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Glutamate delta-1 (GluD1) receptors are expressed throughout the forebrain during development with high levels in the hippocampus during adulthood. We have recently shown that deletion of GluD1 receptor results in aberrant emotional and social behaviors such as hyperaggression and depression-like behaviors and social interaction deficits. Additionally, abnormal expression of synaptic proteins was observed in amygdala and prefrontal cortex of GluD1 knockout mice (GluD1 KO). However the role of GluD1 in learning and memory paradigms remains unknown. In the present study we evaluated GluD1 KO in learning and memory tests. In the eight-arm radial maze GluD1 KO mice committed fewer working memory errors compared to wildtype mice but had normal reference memory. Enhanced working memory in GluD1 KO was also evident by greater percent alternation in the spontaneous Y-maze test. No difference was observed in object recognition memory in the GluD1 KO mice. In the Morris water maze test GluD1 KO mice showed no difference in acquisition but had longer latency to find the platform in the reversal learning task. GluD1 KO mice showed a deficit in contextual and cue fear conditioning but had normal latent inhibition. The deficit in contextual fear conditioning was reversed by D-Cycloserine (DCS) treatment. GluD1 KO mice were also found to be more sensitive to foot-shock compared to wildtype. We further studied molecular changes in the hippocampus, where we found lower levels of GluA1, GluA2 and GluK2 subunits while a contrasting higher level of GluN2B in GluD1 KO. Additionally, we found higher postsynaptic density protein 95 (PSD95) and lower glutamate decarboxylase 67 (GAD67) expression in GluD1 KO. We propose that GluD1 is crucial for normal functioning of synapses and absence of GluD1 leads to specific abnormalities in learning and memory. These findings provide novel insights into the role of GluD1 receptors in the central nervous system.

The delta family of ionotropic glutamate receptors consists of glutamate δ1 (GluD1) and glutamate δ2 (GluD2) receptors. While the role of GluD2 in the regulation of cerebellar physiology is well understood, the function of GluD1 in the central nervous system remains elusive. We demonstrate for the first time that deletion of GluD1 leads to abnormal emotional and social behaviors. We found that GluD1 knockout mice (GluD1 KO) were hyperactive, manifested lower anxiety-like behavior, depression-like behavior in a forced swim test and robust aggression in the resident-intruder test. Chronic lithium rescued the depression-like behavior in GluD1 KO. GluD1 KO mice also manifested deficits in social interaction. In the sociability test, GluD1 KO mice spent more time interacting with an inanimate object compared to a conspecific mouse. D-Cycloserine (DCS) administration was able to rescue social interaction deficits observed in GluD1 KO mice. At a molecular level synaptoneurosome preparations revealed lower GluA1 and GluA2 subunit expression in the prefrontal cortex and higher GluA1, GluK2 and PSD95 expression in the amygdala of GluD1 KO. Moreover, DCS normalized the lower GluA1 expression in prefrontal cortex of GluD1 KO. We propose that deletion of GluD1 leads to aberrant circuitry in prefrontal cortex and amygdala owing to its potential role in presynaptic differentiation and synapse formation. Furthermore, these findings are in agreement with the human genetic studies suggesting a strong association of GRID1 gene with several neuropsychiatric disorders including schizophrenia, bipolar disorder, autism spectrum disorders and major depressive disorder.

Despite strong evidence for NMDA receptor (NMDAR) hypofunction as an underlying factor for cognitive disorders, the precise roles of various NMDAR subtypes remains unknown. The GluN2C-containing NMDARs exhibit unique biophysical properties and expression pattern, and lower expression of GluN2C subunit has been reported in postmortem brains from schizophrenia patients. We found that loss of GluN2C subunit leads to a shift in cortical excitatory-inhibitory balance towards greater inhibition. Specifically, pyramidal neurons in the medial prefrontal cortex (mPFC) of GluN2C knockout mice have reduced mEPSC frequency and dendritic spine density and a contrasting higher frequency of mIPSCs. In addition a greater number of perisomatic GAD67 puncta was observed suggesting a potential increase in parvalbumin interneuron inputs. At a network level the GluN2C knockout mice were found to have a more robust increase in power of oscillations in response to NMDAR blocker MK-801. Furthermore, GluN2C heterozygous and knockout mice exhibited abnormalities in cognition and sensorimotor gating. Our results demonstrate that loss of GluN2C subunit leads to cortical excitatory-inhibitory imbalance and abnormal neuronal oscillations associated with neurodevelopmental disorders.

