Deficits In Models Research Articles

Intrahippocampal Adeno-Associated Virus-Mediated Overexpression of Nerve Growth Factor Reverses 192IgG-Saporin-Induced Impairments of Hippocampal Plasticity and Behavior.

One of the aspects of Alzheimer disease is loss of cholinergic neurons in the basal forebrain, which leads to development of cognitive impairment. Here, we used a model of cholinergic deficit caused by immunotoxin 192IgG-saporin to study possible beneficial effects of adeno-associated virus (AAV)–mediated overexpression of nerve growth factor (NGF) in the hippocampus of rats with cholinergic deficit. Suspension of recombinant AAV carrying control cassette or cassette with NGF was injected into both hippocampi of control rats or rats with cholinergic deficit induced by intraseptal injection of 192IgG-saporin. Analysis of choline acetyltransferase (ChAT) immunostaining showed that NGF overexpression in the hippocampus did not prevent strong loss of ChAT-positive neurons in the septal area caused by the immunotoxin. Induction of cholinergic deficit in the hippocampus led to impairments in Y-maze and beam-walking test but did not affect behavioral indices in the T-maze, open field test, and inhibitory avoidance training. NGF overexpression in the rats with cholinergic deficit restored normal animal behavior in Y-maze and beam-walking test. Recording of field excitatory postsynaptic potentials in vivo in the hippocampal CA1 area showed that induction of cholinergic deficit decreased magnitude of long-term potentiation (LTP) and prevented a decrease in paired-pulse ratio after LTP induction, and NGF overexpression reversed these negative changes in hippocampal synaptic characteristics. The beneficial effect of NGF was not associated with compensatory changes in the number of cells that express NGF receptors TrkA and NGFR in the hippocampus and medial septal area. NGF overexpression also did not prevent a 192IgG-saporin–induced decrease in the activity of acetylcholine esterase in the hippocampus. We conclude that NGF overexpression in the hippocampus under conditions of cholinergic deficit induces beneficial effects which are not related to maintenance of cholinergic function.

Imagine Your Crossed Hands as Uncrossed: Visual Imagery Impacts the Crossed-Hands Deficit.

Successful interaction with our environment requires accurate tactile localization. Although we seem to localize tactile stimuli effortlessly, the processes underlying this ability are complex. This is evidenced by the crossed-hands deficit, in which tactile localization performance suffers when the hands are crossed. The deficit results from the conflict between an internal reference frame, based in somatotopic coordinates, and an external reference frame, based in external spatial coordinates. Previous evidence in favour of the integration model employed manipulations to the external reference frame (e.g., blindfolding participants), which reduced the deficit by reducing conflict between the two reference frames. The present study extends this finding by asking blindfolded participants to visually imagine their crossed arms as uncrossed. This imagery manipulation further decreased the magnitude of the crossed-hands deficit by bringing information in the two reference frames into alignment. This imagery manipulation differentially affected males and females, which was consistent with the previously observed sex difference in this effect: females tend to show a larger crossed-hands deficit than males and females were more impacted by the imagery manipulation. Results are discussed in terms of the integration model of the crossed-hands deficit.

The beta component of gamma-band auditory steady-state responses in patients with schizophrenia

The mechanisms underlying circuit dysfunctions in schizophrenia (SCZ) remain poorly understood. Auditory steady-state responses (ASSRs), especially in the gamma and beta band, have been suggested as a potential biomarker for SCZ. While the reduction of 40 Hz power for 40 Hz drive has been well established and replicated in SCZ patients, studies are inconclusive when it comes to an increase in 20 Hz power during 40 Hz drive. There might be several factors explaining the inconsistencies, including differences in the sensitivity of the recording modality (EEG vs MEG), differences in stimuli (click-trains vs amplitude-modulated tones) and large differences in the amplitude of the stimuli. Here, we used a computational model of ASSR deficits in SCZ and explored the effect of three SCZ-associated microcircuit alterations: reduced GABA activity, increased GABA decay times and NMDA receptor hypofunction. We investigated the effect of input strength on gamma (40 Hz) and beta (20 Hz) band power during gamma ASSR stimulation and saw that the pronounced increase in beta power during gamma stimulation seen experimentally could only be reproduced in the model when GABA decay times were increased and only for a specific range of input strengths. More specifically, when the input was in this specific range, the rhythmic drive at 40 Hz produced a strong 40 Hz rhythm in the control network; however, in the ‘SCZ-like’ network, the prolonged inhibition led to a so-called ‘beat-skipping’, where the network would only strongly respond to every other input. This mechanism was responsible for the emergence of the pronounced 20 Hz beta peak in the power spectrum. The other two microcircuit alterations were not able to produce a substantial 20 Hz component but they further narrowed the input strength range for which the network produced a beta component when combined with increased GABAergic decay times. Our finding that the beta component only existed for a specific range of input strengths might explain the seemingly inconsistent reporting in experimental studies and suggests that future ASSR studies should systematically explore different amplitudes of their stimuli. Furthermore, we provide a mechanistic link between a microcircuit alteration and an electrophysiological marker in schizophrenia and argue that more complex ASSR stimuli are needed to disentangle the nonlinear interactions of microcircuit alterations. The computational modelling approach put forward here is ideally suited to facilitate the development of such stimuli in a theory-based fashion.

