High-resolution omics of vascular ageing and inflammatory pathways in neurodegeneration.

High-resolution omics, particularly single-cell and spatial transcriptomic profiling, are rapidly enhancing our comprehension of the normal molecular diversity of gliovascular cells, as well as their age-related changes that contribute to neurodegeneration. With more omic profiling studies being conducted, it is becoming increasingly essential to synthesise valuable information from the rapidly accumulating findings. In this review, we present an overview of the molecular features of neurovascular and glial cells that have been recently discovered through omic profiling, with a focus on those that have potentially significant functional implications and/or show cross-species differences between human and mouse, and that are linked to vascular deficits and inflammatory pathways in ageing and neurodegenerative disorders. Additionally, we highlight the translational applications of omic profiling, and discuss omic-based strategies to accelerate biomarker discovery and facilitate disease course-modifying therapeutics development for neurodegenerative conditions.

Antibody stabilization for thermally accelerated deep immunostaining.

Antibodies have diverse applications due to their high reaction specificities but are sensitive to denaturation when a higher working temperature is required. We have developed a simple, highly scalable and generalizable chemical approach for stabilizing off-the-shelf antibodies against thermal and chemical denaturation. We demonstrate that the stabilized antibodies (termed SPEARs) can withstand up to 4 weeks of continuous heating at 55 °C and harsh denaturants, and apply our method to 33 tested antibodies. SPEARs enable flexible applications of thermocycling and denaturants to dynamically modulate their binding kinetics, reaction equilibrium, macromolecular diffusivity and aggregation propensity. In particular, we show that SPEARs permit the use of a thermally facilitated three-dimensional immunolabeling strategy (termed ThICK staining), achieving whole mouse brain immunolabeling within 72 h, as well as nearly fourfold deeper penetration with threefold less antibodies in human brain tissue. With faster deep-tissue immunolabeling and broad compatibility with tissue processing and clearing methods without the need for any specialized equipment, we anticipate the wide applicability of ThICK staining with SPEARs for deep immunostaining.

APOE2 protects against Aß pathology by improving neuronal mitochondrial function through ERRα signaling.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease and apolipoprotein E (APOE) genotypes (APOE2, APOE3, and APOE4) show different AD susceptibility. Previous studies indicated that individuals carrying the APOE2 allele reduce the risk of developing AD, which may be attributed to the potential neuroprotective role of APOE2. However, the mechanisms underlying the protective effects of APOE2 is still unclear. METHODS: We analyzed single-nucleus RNA sequencing and bulk RNA sequencing data of APOE2 and APOE3 carriers from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort. We validated the findings in SH-SY5Y cells and AD model mice by evaluating mitochondrial functions and cognitive behaviors respectively. RESULTS: The pathway analysis of six major cell types revealed a strong association between APOE2 and cellular stress and energy metabolism, particularly in excitatory and inhibitory neurons, which was found to be more pronounced in the presence of beta-amyloid (Aß). Moreover, APOE2 overexpression alleviates Aß1-42-induced mitochondrial dysfunction and reduces the generation of reactive oxygen species in SH-SY5Y cells. These protective effects may be due to ApoE2 interacting with estrogen-related receptor alpha (ERRα). ERRα overexpression by plasmids or activation by agonist was also found to show similar mitochondrial protective effects in Aß1-42-stimulated SH-SY5Y cells. Additionally, ERRα agonist treatment improve the cognitive performance of Aß injected mice in both Y maze and novel object recognition tests. ERRα agonist treatment increased PSD95 expression in the cortex of agonist-treated-AD mice. CONCLUSIONS: APOE2 appears to enhance neural mitochondrial function via the activation of ERRα signaling, which may be the protective effect of APOE2 to treat AD.

Genome-wide association study of resistance to anthracnose in pepper (Capsicum chinense) germplasm.

