Dendritic Density Research Articles

Blockage of Drp1 phosphorylation at Ser579 protects neurons against Aβ1‑42‑induced degeneration.

Alzheimer's disease (AD), one of the most common types of chronic neurodegenerative diseases, is pathologically characterized by the formation of amyloid β (Aβ) peptide-containing plaques and neurofibrillary tangles. Among Aβ peptides, Aβ1–42 induces neuronal toxicity and neurodegeneration. In our previous studies, Cdk5 was found to regulate Aβ1–42-induced mitochondrial fission via the phosphorylation of dynamin-related protein 1 (Drp1) at Ser579. However, whether blockage of Drp1 phosphorylation at Ser579 protects neurons against Aβ1–42-induced degeneration remains to be elucidated. Thus, the aim the present study was to examine the effect of mutant Drp1-S579A on neurodegeneration and its underlying mechanism. First, the phosphorylation-defect (phospho-defect) mutant, Lenti-Drp1-S579A was constructed. Phospho-defect Drp1-S579A expression was detected in primary cultures of mouse cortical neurons infected with Lenti-Drp1-S579A using western blotting and it was found to successfully attenuate the phosphorylation of endogenous Drp1 at Ser579. In primary neuronal cultures, the neuronal processes were evaluated under microscopy. Treatment with 10 µM Aβ1–42 significantly decreased dendritic density and length, spine outgrowth and synapse number. As expected, infection of neurons with Lenti-Drp1-S579A efficiently alleviated the inhibitory effect of Aβ1–42 on neurite outgrowth and synapse density. In addition, infection with Lenti-Drp1-S579A abolished the cleavage of caspase-3 and apoptosis in neurons exposed to Aβ1–42. Thus, the current data demonstrated that blockage of Drp1 phosphorylation at Ser579 may be an effective strategy to protect neurons against Aβ1–42-induced degeneration and apoptosis. These findings underline the therapeutic potential of targeting Drp1 in the treatment of AD.

Left lateralization of neonatal caudate microstructure affects emerging language development at 24 months.

The complex interaction between brain and behaviour in language disorder is well established. Yet to date, the imaging literature in the language disorder field has continued to pursue heterogeneous and relatively small clinical cross‐sectional samples, with emphasis on cortical structures and volumetric analyses of subcortical brain structures. In our current work, we aimed to go beyond this state of knowledge to focus on the microstructural features of subcortical brain structures (specifically the caudate nucleus) in a large cohort of neonates and study its association with emerging language skills at 24 months. Variations in neonatal brain microstructure could be interpreted as a proxy for in utero brain development. As language development is highly dependent on cognitive function and home literacy environment, we also examined their effect on the caudate–language function relationship utilizing a conditional process model. Our findings suggest that emerging language development at 24 months is influenced by the degree of left lateralization of neonatal caudate microstructure, indexed by diffusion tensor imaging (DTI)‐derived fractional anisotropy (FA). FA is an indirect measure of neuronal and dendritic density within grey matter structures. We also found that the caudate–language function relationship is partially mediated by cognitive function. The conditional indirect effect of left caudate FA on language composite score through cognitive function was only statistically significant at low levels of home literacy score (−1 standard deviation [SD]). The authors proposed that this may be related to ‘compensatory’ development of cognitive skills in less favourable home literacy environments.

Childhood exercise predicts response inhibition in later life via changes in brain connectivity and structure

Participation in exercise during early life (i.e., childhood through adolescence) enhances response inhibition; however, it is unclear whether participation in exercise during early life positively predicts response inhibition in later life. This historical cohort study was designed to clarify whether participation in exercise (e.g., structured sports participation) during early life predicts response inhibition in adulthood and if so, to reveal the brain connectivity and cortical structures contributing to this association. We analyzed data derived from 214 participants (women = 104, men = 110; age: 26‒69 years). Results indicated that participation in exercise during childhood (before entering junior high school; ≤ 12 years old) significantly predicted better response inhibition. No such association was found if exercise participation took place in early adolescence or later (junior high school or high school; ≥ 12 years old). The positive association of exercise participation during childhood with response inhibition was moderated by decreased structural and functional connectivity in the frontoparietal (FPN), cingulo-opercular (CON), and default mode networks (DMN), and increased inter-hemispheric structural networks. Greater cortical thickness and lower levels of dendritic arborization and density in the FPN, CON, and DMN also moderated this positive association. Our results suggest that participation in exercise during childhood positively predicts response inhibition later in life and that this association can be moderated by changes in neuronal circuitry, such as increased cortical thickness and efficiency, and strengthened inter-hemispheric connectivity.

