ResearchPad - hippocampus https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Diffusion MRI reveals in vivo and non-invasively changes in astrocyte function induced by an aquaporin-4 inhibitor]]> https://www.researchpad.co/article/elastic_article_14694 The Glymphatic System (GS) has been proposed as a mechanism to clear brain tissue from waste. Its dysfunction might lead to several brain pathologies, including the Alzheimer’s disease. A key component of the GS and brain tissue water circulation is the astrocyte which is regulated by acquaporin-4 (AQP4), a membrane-bound water channel on the astrocytic end-feet. Here we investigated the potential of diffusion MRI to monitor astrocyte activity in a mouse brain model through the inhibition of AQP4 channels with TGN-020. Upon TGN-020 injection, we observed a significant decrease in the Sindex, a diffusion marker of tissue microstructure, and a significant increase of the water diffusion coefficient (sADC) in cerebral cortex and hippocampus compared to saline injection. These results indicate the suitability of diffusion MRI to monitor astrocytic activity in vivo and non-invasively.

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<![CDATA[Differences in splicing defects between the grey and white matter in myotonic dystrophy type 1 patients]]> https://www.researchpad.co/article/elastic_article_14627 Myotonic dystrophy type 1 (DM1) is a multi-system disorder caused by CTG repeats in the myotonic dystrophy protein kinase (DMPK) gene. This leads to the sequestration of splicing factors such as muscleblind-like 1/2 (MBNL1/2) and aberrant splicing in the central nervous system. We investigated the splicing patterns of MBNL1/2 and genes controlled by MBNL2 in several regions of the brain and between the grey matter (GM) and white matter (WM) in DM1 patients using RT-PCR. Compared with amyotrophic lateral sclerosis (ALS, as disease controls), the percentage of spliced-in parameter (PSI) for most of the examined exons were significantly altered in most of the brain regions of DM1 patients, except for the cerebellum. The splicing of many genes was differently regulated between the GM and WM in both DM1 and ALS. In 7 out of the 15 examined splicing events, the level of PSI change between DM1 and ALS was significantly higher in the GM than in the WM. The differences in alternative splicing between the GM and WM may be related to the effect of DM1 on the WM of the brain.

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<![CDATA[Early correction of synaptic long-term depression improves abnormal anxiety-like behavior in adult GluN2B-C456Y-mutant mice]]> https://www.researchpad.co/article/elastic_article_13831 Mice that carry a heterozygous, autism spectrum disorder-risk C456Y mutation in the NMDA receptor (NMDAR) subunit GluN2B show decreased protein levels, hippocampal NMDAR currents, and NMDAR-dependent long-term depression and have abnormal anxiolytic-like behavior. Early, but not late, treatment of the young mice with the NMDAR agonist D-cycloserine rescues these phenotypes.

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<![CDATA[Proteomic analysis of protein composition of rat hippocampus exposed to morphine for 10 days; comparison with animals after 20 days of morphine withdrawal]]> https://www.researchpad.co/article/N2838fdc6-dc33-429a-ba0d-e2e831e6a950

Opioid addiction is recognized as a chronic relapsing brain disease resulting from repeated exposure to opioid drugs. Cellular and molecular mechanisms underlying the ability of organism to return back to the physiological norm after cessation of drug supply are not fully understood. The aim of this work was to extend our previous studies of morphine-induced alteration of rat forebrain cortex protein composition to the hippocampus. Rats were exposed to morphine for 10 days and sacrificed 24 h (groups +M10 and −M10) or 20 days after the last dose of morphine (groups +M10/−M20 and −M10/−M20). The six altered proteins (≥2-fold) were identified in group (+M10) when compared with group (−M10) by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). The number of differentially expressed proteins was increased to thirteen after 20 days of the drug withdrawal. Noticeably, the altered level of α-synuclein, β-synuclein, α-enolase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was also determined in both (±M10) and (±M10/−M20) samples of hippocampus. Immunoblot analysis of 2D gels by specific antibodies oriented against α/β-synucleins and GAPDH confirmed the data obtained by 2D-DIGE analysis. Label-free quantification identified nineteen differentially expressed proteins in group (+M10) when compared with group (−M10). After 20 days of morphine withdrawal (±M10/−M20), the number of altered proteins was increased to twenty. We conclude that the morphine-induced alteration of protein composition in rat hippocampus after cessation of drug supply proceeds in a different manner when compared with the forebrain cortex. In forebrain cortex, the total number of altered proteins was decreased after 20 days without morphine, whilst in hippocampus, it was increased.