BACKGROUND: Anthracnose is a fungal disease caused by Colletotrichum spp. that has a significant impact on worldwide pepper production. Colletotrichum scovillei is the most common pathogenic anthracnose-causing species in the Republic of Korea. RESULTS: The resistances of 197 pepper (Capsicum chinense) accessions deposited in Korea's National Agrobiodiversity Center were evaluated for their response against the virulent pathogens Colletotrichum acutatum isolate 'KSCa-1' and C. scovillei isolate 'Hana') in the field and in vitro methods for three consecutive years (2018 to 2020). The severity of the disease was recorded and compared between inoculation methods. Six phenotypically resistant pepper accessions were selected based on three years of disease data. All of the selected resistant pepper accessions outperformed the control resistant pepper in terms of resistance (PI 594,137). A genome-wide association study (GWAS) was carried out to identify single nucleotide polymorphisms (SNPs) associated with anthracnose resistance. An association analysis was performed using 53,518 SNPs and the disease score of the 2020 field and in vitro experiment results. Both field and in vitro experiments revealed 25 and 32 significantly associated SNPs, respectively. These SNPs were found on all chromosomes except Ch06 and Ch07 in the field experiment, whereas in the in vitro experiment they were found on all chromosomes except Ch04 and Ch11. CONCLUSION: In this study, six resistant C. chinense accessions were selected. Additionally, in this study, significantly associated SNPs were found in a gene that codes for a protein kinase receptor, such as serine/threonine-protein kinase, and other genes that are known to be involved in disease resistance. This may strengthen the role of these genes in the development of anthracnose resistance in Capsicum spp. As a result, the SNPs discovered to be strongly linked in this study can be used to identify a potential marker for selecting pepper material resistant to anthracnose, which will assist in the development of resistant varieties.

Comparing machine learning-derived MRI-based and blood-based neurodegeneration biomarkers in predicting syndromal conversion in early AD.

INTRODUCTION: We compared the machine learning-derived, MRI-based Alzheimer's disease (AD) resemblance atrophy index (AD-RAI) with plasma neurofilament light chain (NfL) level in predicting conversion of early AD among cognitively unimpaired (CU) and mild cognitive impairment (MCI) subjects. METHODS: We recruited participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had the following data: clinical features (age, gender, education, Montreal Cognitive Assessment [MoCA]), structural MRI, plasma biomarkers (p-tau181 , NfL), cerebrospinal fluid biomarkers (CSF) (Aß42, p-tau181 ), and apolipoprotein E (APOE) ε4 genotype. We defined AD using CSF Aß42 (A+) and p-tau181 (T+). We defined conversion (C+) if a subject progressed to the next syndromal stage within 4 years. RESULTS: Of 589 participants, 96 (16.3%) were A+T+C+. AD-RAI performed better than plasma NfL when added on top of clinical features, plasma p-tau181 , and APOE ε4 genotype (area under the curve [AUC] = 0.832 vs. AUC = 0.650 among CU, AUC = 0.853 vs. AUC = 0.805 among MCI) in predicting A+T+C+. DISCUSSION: AD-RAI outperformed plasma NfL in predicting syndromal conversion of early AD. HIGHLIGHTS: AD-RAI outperformed plasma NfL in predicting syndromal conversion among early AD. AD-RAI showed better metrics than volumetric hippocampal measures in predicting syndromal conversion. Combining clinical features, plasma p-tau181 and apolipoprotein E (APOE) with AD-RAI is the best model for predicting syndromal conversion.

A Comprehensive Genome-Wide Association Study of Carotenoid and Capsaicinoid Contents in Capsicum chinense Germplasm.