Anti-nociceptive effects of ECa 233 a standardized extract of Centella asiatica (L.) Urban on chronic neuropathic orofacial pain in mice

Ethnopharmacological relevanceECa 233 is a standardized extract of Centella asiatica (L.) Urban, a herb traditionally used to treat a number of diseases including neurological disorders. Accordingly, ECa 233 showed benefits on animal models of cognitive deficits, chronic stress and Parkinson's disease. Analgesic activity of ECa 233 was shown in Tail's flick test in rodent and relieving aphthous ulcer pain in man. Moreover, acute and sub-chronic toxicity testing in rodents and pharmacokinetic study in healthy volunteers, clinical trial phase I demonstrated good safety profiles of ECa 233. Aim of the studyThis study aims to evaluate the anti-nociceptive effects of ECa 233 and its synergistic effect with gabapentin on chronic neuropathic orofacial pain after 3 weeks infraorbital nerve chronic constriction injury in mice. The peripheral and central nociceptive activities are also examined. Materials and methodsChronic neuropathic orofacial pain was induced by 3 weeks infraorbital nerve chronic constriction injury. Mice were treated with ECa 233 (30, 100 and 300 mg/kg) and gabapentin (10 mg/kg) by oral gavage starting on day 21 and going on for 14 consecutive days. Mechanical hyperalgesia and allodynia were measured on day 7, 14, 21, 28 and 35 after infraorbital nerve chronic constriction injury. At the end of the experiment, mice were observed for the sedative effect using the locomotor activity, the calcitonin gen-related peptide in trigeminal ganglion and c-fos expression in trigeminal nucleus caudalis were investigated after euthanasia. ResultsInfraorbital nerve chronic constriction injury gradually induced marked ipsilateral mechanical hyperalgesia and allodynia. The maximum hyperalgesia and allodynia response presented on day 21 and the response was remained constant until day 35. Treatment with either 300 mg/kg ECa 233 or 10 mg/kg gabapentin were able to attenuate mechanical hyperalgesia and allodynia. The downregulation of calcitonin gen-related peptide on ipsilateral trigeminal ganglion were observed in ECa 233 at 100 and 300 mg/kg and 10 mg/kg gabapentin-treated groups. The c-fos expression on ipsilateral trigeminal nucleus caudalis was also decreased in 300 mg/kg ECa 233 and 10 mg/kg gabapentin-treated groups. ConclusionECa 233 reduced hyperalgesia and allodynia by modulating the peripheral calcitonin gen-related peptide expression consequently alleviate the nociceptive activity in trigeminal nucleus caudalis. Further clinical trial to proof ECa 233's efficacy in neuropathic pain in man as well as possible attributable mechanism of action should be further investigated.