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<![CDATA[Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study]]> https://www.researchpad.co/article/Nf62c48b8-7c01-44cc-9110-a611b974b3f9

Background

There is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways.

Methods and findings

We first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus [ITG] and middle frontal gyrus [MFG]), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) (neuritic plaque burden), and Braak (neurofibrillary pathology) scores. We found significant alterations in concentrations of metabolites in AD relative to CN samples, as well as associations with severity of both CERAD and Braak, mainly in the ITG. These metabolites represented biochemical reactions in the (1) methionine cycle (choline: lower in AD, p = 0.003; S-adenosyl methionine: higher in AD, p = 0.005); (2) transsulfuration and glutathione synthesis (cysteine: higher in AD, p < 0.001; reduced glutathione [GSH]: higher in AD, p < 0.001); (3) polyamine synthesis/catabolism (spermidine: higher in AD, p = 0.004); (4) urea cycle (N-acetyl glutamate: lower in AD, p < 0.001); (5) glutamate-aspartate metabolism (N-acetyl aspartate: lower in AD, p = 0.002); and (6) neurotransmitter metabolism (gamma-amino-butyric acid: lower in AD, p < 0.001). Utilizing three Gene Expression Omnibus (GEO) datasets, we then examined mRNA expression levels of 71 genes encoding enzymes regulating key reactions within these pathways in the entorhinal cortex (ERC; AD: n = 25; CN: n = 52) and hippocampus (AD: n = 29; CN: n = 56). Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression levels of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. Our study has limitations: our metabolomics assays measured only a small proportion of all metabolites participating in the pathways we examined. Our study is also cross-sectional, limiting our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression. Additionally, the relatively small number of brain tissue samples may have limited our power to detect alterations in all pathway-specific metabolites and their genetic regulators.

Conclusions

In this study, we observed broad dysregulation of transmethylation and polyamine synthesis/catabolism, including abnormalities in neurotransmitter signaling, urea cycle, aspartate-glutamate metabolism, and glutathione synthesis. Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to AD.

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<![CDATA[Trans ε viniferin decreases amyloid deposits and inflammation in a mouse transgenic Alzheimer model]]> https://www.researchpad.co/article/5c76fe09d5eed0c484e5b330

As Alzheimer’s disease (AD) induces several cellular and molecular damages, it could be interesting to use multi-target molecules for therapeutics. We previously published that trans ε-viniferin induced the disaggregation of Aβ42 peptide and inhibited the inflammatory response in primary cellular model of AD. Here, effects of this stilbenoid were evaluated in transgenic APPswePS1dE9 mice. We report that trans ε-viniferin could go through the blood brain barrier, reduces size and density of amyloid deposits and decreases reactivity of astrocytes and microglia, after a weekly intraperitoneal injection at 10 mg/kg from 3 to 6 months of age.

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<![CDATA[A neural hallmark of auditory implicit learning is altered in older adults]]> https://www.researchpad.co/article/5c5b5256d5eed0c4842bc694

Temporal regularities in the environment are often learned implicitly. In an auditory target-detection paradigm using EEG, Jongsma and colleagues (2006) showed that the neural response to these implicit regularities results in a reduction of the P3-N2 complex. Here, we utilized the same paradigm, this time in both young and old participants, to determine if this EEG signature of implicit learning was altered with age. Behaviorally, both groups of participants showed similar benefits for the presence of temporal regularity, with faster and more accurate responses given when the auditory targets were presented in a temporally regular vs. random pattern. In the brain, the younger adults showed the expected decrease in amplitude of this complex for regular compared to irregular trials. Older adults, in contrast, showed no difference in the amplitude of the P3-N2 complex between the irregular and regular condition. These data suggest that, although auditory implicit learning may be behaviorally spared in aging, older adults are not using the same neural substrates as younger adults to achieve this.