Opioid-seeking behaviors depend on glutamatergic plasticity in the nucleus accumbens core (NAcc). Here we investigated whether the behavioral and synaptic effects of opioids are influenced by acid-sensing ion channel 1A (ASIC1A). We tested the effects of ASIC1A on responses to several opioids and found that Asic1a−/− mice had elevated behavioral responses to acute opioid administration as well as opioid seeking behavior in conditioned place preference (CPP). Region-restricted restoration of ASIC1A in NAcc was sufficient to reduce opioid CPP, suggesting NAcc is an important site of action. We next tested the effects of oxycodone withdrawal on dendritic spines in NAcc. We found effects of oxycodone and ASIC1A that contrasted with changes previously described following cocaine withdrawal. Finally, we examined α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated and N-methyl-D-aspartic acid (NMDA) receptor-mediated synaptic currents in NAcc. Oxycodone withdrawal, like morphine withdrawal, increased the AMPAR/NMDAR ratio in Asic1a+/+ mice, whereas oxycodone withdrawal reduced the AMPAR/NMDAR ratio in Asic1a−/− mice. A single dose of oxycodone was sufficient to induce this paradoxical effect in Asic1a−/− mice, suggesting an increased sensitivity to oxycodone. We conclude that ASIC1A plays an important role in the behavioral and synaptic effects of opioids and may constitute a potential future target for developing novel therapies.

RationaleThe infralimbic cortex (IL) and its downstream projection target the nucleus accumbens shell (NAshell) mediate the active suppression of cocaine-seeking behavior. Although an optogenetic approach would be beneficial for stimulating the IL and its efferents to study their role during reinstatement of cocaine seeking, the use of channelrhodopsin introduces significant difficulties, as optimal stimulation parameters are not known.ObjectivesThe present experiments utilized a stable step-function opsin (SSFO) to potentiate endogenous activity in the IL and in IL terminals in the NAshell during cocaine-seeking tests to determine how these manipulations affect cocaine-seeking behaviors.MethodsRats first underwent 6-h access cocaine self-administration followed by 21–27 days in the homecage. Rats then underwent cue-induced and cocaine-primed drug-seeking tests during which the optogenetic manipulation was given. The same rats then underwent extinction training, followed by cue-induced and cocaine-primed reinstatements.ResultsPotentiation of endogenous IL activity did not significantly alter cue-induced or cocaine-primed drug seeking following the homecage period. However, following extinction training, enhancement of endogenous IL activity attenuated cue-induced reinstatement by 35% and cocaine-primed reinstatement by 53%. Stimulation of IL terminals in the NAshell did not consistently alter cocaine-seeking behavior.ConclusionThese results suggest the utility of an SSFO-based approach for enhancing activity in a structure without driving specific patterns of neuronal firing. However, the utility of an SSFO-based approach for axon terminal stimulation remains unclear. Moreover, these results suggest that the ability of the IL to reduce cocaine seeking depends, at least in part, on rats first having undergone extinction training.

Introduction: Brain tumor, marked by abnormal and rapid cell growth, poses severe health risks and requires accurate diagnosis for effective treatment. Classifying brain tumors using deep learning techniques applied to Magnetic Resonance Imaging (MRI) images has attracted the attention of many researchers, and specifically, reducing the bias of models and enhancing robustness is still a very pertinent active topic of attention. Methods: For capturing diverse information from different feature sets, we propose a Features Concatenation-based Brain Tumor Classification (FCBTC) Framework using Hybrid Deep Learning Models. For this, we have chosen three pretrained models—ResNet50; VGG16; and DensetNet121—as the baseline models. Our proposed hybrid models are built by the fusion of feature vectors. Results: The testing phase results show that, for the FCBTC Model-3, values for Precision, Recall, F1-score, and Accuracy are 98.33%, 98.26%, 98.27%, and 98.40%, respectively. This reinforces our idea that feature diversity does improve the classifier’s performance. Conclusions: Comparative performance evaluation of our work shows that, the proposed hybrid FCBTC Models have performed better than other proposed baseline models.