A Novel Heptapeptide, GPPGPAG Transfers to the Brain, and Ameliorates Memory Dysfunction and Dendritic Atrophy in Alzheimer's Disease Model Mice.

We investigated the effects of a heptapeptide, GPPGPAG, on memory improvement and neuritic regeneration in Alzheimer’s disease models to evaluate its potency as a new anti-Alzheimer’s disease (AD) therapy. The anti-AD effects of GPPGPAG were evaluated in Aβ-treated cortical neurons and 5XFAD, a mouse model of AD. Exposure of cortical neurons to Aβ25-35 for 3 days resulted in atrophy of axons and dendrites. Treatment with GPPGPAG improved the dendritic atrophy of Aβ-treated cortical neurons, but not axonal atrophy. Postsynaptic and presynaptic densities under Aβ1-42 exposure were increased by GPPGPAG post treatment. Oral administration of GPPGPAG to 5XFAD mice for 15 days improved significantly object recognition memory and dendritic density. Direct infusion of GPPGPAG into the lateral ventricle of 5XFAD mice for 28 days improved object recognition memory. Following oral administration of GPPGPAG in mice, the undigested heptapeptide was detected in the plasma and cerebral cortex. Analysis of target protein of GPPGPAG in neurons by DARTS method identified 14-3-3ε as a bound protein. The protective effect of GPPGPAG on Aβ1-42-induced dendritic atrophy was canceled by knockdown of 14-3-3ε. Taken together, these results suggest that GPPGPAG is orally available, transfers to the brain, and ameliorates memory dysfunction in AD brain, which is possibly mediated by 14-3-3ε-related dendritic restoration.

Burst of Corneal Dendritic Cells during Trastuzumab and Paclitaxel Treatment.

During breast cancer therapy, paclitaxel and trastuzumab are both associated with adverse effects such as chemotherapy-induced peripheral neuropathy and other systemic side effects including ocular complications. Corneal nerves are considered part of the peripheral nervous system and can be imaged non-invasively by confocal laser scanning microscopy (CLSM) on the cellular level. Thus, in vivo CLSM imaging of structures of the corneal subbasal nerve plexus (SNP) such as sensory nerves or dendritic cells (DCs) can be a powerful tool for the assessment of corneal complications during cancer treatment. During the present study, the SNP of a breast cancer patient was analyzed over time by using large-scale in vivo CLSM in the course of paclitaxel and trastuzumab therapy. The same corneal regions could be re-identified over time. While the subbasal nerve morphology did not alter significantly, a change in dendritic cell density and an additional local burst within the first 11 weeks of therapy was detected, indicating treatment-mediated corneal inflammatory processes. Ocular structures such as nerves and dendritic cells could represent useful biomarkers for the assessment of ocular adverse effects during cancer therapy and their management, leading to a better visual prognosis.

Can in vivo confocal microscopy differentiate between sub‐types of dry eye disease? A review

Many studies utilised in vivo confocal microscopy (IVCM) to associate variations in corneal structures with dry eye disease (DED). However, DED is an umbrella term that covers various aetiologies and presentations. This review analyses populations by DED aetiology to determine the relationships between IVCM parameters and specific DED sub-types. It focuses on the most commonly examined structures, sub-basal nerves and dendritic cells. Across the literature, most studies found individuals with immune-mediated DED had lower sub-basal nerve fibre number and density than controls, with smaller differences between non-immune DED and controls. However, wide ranges of values reported across studies demonstrate considerable overlap between DED sub-types and controls, rendering these metrics less helpful when diagnosing an individual patient. Dendritic cell density was considerably higher in individuals with immune-mediated DED than in non-immune DED or controls. As such, dendritic cell density may be a better indicator of DED associated with a systemic immune-mediated process.