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<![CDATA[Long-term Chinese calligraphic handwriting training has a positive effect on brain network efficiency]]> https://www.researchpad.co/article/5c79afcdd5eed0c4841e37a3

As a visual art form, Chinese calligraphic handwriting (CCH) has been found to correlate with certain brain activity and to induce functional connectivity reorganization of the brain. This study investigated the effect of long-term CCH training on brain functional plasticity as assessed with network measures. With the resting-state fMRI data from 31 participants with at least five years of CCH training and 40 controls, we constructed brain functional networks, examined group differences at both the whole brain and modular levels, and correlated the topological characteristics with calligraphy skills. We found that, compared to the control group, the CCH group showed shorter characteristic path lengths and higher local efficiency in certain brain areas in the frontal and parietal cortices, limbic system, basal ganglia, and thalamus. Moreover, these network measures in the cingulate cortex, caudate nucleus, and thalamus were associated with CCH performance (i.e., copying and creating skills). These results suggest that long-term CCH training has a positive effect on the topological characteristics of brain networks.

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<![CDATA[Large-scale network interactions supporting item-context memory formation]]> https://www.researchpad.co/article/5c40f760d5eed0c484385fe2

Episodic memory is thought to involve functional interactions of large-scale brain networks that dynamically reconfigure depending on task demands. Although the hippocampus and closely related structures have been implicated, little is known regarding how large-scale and distributed networks support different memory formation demands. We investigated patterns of interactions among distributed networks while human individuals formed item-context memories for two stimulus categories. Subjects studied object-scene and object-location associations in different fMRI sessions. Stimulus-responsive brain regions were organized based on their fMRI interconnectivity into networks and modules using probabilistic module-detection algorithms to maximize measurement of individual differences in modular structure. Although there was a great deal of consistency in the modular structure between object-scene and object-location memory formation, there were also significant differences. Interactions among functional modules predicted later memory accuracy, explaining substantial portions of variability in memory formation success. Increased interactivity of modules associated with internal thought and anti-correlation of these modules with those related to stimulus-evoked processing robustly predicted object-scene memory, whereas decreased interactivity of stimulus-evoked processing modules predicted object-location memory. Assessment of individual differences in network organization therefore allowed identification of distinct patterns of functional interactions that robustly predicted memory formation. This highlights large-scale brain network interactions for memory formation and indicates that although networks are largely robust to task demands, reconfiguration nonetheless occurs to support distinct memory formation demands.

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<![CDATA[Effects of early adversity on the brain: Larger-volume anterior cingulate cortex in AIDS orphans]]> https://www.researchpad.co/article/5c46658cd5eed0c484519b78

Multiple studies have revealed that adolescent AIDS orphans have more psychosocial problems than healthy adolescents. However, little is known about whether and how the brain structures of adolescent AIDS orphans differ from those of healthy adolescents. Here, we used magnetic resonance imaging to compare adolescent AIDS orphans reared in institutions (N = 20) with a sex- and age-matched group of healthy adolescents reared in families (N = 20) in China using a voxel-based morphometry analysis. First, we found that both total gray- and white-matter volumes did not differ between groups. Second, after correcting for age, sex, and total gray-matter volume, the AIDS orphan group demonstrated smaller hippocampal volumes, larger anterior cingulate cortex (ACC) volumes, and no differences in the amygdala. Third, a whole-brain analysis identified higher gray-matter volume of the ACC in the AIDS orphan group than in the control group. The preliminary findings of this study highlight the need for future research to confirm the sensitivity of the hippocampus and ACC to early adversity.