Mouse model of voluntary movement deficits induced by needlestick injuries to the primary motor cortex

BackgroundMotor handicap is prevalent in patients with traumatic brain injury, but currently. there is a challenging task to prevent the degeneration of motor neurons and to fully recover the. voluntary movement after injury. New methodFor the first time, we propose to apply needlestick injuries to the primary motor cortex to create mouse model of voluntary movement deficits. Rotarod test, cylinder test and forepaw grip strength test were used to assay motor coordination of both C57BL/6 J and the triple immunodeficient NCG mice. Immunofluorescence staining of PKC-gamma, UCHL1, GFAP, Iba1 and Fluoro-Jade C was performed to analyze the numbers of motor neurons, microglia, astrocytes and degenerating neurons. ResultsMice on either C57BL/6 J or immunodeficient background with the unilateral primary motor cortex injury exhibit motor neuron death, activation of glial cells and deficits in voluntary movement. ConclusionsThe main finding of this study was that the unilateral primary motor cortex injured by needlesticks leads to reactive gliosis, motor neuron death and voluntary movement deficits in mice. This needlestick injury model of primary motor cortex might be useful for future exploration of underlying mechanisms of motor neuron degeneration and of promising treatment modalities such as cell transplantation to improve locomotor deficiency following neurotrauma.

Auditory Brainstem Responses Predict Behavioral Deficits in Rats with Varying Levels of Noise-Induced Hearing Loss

Intense noise exposure is a leading cause of hearing loss, which results in degraded speech sound discrimination ability, particularly in noisy environments. The development of an animal model of speech discrimination deficits due to noise induced hearing loss (NIHL) would enable testing of potential therapies to improve speech sound processing. Rats can accurately detect and discriminate human speech sounds in the presence of quiet and background noise. Further, it is known that profound hearing loss results in functional deafness in rats. In this study, we generated rats with a range of impairments which model the large range of hearing impairments observed in patients with NIHL. One month after noise exposure, we stratified rats into three distinct deficit groups based on their auditory brainstem response (ABR) thresholds. These groups exhibited markedly different behavioral outcomes across a range of tasks. Rats with moderate hearing loss (30 dB shifts in ABR threshold) were not impaired in speech sound detection or discrimination. Rats with severe hearing loss (55 dB shifts) were impaired at discriminating speech sounds in the presence of background noise. Rats with profound hearing loss (70 dB shifts) were unable to detect and discriminate speech sounds above chance level performance. Across groups, ABR threshold accurately predicted behavioral performance on all tasks. This model of long-term impaired speech discrimination in noise, demonstrated by the severe group, mimics the most common clinical presentation of NIHL and represents a useful tool for developing and improving interventions to target restoration of hearing.

Resveratrol prevents lipopolysaccharide-induced cognitive impairment in rats through regulation of hippocampal GluA1-containing AMPA receptors

Background: Evidence suggests that dysregulation in AMPA-type glutamate receptors (AMPA-Rs) has been associated with the pathogenesis of Alzheimer's disease (AD), especially during its early phase. Hence, the present study was performed to elucidate the impact of resveratrol (RV) on hippocampal expression of AMPA-Rs in a rat model of AD. Methods: A rat model of cognitive deficits was developed by a stereotactic intracerebroventricular infusion of lipopolysaccharide (LPS) in male Wistar rats (n=24). The LPS+RV30 group (n=12) received intraperitoneal injections of RV (30 mg/kg) at 30 min, 12 h, and 24 h before LPS injection. Meanwhile, the model (LPS) and sham (SO) groups only were treated with the vehicle solution (normal saline containing 1% ethanol). One day after the LPS infusion, the mRNA expressions of AMPA-Rs subunits (Gria1-4) were evaluated by RT–PCR. In addition, hippocampal levels of lipid peroxidation, superoxide dismutase, and nitric oxide were assessed. Seven days after the LPS challenge, the remaining animals (n=6 each group) were subjected to the Y-maze task, and the expression and localization of GluA1-containing AMPA-Rs in their hippocampi were investigated immunohistochemically. Results: Pretreatment with RV prevented LPS-induced cognitive dysfunction in rats and enhanced their working memory performance. Moreover, RV could moderately prevent oxidant-antioxidant imbalance in rats' hippocampi. RT-PCR results revealed that the hippocampal mRNA expression of the Gria1 was significantly reduced, while the expressions of Gria2 and Gria3 were increased in LPS-challenged rats. RV significantly modulated the alteration in the Gria1 mRNA expression; however, it could not influence the Gria2 and Gria3 mRNA expressions. The immunohistochemical assessment showed a significantly reduced immunoreactivity for GluA1-containing AMPA-Rs in all hippocampal subfields of the LPS group, and RV could effectively ameliorate the alteration. Conclusion: This study is the first to report that RV could modulate GluA1-containing AMPA-Rs dysregulation in a rat AD model.