Corneal confocal microscopy differentiates inflammatory from diabetic neuropathy

BackgroundImmune-mediated neuropathies, such as chronic inflammatory demyelinating polyneuropathy (CIDP) are treatable neuropathies. Among individuals with diabetic neuropathy, it remains a challenge to identify those individuals who develop CIDP. Corneal confocal microscopy (CCM) has been shown to detect corneal nerve fiber loss and cellular infiltrates in the sub-basal layer of the cornea. The objective of the study was to determine whether CCM can distinguish diabetic neuropathy from CIDP and whether CCM can detect CIDP in persons with coexisting diabetes.MethodsIn this multicenter, case-control study, participants with CIDP (n = 55) with (n = 10) and without (n = 45) diabetes; participants with diabetes (n = 58) with (n = 28) and without (n = 30) diabetic neuropathy, and healthy controls (n = 58) underwent CCM. Corneal nerve fiber density (CNFD), corneal nerve fiber length (CNFL), corneal nerve branch density (CNBD), and dendritic and non-dendritic cell density, with or without nerve fiber contact were quantified.ResultsDendritic cell density in proximity to corneal nerve fibers was significantly higher in participants with CIDP with and without diabetes compared to participants with diabetic neuropathy and controls. CNFD, CNFL, and CNBD were equally reduced in participants with CIDP, diabetic neuropathy, and CIDP with diabetes.ConclusionsAn increase in dendritic cell density identifies persons with CIDP. CCM may, therefore, be useful to differentiate inflammatory from non-inflammatory diabetic neuropathy.

Pten is a key intrinsic factor regulating raphe 5-HT neuronal plasticity and depressive behaviors in mice

Serotonin (5-HT)-based antidepressants, selective serotonin reuptake inhibitors (SSRIs) aim to enhance serotonergic activity by blocking its reuptake. We propose PTEN as a target for an alternative approach for regulating 5-HT neuron activity in the brain and depressive behaviors. We show that PTEN is elevated in central 5-HT neurons in the raphe nucleus by chronic stress in mice, and selective deletion of Pten in the 5-HT neurons induces its structural plasticity shown by increases of dendritic branching and density of PSD95-positive puncta in the dendrites. 5-HT levels are elevated and electrical stimulation of raphe neurons evokes more 5-HT release in the brain of condition knockout (cKO) mice with Pten-deficient 5-HT neurons. In addition, the 5-HT neurons remain normal electrophysiological properties but have increased excitatory synaptic inputs. Single-cell RNA sequencing revealed gene transcript alterations that may underlay morphological and functional changes in Pten-deficient 5-HT neurons. Finally, Pten cKO mice and wild-type mice treated with systemic application of PTEN inhibitor display reduced depression-like behaviors. Thus, PTEN is an intrinsic regulator of 5-HT neuron activity, representing a novel therapeutic strategy for producing antidepressant action.

Targeting Alzheimer's disease with multimodal polypeptide-based nanoconjugates.

Alzheimer's disease (AD), the most prevalent form of dementia, remains incurable mainly due to our failings in the search for effective pharmacological strategies. Here, we describe the development of targeted multimodal polypeptide-based nanoconjugates as potential AD treatments. Treatment with polypeptide nanoconjugates bearing propargylamine moieties and bisdemethoxycurcumin or genistein afforded neuroprotection and displayed neurotrophic effects, as evidenced by an increase in dendritic density of pyramidal neurons in organotypic hippocampal culture. The additional conjugation of the Angiopep-2 targeting moiety enhanced nanoconjugate passage through the blood-brain barrier and modulated brain distribution with nanoconjugate accumulation in neurogenic areas, including the olfactory bulb. Nanoconjugate treatment effectively reduced neurotoxic β amyloid aggregate levels and rescued impairments to olfactory memory and object recognition in APP/PS1 transgenic AD model mice. Overall, this study provides a description of a targeted multimodal polyglutamate-based nanoconjugate with neuroprotective and neurotrophic potential for AD treatment.

Face Mask-Related Ocular Surface Modifications During COVID-19 Pandemic: A Clinical, In Vivo Confocal Microscopy, and Immune-Cytology Study.