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<![CDATA[Different temporal windows for CB1 receptor involvement in contextual fear memory destabilisation in the amygdala and hippocampus]]> https://www.researchpad.co/article/5c478c80d5eed0c484bd2b5d

Reconsolidation is a process in which re-exposure to a reminder causes a previously acquired memory to undergo a process of destabilisation followed by subsequent restabilisation. Different molecular mechanisms have been postulated for destabilisation in the amygdala and hippocampus, including CB1 receptor activation, protein degradation and AMPA receptor exchange; however, most of the amygdala studies have used pre-reexposure interventions, while those in the hippocampus have usually performed them after reexposure. To test whether the temporal window for destabilisation is similar across both structures, we trained Lister Hooded rats in a contextual fear conditioning task, and 1 day later performed memory reexposure followed by injection of either the NMDA antagonist MK-801 (0.1 mg/kg) or saline in order to block reconsolidation. In parallel, we also performed local injections of either the CB1 antagonist SR141716A or its vehicle in the hippocampus or in the amygdala, either immediately before or immediately after reactivation. Infusion of SR141716A in the hippocampus prevented the reconsolidation-blocking effect of MK-801 when performed after reexposure, but not before it. In the amygdala, meanwhile, pre-reexposure infusions of SR141716A impaired reconsolidation blockade by MK-801, although the time-dependency of this effect was not as clear as in the hippocampus. Our results suggest the temporal windows for CB1-receptor-mediated memory destabilisation during reconsolidation vary between brain structures. Whether this reflects different time windows for engagement of these structures or different roles played by CB1 receptors in destabilisation across structures remains an open question for future studies.

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<![CDATA[Early alterations in hippocampal perisomatic GABAergic synapses and network oscillations in a mouse model of Alzheimer’s disease amyloidosis]]> https://www.researchpad.co/article/5c478c3dd5eed0c484bd1017

Several lines of evidence imply changes in inhibitory interneuron connectivity and subsequent alterations in oscillatory network activities in the pathogenesis of Alzheimer’s Disease (AD). Recently, we provided evidence for an increased immunoreactivity of both the postsynaptic scaffold protein gephyrin and the GABAA receptor γ2-subunit in the hippocampus of young (1 and 3 months of age), APPPS1 mice. These mice represent a well-established model of cerebral amyloidosis, which is a hallmark of human AD. In this study, we demonstrate a robust increase of parvalbumin immunoreactivity and accentuated projections of parvalbumin positive (PV+) interneurons, which target perisomatic regions of pyramidal cells within the hippocampal subregions CA1 and CA3 of 3-month-old APPPS1 mice. Colocalisation studies confirmed a significant increase in the density of PV+ projections labeled with antibodies against a presynaptic (vesicular GABA transporter) and a postsynaptic marker (gephyrin) of inhibitory synapses within the pyramidal cell layer of CA1 and CA3. As perisomatic inhibition by PV+-interneurons is crucial for the generation of hippocampal network oscillations involved in spatial processing, learning and memory formation we investigated the impact of the putative enhanced perisomatic inhibition on two types of fast neuronal network oscillations in acute hippocampal slices: 1. spontaneously occurring sharp wave-ripple complexes (SPW-R), and 2. cholinergic γ-oscillations. Interestingly, both network patterns were generally preserved in APPPS1 mice similar to WT mice. However, the comparison of simultaneous CA3 and CA1 recordings revealed that the incidence and amplitude of SPW-Rs were significantly lower in CA1 vs CA3 in APPPS1 slices, whereas the power of γ-oscillations was significantly higher in CA3 vs CA1 in WT-slices indicating an impaired communication between the CA3 and CA1 network activities in APPPS1 mice. Taken together, our data demonstrate an increased GABAergic synaptic output of PV+ interneurons impinging on pyramidal cells of CA1 and CA3, which might limit the coordinated cross-talk between these two hippocampal areas in young APPPS1 mice and mediate long-term changes in synaptic inhibition during progression of amyloidosis.