Pepper is a highly important vegetable globally, both economically and nutritionally. However, to efficiently select and identify genetic resources for pepper breeding programs, it is crucial to understand the association between important traits and genetic factors. In this study, we investigated the genetic basis of carotenoid and capsaicinoid content in 160 Capsicum chinense germplasms. The study observed significant variability in carotenoid and capsaicinoid content among the germplasms. Correlation analysis revealed a strong positive correlation between violaxanthin and antheraxanthin. In contrast, capsaicin and dihydrocapsaicin displayed negative correlations with individual carotenoids but exhibited a strong positive correlation between the two compounds (r = 0.90 ***). Genotyping-by-sequencing (GBS) was performed on 160 genotypes of pepper germplasm, which identified 47,810 high-quality SNPs. A comprehensive genome-wide association analysis was performed using these SNPs to identify SNPs associated with carotenoids and capsaicinoids, revealing 193 SNPs that exhibited significant associations. Specifically, 4 SNPs were associated with violaxanthin, 2 with antheraxanthin, 86 with capsorubin, 5 with capsanthin, 63 with zeaxanthin, 3 with ß-cryptoxanthin, and 2 with α-carotene. With further studies, the significantly associated SNPs identified in this study have the potential to be utilized for selecting pepper accessions with high carotenoid and capsaicinoid contents. Additionally, the genes associated with these significant SNPs will be used to understand their roles and involvement in the biosynthesis pathway of carotenoids and capsaicinoids. Understanding the function of these genes can provide insights into the molecular mechanisms underlying the production of these bioactive compounds in pepper. The findings of this study hold valuable implications for selecting pepper varieties with desirable traits and developing breeding programs aimed at enhancing the nutritional and medicinal properties of pepper.

890-nm-excited SHG and fluorescence imaging enabled by an all-fiber mode-locked laser.

We demonstrate second-harmonic generation (SHG) microscopy excited by the ∼890-nm light frequency-doubled from a 137-fs, 19.4-MHz, and 300-mW all-fiber mode-locked laser centered at 1780 nm. The mode-locking at the 1.7-µm window is realized by controlling the emission peak of the gain fiber, and uses the dispersion management technique to broaden the optical spectrum up to 30 nm. The spectrum is maintained during the amplification and the pulse is compressed by single-mode fibers. The SHG imaging performance is showcased on a mouse skull, leg, and tail. Two-photon fluorescence imaging is also demonstrated on C. elegans labeled with green and red fluorescent proteins. The frequency-doubled all-fiber laser system provides a compact and efficient tool for SHG and fluorescence microscopy.

Probiotic supplementation demonstrates therapeutic potential in treating gut dysbiosis and improving neurocognitive function in age-related dementia.

PURPOSE: Probiotics, as live microorganisms that improve intestinal microbial balance, have been implicated in the modulation of neurodegenerative diseases via the microbiome-gut-brain axis by improving gut dysbiosis. This review examines the association between probiotics and neurocognitive function in age-related dementia. METHODS: We searched MEDLINE, Embase, Scopus, Web of Science and Cochrane library for in vivo studies using equivalent combinations of "probiotics" and "dementia" as per PRISMA. From the 52 in vivo studies identified, 5 human and 22 animal studies with comparable quantitative outcomes on neurocognitive/behavioural function were meta-analysed by forest plots, subgroup analysis and meta-regression. The analysis of biomarkers, risk of bias and publication bias were also performed. RESULTS: In elderly humans, probiotics correlates with a non-significant difference of neurocognitive function in Mini-Mental State Examination, but with significant improvement only in those diagnosed with Alzheimer's disease. In animals, probiotics significantly improved neurocognitive function as measured by Morris Water Maze, Y-Maze, and Passive Avoidance. Further analysis by subgrouping and meta-regression found that the probiotics-neurodegeneration association is age dependent in humans but is neither dose dependent nor duration dependent in animals or humans. Analysis of biomarkers suggested that the neurocognitive effect of probiotics is associated with an altered gut microbiome profile, downregulated proteinopathic, inflammatory and autophagic pathways, and upregulated anti-oxidative, neurotrophic, and cholinergic pathways. CONCLUSION: Overall, we report promising results in animal studies but limited evidence of probiotics leading to neurocognitive improvement in humans. More research into probiotics should be conducted, especially on live biotherapeutic products for targeted treatment of gut dysbiosis and age-related dementia.