PurposeThe purpose of this study was to describe the face mask (FM)-related ocular surface changes using clinical tests, in vivo confocal microscopy (IVCM) and impression cytology (IC), and to investigate the Dry Eye-related Quality of life Score (DEQS).MethodsSixty-six patients with dry eye disease (DED) and 62 healthy subjects (group 2) using FM were enrolled. Groups were divided into: groups 1A and 2A: < 3 hours of FM wear; groups 1B and 2B: 3 to 6 hours; and groups 1C and 2C: > 6 hours. Patients underwent DEQS questionnaire, break-up time (BUT), Schirmer test I (STI), fluorescein and lissamine staining (FS and LS), IVCM to determine corneal dendritic cell density (DCD) and goblet cell density (GCD), and IC to measure HLA-DR, at baseline and after 3 months.ResultsFM use duration before enrollment was 27 ± 2.3 and 30 ± 4.1 (days ± SD) for groups 1 and 2 (P > 0.05). After 3 months, DEQS worsened in groups 1B and 1C, STI in groups 1A to 1C, FS and LS in group 1C (P < 0.05); in controls, BUT and FS worsened only in group 2C (P < 0.05). DCD significantly increased in groups 1A to 1C and HLA-DR in groups 1B and 1C (P < 0.05), whereas GCD did not significantly change. DCD and HLA-DR increased only in group 2C (P < 0.05). DEQS significantly correlated with DCD (P = 0.05, r = 0.698; P < 0.001, r = 0.832) and HLA-DR (P = 0.043, r = −0.687; P < 0.001, r = 0.861) at baseline and 3 months.ConclusionsUse of FM increases ocular surface inflammation and negatively impacts the quality of life in patients with DED.Translational RelevanceThe study of the prolonged use of FM effects may be relevant to managing DED.

Analysis of autogenous shrinkage-induced microcracks in concrete from 3D images

A new image analysis procedure for quantifying microcracks from three-dimensional (3D) X-ray microCT images of concrete is presented. The method separates microcracks from air voids and aggregates by combining filtering and morphological operations. It was applied to study the effects of supplementary cementitious materials (SCMs) and curing age on autogenous shrinkage-induced microcracks in low w/b ratio concretes, and to determine the representative elementary volume (REV) for various properties of microcracks and air voids. Results showed that slag and silica fume significantly increased autogenous shrinkage and related microcracking. These SCMs increased volume fraction, width, length, dendritic density, anisotropy, and connectivity of microcracks, but decreased specific surface and tortuosity. Similar trends were observed with age. Comparison between 3D and 2D measurements was made. REV analysis showed that a sampling volume of ~20 × 20 × 25 mm3 is sufficient for characterising most parameters of autogenous shrinkage microcracks and air voids in concrete.

Camouflaged Gold Nanodendrites Enable Synergistic Photodynamic Therapy and NIR Biowindow II Photothermal Therapy and Multimodal Imaging.

Gold nanodendrite (AuND)-based nanotheranostic agents with versatile capabilities were fabricated by optimizing the geometrical configurations (dendrite length and density) of AuND to achieve localized surface plasmon resonance (LSPR) in near-infrared biowindow II (NIR-II), and then subsequently functionalizing with a mitochondria-targeting compound (triphenylphosphonium, TPP), loading with an NIR-photosensitizer (indocyanine green, ICG) and coating with the macrophage cell membrane (MCM) to trap ICG within AuND and selectively interact with MDA-MB-231 cells. The novel AuND-TPP-ICG@MCM system enabled the integration of multimodal fluorescence/photoacoustic/surface-enhanced Raman imaging with synergistic therapies of NIR-II photothermal therapy and NIR-I photodynamic therapy for cancer treatment. Enhanced hyperthermia and elevated production of reactive oxygen species within the tumors via MCM coating and mitochondria targeting afforded a synergistic efficacy for tumor eradication with limited side effects. The demonstrated biocompatibility, multi-imaging capability, and high therapeutic efficiency under NIR laser irradiation indicate the potentials of this multifunctional nanotheranostic platform for clinical utility in cancer therapy.