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<![CDATA[Transcription of human endogenous retroviruses in human brain by RNA-seq analysis]]> https://www.researchpad.co/article/5c37b793d5eed0c484490502

Background

Human endogenous retroviruses (HERV) comprise 8% of the human genome and can be classified into at least 31 families. Increased levels of transcripts from the W and H families of HERV have been observed in association with human diseases, such as multiple sclerosis and schizophrenia. Although HERV transcripts have been detected in many tissues and cell-types based on microarray and PCR studies, the extent of HERV expression in different cell-types and diseases state has been less comprehensively studied.

Results

We examined overall transcription of HERV, and particularly of HERV-W and HERV-H elements in human postmortem brain samples obtained from individuals with psychiatric diagnoses (n = 111) and healthy controls (n = 51) by analyzing publicly available RNA sequencing datasets. Sequence reads were aligned to prototypical sequences representing HERV, downloaded from Repbase. We reported a consistent expression (0.1~0.2% of mappable reads) of different HERV families across three regions of human brains. Spearman correlations revealed highly correlated expression levels between three brain regionsacross 475 consensus sequences. By mapping sequences that aligned to the consensus sequences of HERV-W and HERV-H families to individual loci on chromosome 7, more than 60 loci from each family were identified, part of which are being transcribed. The ERVWE1, locus located at chr7q21.2, exhibited high levels of transcription across the three datasets. Notably, we demonstrated a trend of increased expression of overall HERV, as well as HERV-W family in samples from both schizophrenia and bipolar disorder patients.

Conclusions

The current analyses indicate that RNA sequencing is a useful approach for investigating global expression of repetitive elements, such as HERV, in the human genome. HERV-W/H with the tendency of transcription up-regulation in patients suggests potential implication of HERV-W/H in psychiatric diseases.

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<![CDATA[Glycosaminoglycans from Alzheimer’s disease hippocampus have altered capacities to bind and regulate growth factors activities and to bind tau]]> https://www.researchpad.co/article/5c390c03d5eed0c48491f63f

Glycosaminoglycans (GAGs), including heparan sulfates and chondroitin sulfates, are major components of the extracellular matrix. Upon interacting with heparin binding growth factors (HBGF), GAGs participate to the maintaintenance of tissue homeostasis and contribute to self-healing. Although several processes regulated by HBGF are altered in Alzheimer’s disease, it is unknown whether the brain GAG capacities to bind and regulate the function of HBGF or of other heparin binding proteins, as tau, are modified in this disease. Here, we show that total sulfated GAGs from hippocampus of Alzheimer’s disease have altered capacities to bind and potentiate the activities of growth factors including FGF-2, VEGF, and BDNF while their capacity to bind to tau is remarkable increased. Alterations of GAG structures and capacities to interact with and regulate the activity of heparin binding proteins might contribute to impaired tissue homeostasis in the Alzheimer’s disease brain.

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<![CDATA[Implicit acoustic sequence learning recruits the hippocampus]]> https://www.researchpad.co/article/5c26977ed5eed0c48470fb1a

The exclusive role of the medial temporal lobe in explicit memory has been questioned by several studies reporting medial temporal lobe involvement during implicit learning. Prior studies have demonstrated that hippocampal engagement is present during the implicit learning of perceptual associations, however, it is absent during learning response-related associations. Therefore, it was hypothesized that the function of the medial temporal lobe during implicit learning is related to the extraction of perceptual associations in general. While in most implicit learning tasks visual stimuli were used, the aim of the current functional magnetic resonance imaging (fMRI) study was to detect whether activations within medial temporal lobe structures are also found during implicit learning of auditory associations. In a modified version of the classical serial reaction time task, participants reacted to the presentation of five different tones. Unbeknownst to the participants, the tones were presented with an underlying sequential regularity that could be learned. To avoid an influence of response learning on acoustic associative learning, response buttons were remapped in every trial. After learning, two different tests were used to measure participants’ conscious knowledge about the underlying sequence in order to assess the amount of implicit memory and to exclude participants with explicit knowledge acquired during learning. fMRI results revealed hippocampal activations for implicit learning of the acoustic sequence. When detecting a relation between implicit learning of acoustic associations and hippocampal activations, this study indicated a relation between hippocampal activations and memory formation of perceptual-based relational representation regardless of explicit knowledge. Thus, present findings suggest a general functional role for the formation of sequenced perceptual associations independent of the involvement of awareness.

