towards examining the neurocognitive effects of individual differences within specific aspects of language experience. The DeLuca et al study advances this direction in showing a specificity of neural adaptations to separate aspects of language experience. However, this approach is an early step of several in towards a more comprehensive understanding of the nature of neural adaptation to bilingual language use. This commentary discusses several future directions worth further consideration in research examining bilingualism-induced neuroplasticity.