Factors Affecting Domiciliary Non-Invasive Ventilation Compliance.

Few international studies have investigated factors affecting domiciliary non-invasive ventilation (D-NIV) compliance, and data from the UK are limited. We assessed compliance (defined as ≥ 4 h/night for at least 70% of the time) in a retrospective UK population study, at three time points (0-1 month, 3-4 months and 11-12 months), for all patients commenced on D-NIV over a 5-year period. A total of 359 patients were included. Non-compliant vs. compliant patients were significantly younger (median age 64 (IQR 52-72) vs. 67 (58-75) years, p = 0.032) and more likely to have schizophrenia, consistent at both 3-4 months (5% vs. 1%, p = 0.033) and 11-12 months (5% vs. 2%, p = 0.049). Repeated measures ANOVA demonstrated that the minutes [median (IQR)] of D-NIV used significantly increased at the three time points (0-1 month, 3-4 months and 11-12 months) for patients with hypertension [310 (147.5-431) vs. 341 (89-450) vs. 378 (224.5-477.5), p = 0.003]; diabetes [296.5 (132.5-417.5) vs. 342.5 (94.5-438.5) vs. 382 (247.5-476.25), p = 0.002] and heart failure [293 (177-403) vs. 326 (123-398) vs. 365 (212-493), p = 0.04]. In conclusion, younger and comorbid schizophrenic patients have lower D-NIV compliance rates, and our data suggest that persistence with D-NIV over a year may improve overall use.

Quantitative Susceptibility Mapping of the Hippocampal Fimbria in Alzheimer's Disease.

BACKGROUND: The fimbria is a small white matter bundle that connects the hippocampus to the rest of the brain. Damage to the hippocampal gray matter is established in Alzheimer's disease (AD), but the hippocampal fimbrial status in the pathogenesis of AD is unclear. AD-related demyelination and iron deposition alter the diamagnetic and paramagnetic composition of tissues, which can be measured by quantitative susceptibility mapping (QSM). HYPOTHESIS: AD is associated with microstructural changes in the fimbria that might be detected by QSM. STUDY TYPE: Retrospective cross-sectional study. SUBJECTS: In all, 53 adults comprised of controls (n = 30), subjects with early stage AD (n = 13), and late stage AD (n = 10) who were classified according to their amyloid and tau status and presence of hippocampal atrophy. FIELD STRENGTH / SEQUENCE: 3T; 3D fast-field echo sequence for QSM analysis and 3D T1 -weighted MP-RAGE sequence for anatomical analysis. ASSESSMENT: Segmentation of the left hippocampal fimbria subfield was performed on T1 -weighted images and was applied to the coregistered QSM map for extraction of the mean, median, minimum, and maximum values of QSM. STATISTICAL TESTS: Group comparison of QSM values using analysis of variance (ANOVA) with post-hoc Tukey's test, accuracy of binary differentiation using receiver operating characteristic (ROC), and individual classification using discriminant analysis. RESULTS: QSMmean and QSMmedian values were significantly different among the three groups (P < 0.05) and showed a shifting from negative in the control group to positive in the AD group. The control and early AD subjects, who have normal hippocampal volumes, were differentiated by the QSMmean value (area under the curve [AUC] 0.744, P < 0.05) and the QSMmedian value (AUC 0.782, P < 0.05). Up to 76% of subjects (inclusive of 26 controls and six with early AD) were correctly classified using a model incorporating clinical and radiologic data. DATA CONCLUSION: The fimbria showed higher magnetic susceptibility in AD compared with controls. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3.

Functional organization of excitatory synaptic strength in primary visual cortex.