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<![CDATA[Characterizing changes in glucocorticoid receptor internalization in the fear circuit in an animal model of post traumatic stress disorder]]> https://www.researchpad.co/article/5c141f18d5eed0c484d299ef

Glucocorticoid receptors (GRs) shuttle from the cytoplasm (cy) to the nucleus (nu) when bound with glucocorticoids (i.e. GR internalization) and alter transcriptional activity. GR activation within the fear circuit has been implicated in fear memory and post traumatic stress disorder (PTSD). However, no study to date has characterized GR internalization within the fear circuit during fear memory formation or examined how traumatic stress impacts this process. To address this, we assayed cy and nu GR levels at baseline and after auditory fear conditioning (FC) in the single prolonged stress (SPS) model of PTSD. Cy and nu GRs within the medial prefrontal cortex (mPFC), dorsal hippocampus (dHipp), ventral hippocampus (vHipp), and amygdala (AMY) were assayed using western blot. The distribution of GR in the cy and nu (at baseline and after FC) was varied across individual nodes of the fear circuit. At baseline, SPS enhanced cyGRs in the dHipp, but decreased cyGRs in the AMY. FC only enhanced GR internalization in the AMY and this effect was attenuated by SPS exposure. SPS also decreased cyGRs in the dHipp after FC. The results of this study suggests that GR internalization is varied across the fear circuit, which in turn suggests GR activation is selectively regulated within individual nodes of the fear circuit. The findings also suggest that changes in GR dynamics in the dHipp and AMY modulate the enhancing effect SPS has on fear memory persistence.

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<![CDATA[Study of tau pathology in male rTg4510 mice fed with a curcumin derivative Shiga-Y5]]> https://www.researchpad.co/article/5c12cf25d5eed0c484914007

Intracellular inclusions of aggregated tau appear in neurons and glial cells in a range of neurodegenerative diseases known as tauopathies. Inhibition of pathological changes in tau is a therapeutic target for tauopathy. We recently synthesized a novel curcumin derivative, named Shiga-Y5, and showed that Shiga-Y5 inhibited cognitive impairment and amyloid deposition in a mouse model of Alzheimer’s disease. Here we investigated whether Shiga-Y5 inhibited cognitive impairment and tau accumulation in a mouse model of tauopathy, rTg4510. The rTg4510 mouse is a bitransgenic mouse model that uses a system of responder and activator transgenes to express human four-repeat tau with the P301L mutation. This strain is obtained by crossing tetO-MAPT*P301L mouse line (on a FVB/NJ background) with CaMKII-tTA mouse line (on a C57BL/6J background). Male rTg4510 mice and wild-type mice were fed with a standard chow diet with or without Shiga-Y5 (500 ppm) for 4 months. Behavioral tests were conducted from 5.5 months of age, and the mice were sacrificed at 6 months of age. There were no significant changes in behavioral performance in rTg4510 mice fed with SY5-containing chow diet compared with rTg4510 mice fed with control chow diet. Histological and biochemical analyses also showed no significant alterations in tau accumulation by the treatment with SY5. One of noticeable finding in this study was that rTg4510 mice on a F1 female FVB/NJ x male C57BL/6J background showed more severe tau accumulation than rTg4510 mice on a F1 female C57BL/6J x male FVB/NJ background. Further studies to clarify the mechanisms underlying tau aggregation may help to develop therapeutic approaches aimed at preventing this pathological feature.

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<![CDATA[BOLD fMRI effects of transcutaneous vagus nerve stimulation in patients with chronic tinnitus]]> https://www.researchpad.co/article/5c084232d5eed0c484fcc23d

Objective

Vagus nerve stimulation (VNS) is a neuromodulation method used for treatment of epilepsy and depression. Transcutaneous VNS (tVNS) has been gaining popularity as a noninvasive alternative to VNS. Previous tVNS neuroimaging studies revealed brain (de)activation patterns that involved multiple areas implicated in tinnitus generation and perception. In this study, functional magnetic resonance imaging (fMRI) was used to explore the effects of tVNS on brain activity in patients with tinnitus.