In Vivo Confocal Microscopy in Blepharitis Patients with Ocular Demodex Infestation

ABSTRACT Purpose To compare corneal in-vivo confocal microscopy (IVCM) findings in patients with seborrheic blepharitis with healthy controls and to evaluate the correlation with the Demodex load. Methods Sixty-two Demodex positive seborrheic blepharitis patients and 24 controls were included. Four eyelashes from each eye were examined. The median value of Demodex count (5 mites/eye) was assigned as the cutoff value to create low and high Demodex infestation subgroups. Corneal nerve parameters (fiber length;CNFL, fiber density;CNFD, branch length;CNBL, branch density;CNBD) and dendritic cell density (DCD) were analyzed by IVCM for all participants. Results The mean DCD of eyes in low (37.62 ± 25.18 cells/mm2) and high (76.00 ± 44.00 cells/mm2) Demodex load groups were significantly higher than those in the control group (14.25 ± 2.68 cells/mm2) (p < .001). CNFL, CNFD, CNBL and CNBD were significantly lower in low and high Demodex groups compared to controls (p < .001). Conclusions Demodex positive seborrheic blepharitis patients showed significantly reduced density of corneal nerves and elevated DCD levels.

Enabling interfacial stability via 3D networking single ion conducting nano fiber electrolyte for high performance lithium metal batteries

Enabling high ion conductivity, lithium-ion transference number (tLi+) and excellent interfacial compatibility of polymer electrolyte with lithium metal anode/cathode plays a vital role in surmounting the challenges of uncontrollable lithium (Li) dendrite and low energy density of Li metal batteries (LMBs). In this contribution, a highly porous three-dimensional (3D) semi-interpenetrated polymer networks (semi-IPNs) based single ion conducting electrospun fiber-gel composite polymer electrolyte (es-FGPE) is prepared by thermal-initiated in situ polymerization of the pentaerythritol tetra-acrylate (PETEA) units in a single ion conducting polymer electrospun nano fiber SPCE membrane (es-SIPE) inside the batteries. The as-fabricated es-FGPE assembled LiFePO4 (LFP)/Li metal batteries demonstrates a high C-rate discharge capacity and an outstanding cyclability with a capacity retention of 82.5% after 1000 cycles at 1C (1 = 170 mA g−1). It is noted that in situ polymerization of the semi-IPNs inside the batteries can afford to a multifunctional breakthrough of enhancing ionic conductivity, reinforcing lithium anode and LFP cathode interfaces. We believe that the present semi-IPNs highlight the significance of the enhancement of the interfacial properties of both a cathode and a Li metal anode for achieving real application of lithium metal anode.

DL-3-n-butylphthalide ameliorates diabetes-associated cognitive decline by enhancing PI3K/Akt signaling and suppressing oxidative stress.

DL-3-n-Butylphthalide (DL-NBP), a small molecular compound extracted from the seeds of Apium graveolens Linn (Chinese celery), has been shown to exert neuroprotective effects due to its anti-inflammatory, anti-oxidative and anti-apoptotic activities. DL-NBP not only protects against ischemic cerebral injury, but also ameliorates vascular cognitive impairment in dementia patients including AD and PD. In the current study, we investigated whether and how DL-NBP exerted a neuroprotective effect against diabetes-associated cognitive decline (DACD) in db/db mice, a model of type-2 diabetes. db/db mice were orally administered DL-NBP (20, 60, 120 mg· kg-1· d-1) for 8 weeks. Then the mice were subjected to behavioral test, their brain tissue was collected for morphological and biochemical analyses. We showed that oral administration of DL-NBP significantly ameliorated the cognitive decline with improved learning and memory function in Morris water maze testing. Furthermore, DL-NBP administration attenuated diabetes-induced morphological alterations and increased neuronal survival and restored the levels of synaptic protein PSD95, synaptophysin and synapsin-1 as well as dendritic density in the hippocampus, especially at a dose of 60 mg/kg. Moreover, we revealed that DL-NBP administration suppressed oxidative stress by upregulating Nrf2/HO-1 signaling, and increased brain-derived neurotrophic factor (BDNF) expression by activating PI3K/Akt/CREB signaling in the hippocampus. These beneficial effects of DL-NBP were observed in high glucose-treated PC12 cells. Our results suggest that DL-NBP maybe a potential pharmacologic agent for the treatment of DACD.

The Antidepressant Effects of Resveratrol are Accompanied by the Attenuation of Dendrite/Dendritic Spine Loss and the Upregulation of BDNF/p-cofilin1 Levels in Chronic Restraint Mice.