Rat Models of Vocal Deficits in Parkinson's Disease.

Parkinson’s disease (PD) is a progressive, degenerative disorder that affects 10 million people worldwide. More than 90% of individuals with PD develop hypokinetic dysarthria, a motor speech disorder that impairs vocal communication and quality of life. Despite the prevalence of vocal deficits in this population, very little is known about the pathological mechanisms underlying this aspect of disease. As such, effective treatment options are limited. Rat models have provided unique insights into the disease-specific mechanisms of vocal deficits in PD. This review summarizes recent studies investigating vocal deficits in 6-hydroxydopamine (6-OHDA), alpha-synuclein overexpression, DJ1-/-, and Pink1-/- rat models of PD. Model-specific changes to rat ultrasonic vocalization (USV), and the effects of exercise and pharmacologic interventions on USV production in these models are discussed.

Fatigue risk management based on self-reported fatigue: Expanding a biomathematical model of fatigue-related performance deficits to also predict subjective sleepiness

Biomathematical models of fatigue can be used to predict neurobehavioral deficits during sleep/wake or work/rest schedules. Current models make predictions for objective performance deficits and/or subjective sleepiness, but known differences in the temporal dynamics of objective versus subjective outcomes have not been addressed. We expanded a biomathematical model of fatigue previously developed to predict objective performance deficits as measured on the Psychomotor Vigilance Test (PVT) to also predict subjective sleepiness as self-reported on the Karolinska Sleepiness Scale (KSS). Four model parameters were re-estimated to capture the distinct dynamics of the KSS and account for the scale difference between KSS and PVT. Two separate ensembles of datasets – drawn from laboratory studies of sleep deprivation, sleep restriction, simulated night work, napping, and recovery sleep – were used for calibration and subsequent validation of the model for subjective sleepiness. The expanded model was found to exhibit high prediction accuracy for subjective sleepiness, while retaining high prediction accuracy for objective performance deficits. Application of the validated model to an example scenario based on cargo aviation operations revealed divergence between predictions for objective and subjective outcomes, with subjective sleepiness substantially underestimating accumulating objective impairment, which has important real-world implications. In safety-sensitive operations such as commercial aviation, where self-ratings of sleepiness are used as part of fatigue risk management, the systematic differences in the temporal dynamics of objective versus subjective measures of functional impairment point to a potentially significant risk evaluation sensitivity gap. The expanded biomathematical model of fatigue presented here provides a useful quantitative tool to bridge this previously unrecognized gap.

Therapeutic Potential of Cannabidiol and WIN 55, 212‐2‐mesylate for Treatment of Anxiety

As the medicalization of marijuana occurs across the United States, the psychoactive component of the cannabis plant, Delta9-Tetrahydrocannabinol (THC), has gained recognition for its therapeutic potential. Meanwhile, its non-psychoactive counterpart, cannabidiol (CBD), has been marketed to treat Parkinson's disease, Chron's disease, dystonia, attention-deficit hyperactivity disorder (ADHD), inflammation, depression, fibromyalgia, epilepsy, and most commonly, anxiety. Given the over the counter accessibility of CBD and the fact that anxiety disorders are the most common type of mental illness in the United States, our objective was to access the therapeutic potential of cannabinoid receptor agonists and antagonists for treatment of anxiety. We hypothesized that CBD might be anxiolytic when chronically administered to a newly found mouse model of anxiety and attention deficit (Kv1.3-/- mice). Similarly to THC, WIN 55, 212-2-mesylate (WIN) is an agonist for the cannabinoid receptors CB1 and CB2, but it is not known to have any psychoactive properties. CBD is an antagonist for CB1 and CB2 receptors, and we used a CBD isolate to ensure purity. Our methods employed two-month-old Kv1.3-/- or wildtype mice that were phenotyped for anxiety behaviors using three assays, namely the elevated plus maze (EPM), the light-dark box (LDB), and the marble burying test. Mice were dosed daily, 30 minutes prior to performing a behavioral test. Mice of both sexes were separated into cohorts in which they were designated to receive an intraperitoneal injection of either drug (WIN55 = 1 mg/kg; CBD = 5 mg/kg) or vehicle solution at equivalent volume. Acute cohorts were defined as daily dosage for 5 days and chronic cohorts were treated with 20 doses over a 30 day interval. Without drug treatment, both genotypes exhibited anxiety-like behaviors in the LDB and EPM tasks, preferring dark side or closed arms of the apparatuses, respectively. For acute WIN treatment, Kv1.3-/- mice showed lessened anxiety in the LDB (increased time in light, decreased time in dark), however, following chronic WIN treatment, they showed no change in LDB behavior. In contrast, in wildtype mice, neither acute nor chronic WIN treatment changed LDB behaviors. Both acute and chronic WIN treatment in Kv1.3-/- mice mitigated anxiety in the EPM test (mice decreased time in the closed arms), whereas the same in wildtype mice showed no effect of anxiety if acutely administered and heightened anxiety following chronic treatment (mice increased time in closed arms). For cohorts treated acutely with CBD, Kv1.3-/- mice showed enhanced anxiety behaviors in the LDB (mice decreased time in light and increased time in dark). Mice of both genotypes showed enhanced anxiety behaviors in the EPM (mice increased time in the closed arms) following acute CBD treatment.In conclusion, our data did not support our hypothesis and showed that CBD may act as an anxiogenic drug in both wildtype and Kv1.3-/- mice.WIN acted as an anxiolytic drug for mice with trait anxiety (Kv1.3-/-), which was ineffective in these mice long-term, and ineffective acutely in wildtype mice exposed to state anxiety.