MYCN (master regulator of cell cycle entry and proliferative metabolism) gene amplification defines a molecular subgroup of spinal cord ependymomas that show high-grade morphology and aggressive behavior. Demonstration of MYCN amplification by DNA methylation or fluorescence-in situ hybridization (FISH) is required for diagnosis. We aimed to (i) assess prevalence and clinicopathological features of MYCN -amplified spinal ependymomas and (ii) evaluate utility of immunohistochemistry (IHC) for MYCN protein as a surrogate for molecular testing. A combined retrospective–prospective study spanning 8 years was designed during which all spinal cord ependymomas with adequate tissue were subjected to MYCN FISH and MYCN IHC. Among 77 spinal cord ependymomas included, MYCN amplification was identified in 4 samples from 3 patients (3/74, 4%) including two (1st and 2nd recurrences) from the same patient. All patients were adults (median age at diagnosis of 32 years) including two females and one male. The index tumors were located in thoracic ( n  = 2) and lumbar ( n  = 1) spinal cord. One of the female patients had neurofibromatosis type 2 (NF2). All four tumors showed anaplastic histology. Diffuse expression of MYCN protein was seen in all four MYCN- amplified samples but in none of the non-amplified cases, thus showing 100% concordance with FISH results. On follow-up, the NF2 patient developed widespread spinal dissemination while another developed recurrence proximal to the site of previous excision. To conclude, MYCN -amplified spinal ependymomas are rare tumors, accounting for ~ 4% of spinal cord ependymomas. Within the limitation of small sample size, MYCN IHC showed excellent concordance with MYCN gene amplification.

Art encompasses a wide variety of human endeavours and their outputs, all of which include the exercise of creative or inventive aptitude and aim to convey some aspect of technical mastery, aesthetic excellence, emotional impact, or intellectual complexity. Art has been understood quite differently by different people at different times throughout history and in different cultures. Traditional Western visual arts include the mediums of sculpture, architecture, and art. A larger description of the arts would encompass not just the visual arts, but also literature, music, cinema, and other multimedia like interactive media. Before the 17th century, there was no clear demarcation between the arts and the sciences; all forms of expertise were considered to be art. In contemporary use, which emerged from the 17th century and places a premium on aesthetics, fine arts are considered to be distinct from other types of learned expertise, such as decorative or practical arts.

Background and Aims: Viscoelastic tests such as rotational thromboelastometry (ROTEM) provide a quick and holistic assessment of coagulation status to guide transfusion during liver transplant (LT). Conventional coagulation tests (CCTs) measure single parameters in isolation, and also the results are delayed hampering management of patients during surgery. We evaluated the correlation of early ROTEM-derived parameters with CCTs and also assessed the ability of ROTEM-derived parameters to predict thrombocytopaenia and hypofibrinogenaemia during LT in patients with end-stage liver disease (ESLD). Methods: This retrospective study was carried out in 100 patients with decompensated ESLD undergoing LT. Correlation between CCTs and ROTEM parameters was analyzed. Receiver operating characteristic curves with area under the curve were used to determine the cut-off values of A5 andA10 on EXTEM and FIBTEM. Results: The values of A5EXTEM and A10EXTEM highly correlated with fibrinogen levels and platelet count, whereas A5FIBTEM and A10FIBTEM correlated well with fibrinogen levels. A5EXTEM<21 mm and A10EXTEM<28 mm correlated with a platelet count <75,000 mm−3, whereas A5EXTEM<18 mm and A10EXTEM<25 mm correlated with a platelet count <50,000 mm−3. Fibrinogen levels <100 mg/dL better correlated with A5FIBTEM<5 mm, A10FIBTEM<6 mm, A5EXTEM<21 mm and A10EXTEM<30 mm. Conclusion: Early ROTEM parameters A5 and A10 of both EXTEM and FIBTEM had an excellent correlation with thrombocytopaenia and hypofibrinogenaemia and may potentially guide early transfusion of relevant blood products during LT.