Depression afflicts more than 300 million people worldwide, but there is currently no universally effective drug in clinical practice. In this study, chronic restraint stress (CRS)-induced mice depression model was used to study the antidepressant effects of resveratrol and its mechanism. Our results showed that resveratrol significantly attenuated depression-like behavior in mice. Consistent with behavioral changes, resveratrol significantly attenuated CRS-induced reduction in the density of dendrites and dendritic spines in both hippocampus and medial prefrontal cortex (mPFC). Meanwhile, in hippocampus and mPFC, resveratrol consistently alleviated CRS-induced cofilin1 activation by increasing its ser3 phosphorylation. In addition, cofilin1 immunofluorescence distribution in neuronal inner peri-membrane in controls, and cofilin1 diffusely distribution in the cytoplasm in CRS group were common in hippocampus. However, the distribution of cofilin1 in mPFC was reversed. Pearson's correlation analysis revealed that there was a significant positive correlation found between the sucrose consumption in sucrose preference test and the dendrite density in multiple sub-regions of hippocampus and mPFC, and a significant negative correlation between the immobility time in tail suspension test and the dendrite/dendritic spine density in several different areas of hippocampus and mPFC. P-cofilin1 was significantly positively correlated with the overall dendritic spine density in mPFC as well as with the overall dendrite density or BDNF in the hippocampus. Our results suggest that the BDNF/cofilin1 pathway, in which cofilin1 may be activated in a brain-specific manner, was involved in resveratrol's attenuating the dendrite and dendritic spine loss and behavioral abnormality.

General practice during COVID-19: an FY2's perspective.

<h3>ABSTRACT</h3> Patients with Fragile X syndrome, the leading monogenetic cause of autism, suffer from impairments related to the prefrontal cortex including working memory and attention. Synaptic inputs to the distal dendrites of layer 5 pyramidal neurons in the prefrontal cortex have a weak influence on the somatic membrane potential. To overcome this filtering, distal inputs are transformed into local dendritic Na⁺ spikes, which propagate to the soma and trigger action potential output. Layer 5 extratelencephalic (ET) PFC neurons project to the brainstem and various thalamic nuclei and are therefore well positioned to integrate task-relevant sensory signals and guide motor actions. We used current clamp and outside-out patch clamp recording to investigate dendritic spike generation in ET neurons from male wild type and <i>Fmr1</i> knockout (FX) mice. The threshold for dendritic spikes was more depolarized in FX neurons compared to wild type. Analysis of voltage responses to simulated in vivo “noisy” current injections showed that a larger dendritic input stimulus was required to elicit dendritic spikes in FX ET dendrites compared wild type. Patch clamp recordings revealed that the dendritic Na⁺ conductance was significantly smaller in FX ET dendrites. Taken together, our results suggest that input-output transformation is impaired in ET neurons of the PFC in FX mice. Considering our prior findings that somatic D-type K⁺ and dendritic HCN-channel function is reduced in ET neurons, we suggest that the integration of information by PFC circuits is fundamentally altered in Fragile X syndrome. <h3>KEY POINTS</h3> Dendritic spike threshold is depolarized in Layer 5 PFC neurons in FX mice Simultaneous somatic and dendritic recording with white noise current injections revealed that larger dendritic stimuli were required to elicit dendritic spikes in FX ET neurons Outside-out patch clamp recording revealed that dendritic sodium conductance density was lower in FX ET neurons

Dendritic cells and vitamin D in dry eye disease

To study the role of dendritic cells and vitamin D in troublesome evaporative dry eye diseases. Materials and Methods: This is a cross sectional study which includes 108 patients having evaporative dry eye disease and 86 normal healthy volunteers. Ocular surface index, Shirmer’s test and tear film break up time, corneal dendritic cell density, vitamin D and cytokines in serum/tear were estimated. Vitamin D, cytokine in serum/tear and corneal dendritic cell density were estimated. Result: Higher dendritic cell density noticed in evaporative dry eye disease patients compared to control group volunteers and revealed positive correlation with ocular surface index (P Conclusion: Vitamin D has significant role in dry eye disease and its inflammation. Vitamin D therapy can be considered as an added treatment for dry eye disease. Keywords: Dendritic cells, Vitamin D, Inflammatory cells, Dry eye.