NMDA Receptors Antagonist Prevents Memory Deficit Produced by Reconsolidation Impairment in Young Chicks

Alzheimer's disease is the most common cause of dementia. Despite numerous studies of its pathogenesis, processes leading to memory decay in Alzheimer's disease and tactics for its prevention are still in infancy. Here we propose a new hypothesis of memory autodegradation process in the brain compromised by neurodegeneration. A retrieval of an old consolidated memory, especially under conditions of novelty can render it to a labile form. This requires subsequent repeated consolidation, or reconsolidation. We argue that when an old memory is retrieved in the brain where reconsolidation processes are impaired by neurodegeneration, the original memory does not stabilize and degrades. Thus, being activated in a pathologically altered brain, memory trace weakens itself. If this suggestion is correct, then autodegradation of old memory in the impaired brain can be prevented by inhibiting its labilization during the retrieval. We started testing this hypothesis by employing a behavioral model of memory deficit produced by pharmacological impairment of memory reconsolidation in a one-trial passive avoidance learning model in young chicks (Gallus gallus domesticus). In previous experiments we demonstrated that retrieval of the passive avoidance memory paired with administration of a protein synthesis inhibitor anisomycin (ANI) or a glycosylation inhibitor 2-deoxygalactose (2DGal) resulted in the recall deficit. Here, we tested whether this memory impairment could be rescued by prevention of the memory labilization process. Two-days old chicks were trained in the passive avoidance learning model. Two hours after the training they were presented with a reminder paired with bilateral intraventricular administration of ANI (80 mkg) or 2DGal (3.28 mg) 5 min prior to the reminder. Additionally, 30 min before the reminder the animals received systemic administration of a non-competitive NMDA receptors antagonist MK801 (0.3 mg/kg) in order to access the possibility to prevent memory labilization and its effect. The control groups received physiological saline intraventricularly and intraperitoneally. The avoidance recall was tested 2 h after the reminder. The avoidance recall was significantly impaired in the animals which received ANI or 2DGal 5 min before the reminder as compared with control groups receiving no reminder or reminder coupled with physiological saline injection. Thus, inhibition of protein synthesis or glycoprotein fucosylation prevented reconsolidation of the reactivated memory producing amnesia. However, administration of NMDA antagonist MK801 prior to the inhibitor/reminder treatment prevented memory impairment resulting in high avoidance level that did not differ from the control groups recall. Thus, we have shown that memory deficit produced by memory retrieval under conditions of impaired protein synthesis can be protected by the preceding administration of NMDA receptor antagonist. We suggest that this effect might be due to prevention of reminder-induces memory trace destabilization which preserved the integrity of the original memory trace.

Systems genetic analysis of nicotine withdrawal deficits in hippocampus-dependent learning.