Methods

Thirty-six patients with chronic tinnitus received tVNS to the inner tragus, cymba conchae, and earlobe (sham stimulation).

Results

The locus coeruleus and nucleus of the solitary tract in the brainstem were activated in response to stimulation of both locations compared with the sham stimulation. The cochlear nuclei were also activated, which was not observed in healthy subjects with normal hearing. Multiple auditory and limbic structures, as well as other brain areas associated with generation and perception of tinnitus, were deactivated by tVNS, particularly the parahippocampal gyrus, which was recently speculated to cause tinnitus in hearing-impaired patients.

Conclusions

tVNS via the inner tragus or cymba conchae suppressed neural activity in the auditory, limbic, and other tinnitus-related non-auditory areas through auditory and vagal ascending pathways in tinnitus patients. The results from this study are discussed in the context of several existing models of tinnitus. They indicate that the mechanism of action of tVNS might be involved in multiple brain areas responsible for the generation of tinnitus, tinnitus-related emotional annoyance, and their mutual reinforcement.

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<![CDATA[Serial representation of items during working memory maintenance at letter-selective cortical sites]]> https://www.researchpad.co/article/5b8acde540307c144d0de055

A key component of working memory is the ability to remember multiple items simultaneously. To understand how the human brain maintains multiple items in memory, we examined direct brain recordings of neural oscillations from neurosurgical patients as they performed a working memory task. We analyzed the data to identify the neural representations of individual memory items by identifying recording sites with broadband gamma activity that varied according to the identity of the letter a subject viewed. Next, we tested a previously proposed model of working memory, which had hypothesized that the neural representations of individual memory items sequentially occurred at different phases of the theta/alpha cycle. Consistent with this model, the phase of the theta/alpha oscillation when stimulus-related gamma activity occurred during maintenance reflected the order of list presentation. These results suggest that working memory is organized by a cortical phase code coordinated by coupled theta/alpha and gamma oscillations and, more broadly, provide support for the serial representation of items in working memory.

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<![CDATA[Deletion of exchange proteins directly activated by cAMP (Epac) causes defects in hippocampal signaling in female mice]]> https://www.researchpad.co/article/5b6945ba463d7e3867f4aca4

Previous studies demonstrate essential roles for the exchange proteins directly activated by cAMP 1 and 2 (Epac1 and Epac2; here collectively referred to as Epac) in the brain. In the hippocampus, Epac contributes to the control of neuronal growth and differentiation and has been implicated in memory and learning as well as in anxiety and depression. In the present study we address the hypothesis that Epac affects hippocampal cellular responses to acute restraint stress. Stress causes activation of the hypothalamus-pituitary-adrenal (HPA)-axis, and glucocorticoid receptor (GR) signaling is essential for proper feedback regulation of the stress response, both in the brain and along the HPA axis. In the hippocampus, GR expression is regulated by cAMP and the brain enriched micro RNA miR-124. Epac has been associated with miR-124 expression in hippocampal neurons, but not in regulation of GR. We report that hippocampal expression of Epac1 and Epac2 increased in response to acute stress in female wild type mice. In female mice genetically deleted for Epac, nuclear translocation of GR in response to restraint stress was significantly delayed, and moreover, miR-124 expression was decreased in these mice. Male mice lacking Epac also showed abnormalities in miR-124 expression, but the phenotype was less profound than in females. Serum corticosterone levels were slightly altered immediately after stress in both male and female mice deleted for Epac. The presented data indicate that Epac1 and Epac2 are involved in controlling cellular responses to acute stress in the mouse hippocampus and provide novel insights into the underlying transcriptional and signaling networks. Interestingly, we observe sex specific differences when Epac is deleted. As the incidence and prevalence of stress-related diseases are higher in women than in men, the Epac knockout models might serve as genetic tools to further elucidate the cellular mechanisms underlying differences between male and female with regard to regulation of stress.

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