Contrasting alterations between cortical and subcortical myelin across age, AD diagnosis, and amyloid and tau pathology as assessed by quantitative R1 mapping

AbstractBackgroundAccumulation of pathology in cortical tissue are early pathological hallmarks of Alzheimer’s disease. High resolution T1w/T2w ratio maps from structural MRI may reflect tissue microstructure with sensitivity to myelin, iron, and dendritic density. Few studies have investigated this in AD with conflicting reports of directionality of T1w/T2w ratios in individuals with AD diagnosis and pathology. However, these ratios will be sensitive to pulse sequences, protocols and bias field inhomogeneities, limiting their utility in clinical and research contexts. Here we employ R1 (=1/T1) relaxometry mapping, a quantitative imaging measure that is sensitive to myelin, to investigate relationships between cortical and subcortical tissue microstructure, age, AD diagnosis, and amyloid and tau pathology.MethodParticipants from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention underwent 3T MRI with whole‐brain, 1mm isotropic MPnRAGE T1 relaxometry with motion correction (Kecskemeti et al., 2016) (N=605/CN, 39/AD; age = 65.49 +/‐ 7.89 yrs) with a subset undergoing lumbar puncture for CSF Aß42/Tau biomarker classification (N = 141/A‐T‐, 26/A+T‐, 22/A‐T+, 18/A+T+). T1‐weighted images were processed using ANTS and CAT12, and transformation warps were applied to produce subcortical R1 maps in MNI space (6mm smoothing) and cortical R1 surface meshes (164k mesh, 5mm smoothing). Vertex‐wise (GM) and voxel‐wise (WM) ANCOVA were performed (p&lt;0.05 FWE corrected). Covariates included age, sex, study protocol, and AD diagnosis in model 1, and age, sex, years between CSF collection and MRI, study protocol, and A/T biomarker group in model 2.ResultSignificant associations between R1 and age, clinical AD diagnosis, and A/T pathology were found (Figure 1A‐C). Post‐hoc tests revealed increased R1 due to A/T pathology driven by A+T+ individuals. In contrast, significant widespread decreases in subcortical R1 were found with age and AD diagnosis (Figure 1D&amp;E), with no significant alterations in subcortical R1 due to biomarker status.ConclusionCortical and subcortical tissue exhibit differential tissue microstructural changes in response to aging, AD diagnosis and pathology. Importantly, increases in cortical R1 in unimpaired A+T+ individuals may reflect increased remyelination prior to the development of cognitive impairment. Future research will assess longitudinal relationships of R1 with age, cognition and markers of neurodegeneration.

Berberine exerts antidepressant-like effects via regulating miR-34a-synaptotagmin1/Bcl-2 axis

ObjectiveBerberine, a cationic alkaloid first isolated in 1917, has been approved by the China Drug Administration for decades. Accumulating evidence demonstrated its antidepressant-like activities in vivo. Our previous study has shown that chronic stress leads to the upregulation of miR-34a in the hippocampus of mice. This study aims to evaluate the underlying miR-34a mediated mechanism of berberine in chronic stress-induced depression in mice. MethodsIn the present study, mice were administered with berberine during chronic stress. Levels of miR-34a, dendritic density, mitochondrial morphology, and neurogenesis were assessed in the hippocampus. Subsequently, miR-34a agomir was used as a pharmacological intervention for the investigation of berberine. ResultsThe results showed that berberine reversed the decrease in sucrose preference and the increase in latency to feed without altering total food consumption. Furthermore, chronic stress-induced overexpression of miR-34a decreased synaptotagmin-1 and Bcl-2 levels, thereby impairing spinal morphology, mitochondria and neurogenesis. Berberine inhibited miR-34a expression, in turn restored synaptotagmin-1 and Bcl-2 levels, and thus improved spinal morphology, mitochondria and neurogenesis in the hippocampus. However, the improvements induced by berberine were totally blocked by the pretreatment of miR-34a agomir, which caused the elevation of miR-34a levels in the hippocampus. ConclusionThis finding demonstrated that miR-34a downregulation was involved in the antidepressant-like effects of berberine in mice exposed to chronic stress.