Cognitive deficits, such as disrupted learning, are a major symptom of nicotine withdrawal. These deficits are heritable, yet their genetic basis is largely unknown. Our lab has developed a mouse model of nicotine withdrawal deficits in learning, using chronic nicotine exposure via osmotic minipumps and fear conditioning. Here, we utilized the BXD genetic reference panel to identify genetic variants underlying nicotine withdrawal deficits in learning. Male and female mice (n = 6-11 per sex per strain, 31 strains) received either chronic saline or nicotine (6.3 mg/kg per day for 12 days), and were then tested for hippocampus-dependent learning deficits using contextual fear conditioning. Quantitative trait locus (QTL) mapping analyses using GeneNetwork identified a significant QTL on Chromosome 4 (82.13 Mb, LRS = 20.03, p < 0.05). Publicly available hippocampal gene expression data were used to identify eight positional candidates (Snacpc3, Mysm1, Rps6, Plaa, Lurap1l, Slc24a2, Hacd4, Ptprd) that overlapped with our behavioral QTL and correlated with our behavioral data. Overall, this study demonstrates that genetic factors impact cognitive deficits during nicotine withdrawal in the BXD recombinant inbred panel and identifies candidate genes for future research.

Effects of Dizocilpine, Midazolam and Their Co-Application on the Trimethyltin (TMT)-Induced Rat Model of Cognitive Deficit.

Research of treatment options addressing the cognitive deficit associated with neurodegenerative disorders is of particular importance. Application of trimethyltin (TMT) to rats represents a promising model replicating multiple relevant features of such disorders. N-methyl-D-aspartate (NMDA) receptor antagonists and gamma-aminobutyric acid type A (GABAA) receptor potentiators have been reported to alleviate the TMT-induced cognitive deficit. These compounds may provide synergistic interactions in other models. The aim of this study was to investigate, whether co-application of NMDA receptor antagonist dizocilpine (MK-801) and GABAA receptor potentiator midazolam would be associated with an improved effect on the TMT-induced model of cognitive deficit. Wistar rats injected with TMT were repeatedly (12 days) treated with MK-801, midazolam, or both. Subsequently, cognitive performance was assessed. Finally, after a 17-day drug-free period, hippocampal neurodegeneration (neuronal density in CA2/3 subfield in the dorsal hippocampus, dentate gyrus morphometry) were analyzed. All three protective treatments induced similar degree of therapeutic effect in Morris water maze. The results of histological analyses were suggestive of minor protective effect of the combined treatment (MK-801 and midazolam), while these compounds alone were largely ineffective at this time point. Therefore, in terms of mitigation of cognitive deficit, the combined treatment was not associated with improved effect.

Blood-brain barrier integrity is the primary target of alcohol abuse

The effects of long-term alcohol consumptions on cognitive function remain elusive with contradictory results. Whilst it is widely accepted that long-term intoxication can cause cognitive impairment, moderate drinking can improve cognitive function. In reality, many older people and those with chronic medical conditions are long-term alcohol consumers in Asian countries. Our previous studies have suggested that long-term alcohol consumption can damage blood-brain barrier (BBB) integrity and aggravate cognitive deficit in APPswe/PS1De9 mice, but little is known about the underlying mechanisms, especially whether this consumption can cause cognitive decline via aggravating BBB damage in people who are exposed to the risk factors for cognitive disorders such as aging or inflammation. These questions were addressed in this study. The mouse models of cognitive deficit induced by d-galactose or lipopolysaccharide, the important risk conditions in human on cognitive function, were used to evaluate the effects of long-term alcohol consumption on the BBB integrity. After alcohol administration for 30 days in these models the BBB integrity was significantly destroyed with remarkably increased permeability and down-regulated protein expression of zonula occludens-1, VE-cadherin, occludin, low-density lipoprotein receptor-related protein-1, receptor for advanced glycation end products, major facilitator superfamily domain-containing protein-2a and aquaporin-4, which is the most closely related with the structure and function of BBB integrity. Meanwhile, the level of oxidative stress in d-galactose mice or inflammatory factors in cortex and serum in lipopolysaccharide mice, which might be involved in the cognitive dysfunctions, was significantly amplified. Furthermore, the impaired memory and hippocampal neuron damage induced by d-galactose and lipopolysaccharide were concurrently aggravated. Collectively, our study provided novel and compelling evidence that the structural and functional proteins for BBB integrity may be the primary targets for the detrimental effects of alcohol abuse that lead to cognitive dysfunction and neurological deficits in high risk populations.

Conceptual uncertainties in groundwater and porewater fluxes estimated by radon and radium mass balances

AbstractRadium isotopes and radon are routinely used as tracers to quantify groundwater and porewater fluxes into coastal and freshwater systems. However, uncertainties associated with the determination of the tracer flux are often poorly addressed and often neglect all the potential errors associated with the conceptualization of the system (i.e., conceptual uncertainties). In this study, we assess the magnitude of some of the key uncertainties related to the determination of the radium and radon inputs supplied by groundwater and porewater fluxes into a waterbody (La Palme Lagoon, France). This uncertainty assessment is addressed through a single model ensemble approach, where a tracer mass balance is run multiple times with variable sets of assumptions and approaches for the key parameters determined through a sensitivity test. In particular, conceptual uncertainties linked to tracer concentration, diffusive fluxes, radon evasion to the atmosphere, and change of tracer inventory over time were considered. The magnitude of porewater fluxes is further constrained using a comparison of independent methods: (1) 224Ra and (2) 222Rn mass balances in overlying waters, (3) a model of 222Rn deficit in sediments, and (4) a fluid‐salt numerical transport model. We demonstrate that conceptual uncertainties are commonly a major source of uncertainty on the estimation of groundwater or porewater fluxes and they need to be taken into account when using tracer mass balances. In the absence of a general framework for assessing these uncertainties, this study provides a practical approach to evaluate key uncertainties associated to radon and radium mass balances.

DNA repair pathways are altered in neural cell models of frataxin deficiency

Friedreich's ataxia (FRDA) is a hereditary and predominantly neurodegenerative disease caused by a deficiency of the protein frataxin (FXN). As part of the overall efforts to understand the molecular basis of neurodegeneration in FRDA, a new human neural cell line with doxycycline-induced FXN knockdown was established. This cell line, hereafter referred to as iFKD-SY, is derived from the human neuroblastoma SH-SY5Y and retains the ability to differentiate into mature neuron-like cells. In both proliferating and differentiated iFKD-SY cells, the induction of FXN deficiency is accompanied by increases in oxidative stress and DNA damage, reduced aconitase enzyme activity, higher levels of p53 and p21, activation of caspase-3, and subsequent apoptosis. More interestingly, FXN-deficient iFKD-SY cells exhibit an important transcriptional deregulation in many of the genes implicated in DNA repair pathways. The levels of some crucial proteins involved in DNA repair appear notably diminished. Furthermore, similar changes are found in two additional neural cell models of FXN deficit: primary cultures of FXN-deficient mouse neurons and human olfactory mucosa stem cells obtained from biopsies of FRDA patients. These results suggest that the deficiency of FXN leads to a down-regulation of DNA repair pathways that synergizes with oxidative stress to provoke DNA damage, which may be involved in the pathogenesis of FRDA. Thus, a failure in DNA repair may be considered a shared common molecular mechanism contributing to neurodegeneration in a number of hereditary ataxias including FRDA.

Animal models of attention deficit and hyperactivity disorder: A critical overview and suggestions

Attention deficit and hyperactivity disorder (ADHD) is a neurodevelopmental and neuropsychiatric disorder that appears as a subset of attention deficit and different subspecies in which both occur together and is generally observed in childhood. Pharmacological agents such as atomoxetine and methylphenidate, which are widely used against the disease, appear with different and important side effects. Since the causes of the disease are not clearly understood, many studies are carried out on various animal models in order to both understand the etiology and develop new treatment models. In this review, a holistic approach to ADHD will be presented and advances in animal models, neuroimaging, neurodevelopmental, and neurochemical conditions will be presented using different perspectives. It is very important to understand how different animal models are effective in the development of pharmacological agents. In addition, comparing ADHD with different types of disease can detect similarities and further strengthen the etiological basis. Our major proposal is to draw attention to the further development of animal models related to the importance of the thalamus, which officially sees a filter of perception. Different animal models are needed to do all this because the disease is not fully modeled, except for the symptoms of ADHD. The current review will conclude that none of the currently discussed models meet all the necessary validation criteria, but that newly created genetic models, therapeutic strategies, and the disease mechanism may be radically important points.

Model of radiation-induced ambulatory dysfunction

Approximately 50% of oncology patients receive radiotherapy, with the dose of radiation often being limited to mitigate normal tissue damage of proximal critical/sensitive structures. Currently, no preclinical models exist to study a putative drug's efficacy in terms of functional recovery of tissues adversely effected by radiation exposure. Such limitations inhibit the development of targeted therapeutics. To this end, we developed a model of radiation-induced soft-tissue damage with quantitative outcomes of tissue function. Mice received a single administration of radiation focused on the posterior limb while under anesthesia. A blinded observer weighed each mouse and performed motors skills assessments weekly for the duration of the study. At the end of the study, mice were euthanized, assessed for hindlimb range of motion and histological analysis was performed, evaluating tissue morphology and fibrotic scarring. Mice presented numerous significant ambulatory deficits that positively correlated with the dose of radiation administered. Irradiated mice presented with reduced range of motion and increased fibrotic scarring upon histological assessment across all dose groups as compared to controls. The current study is the first to describe a preclinical model of functional skeletal muscle deficits following focal radiation injury of a posterior limb, which will be useful for the assessment of novel drug candidates to treat radiotherapy-induced soft-tissue damage.

Butyrate alleviates PTZ-induced mitochondrial dysfunction, oxidative stress and neuron apoptosis in mice via Keap1/Nrf2/HO-1 pathway

This study aims to evaluate the neuroprotective effect of sodium butyrate against the pentylenetetrazol (PTZ)-induced kindling epilepsy. Sodium butyrate (SB) (5, 10 and 20 mg/kg) and sodium valproate for 40 days and PTZ (37 mg/kg) injection every day were conducted for Kunming mice, to investigate seizure intensity and latency, oxidative stress parameters, mitochondrial structure and function, histopathology, and Keap1/Nrf2/HO-1 expressions. It is shown that seizure latency was effectively increased and the intensity of seizures decreased by treatment with sodium butyrate. It was also found to reverse the structural disruption of the mitochondria, reduce the ROS level and improve the levels of NAD + and ATP in the brains of epileptic mice. Furthermore, pretreatment with SB led to an increase in antioxidant enzyme activity (CAT, SOD and GSH-PX) in the brain as well as conferred a neuroprotective effect against neuron loss and apoptosis. The activation of Keap1/Nrf2/HO-1 signals was also identified, in which the antiepileptic effect of SB may be partially due to its anti-mitochondrial injury and neuroprotective activities. Accordingly, the results of a series of functional tests indicate a significant improvement of neurological function following SB treatment. In a mouse model of seizures, brain injury and neurological deficits can be attenuated by treatment with butyrate through the activation of Nrf2 pathway and the improvement of mitochondrial function.

Whole brain proton irradiation in adult Sprague Dawley rats produces dose dependent and non-dependent cognitive, behavioral, and dopaminergic effects

Proton radiotherapy causes less off-target effects than X-rays but is not without effect. To reduce adverse effects of proton radiotherapy, a model of cognitive deficits from conventional proton exposure is needed. We developed a model emphasizing multiple cognitive outcomes. Adult male rats (10/group) received a single dose of 0, 11, 14, 17, or 20 Gy irradiation (the 20 Gy group was not used because 50% died). Rats were tested once/week for 5 weeks post-irradiation for activity, coordination, and startle. Cognitive assessment began 6-weeks post-irradiation with novel object recognition (NOR), egocentric learning, allocentric learning, reference memory, and proximal cue learning. Proton exposure had the largest effect on activity and prepulse inhibition of startle 1-week post-irradiation that dissipated each week. 6-weeks post-irradiation, there were no effects on NOR, however proton exposure impaired egocentric (Cincinnati water maze) and allocentric learning and caused reference memory deficits (Morris water maze), but did not affect proximal cue learning or swimming performance. Proton groups also had reduced striatal levels of the dopamine transporter, tyrosine hydroxylase, and the dopamine receptor D1, effects consistent with egocentric learning deficits. This new model will facilitate investigations of different proton dose rates and drugs to ameliorate the cognitive sequelae of proton radiotherapy.