The strength of synaptic connections fundamentally determines how neurons influence each other's firing. Excitatory connection amplitudes between pairs of cortical neurons vary over two orders of magnitude, comprising only very few strong connections among many weaker ones. Although this highly skewed distribution of connection strengths is observed in diverse cortical areas, its functional significance remains unknown: it is not clear how connection strength relates to neuronal response properties, nor how strong and weak inputs contribute to information processing in local microcircuits. Here we reveal that the strength of connections between layer 2/3 (L2/3) pyramidal neurons in mouse primary visual cortex (V1) obeys a simple rule--the few strong connections occur between neurons with most correlated responses, while only weak connections link neurons with uncorrelated responses. Moreover, we show that strong and reciprocal connections occur between cells with similar spatial receptive field structure. Although weak connections far outnumber strong connections, each neuron receives the majority of its local excitation from a small number of strong inputs provided by the few neurons with similar responses to visual features. By dominating recurrent excitation, these infrequent yet powerful inputs disproportionately contribute to feature preference and selectivity. Therefore, our results show that the apparently complex organization of excitatory connection strength reflects the similarity of neuronal responses, and suggest that rare, strong connections mediate stimulus-specific response amplification in cortical microcircuits.

Diverse coupling of neurons to populations in sensory cortex.

A large population of neurons can, in principle, produce an astronomical number of distinct firing patterns. In cortex, however, these patterns lie in a space of lower dimension, as if individual neurons were "obedient members of a huge orchestra". Here we use recordings from the visual cortex of mouse (Mus musculus) and monkey (Macaca mulatta) to investigate the relationship between individual neurons and the population, and to establish the underlying circuit mechanisms. We show that neighbouring neurons can differ in their coupling to the overall firing of the population, ranging from strongly coupled 'choristers' to weakly coupled 'soloists'. Population coupling is largely independent of sensory preferences, and it is a fixed cellular attribute, invariant to stimulus conditions. Neurons with high population coupling are more strongly affected by non-sensory behavioural variables such as motor intention. Population coupling reflects a causal relationship, predicting the response of a neuron to optogenetically driven increases in local activity. Moreover, population coupling indicates synaptic connectivity; the population coupling of a neuron, measured in vivo, predicted subsequent in vitro estimates of the number of synapses received from its neighbours. Finally, population coupling provides a compact summary of population activity; knowledge of the population couplings of n neurons predicts a substantial portion of their n(2) pairwise correlations. Population coupling therefore represents a novel, simple measure that characterizes the relationship of each neuron to a larger population, explaining seemingly complex network firing patterns in terms of basic circuit variables.

A retrospective study on the risk of tuberculosis in patients with rheumatoid arthritis.

Tuberculosis (TB) is an important preventable infection in patients with rheumatoid arthritis (RA). To determine the risk of TB in patients with RA by comparing with those with non-specific back pain (NSBP), and to identify the risk factors in the RA group. Medical data were retrieved from a centralized electronic database. A total of 1099 patients with RA and 2489 patients with NSBP were identified. Clinical data, comorbidities, and use of individual disease-modifying anti-rheumatic drugs (DMARDs) were retrieved. Risks of TB in patients with RA and NSBP were compared by propensity score (PS) adjusted analysis with known or potential risk factors for TB. Risk factors of TB were also determined in patients with RA. There were 14 cases of TB in RA group and 25 cases in NSBP group. Median duration of follow-up were 11.3 (0.1-21.9) years in RA group and 15.4 (0.1-24.4) years in NSBP group. The risk of TB in patients with RA was 2.53 times higher (HR 2.53; 95% CI 1.29, 4.94; p < 0.01) than in patients with NSBP. After excluding patients on DMARDs, the risk became similar (HR 2.72; 95% CI 0.81, 9.14; p = 0.11). Independent risk factors found were etanercept (HR 7.16; 95% CI 1.41, 36.30; p = 0.02), and previous TB infection (HR 25.23; 95% CI 6.99, 91.09; p < 0.001). The risk of extrapulmonary involvement between RA and NSBP groups was similar (HR 1.21; 95% CI 0.22, 6.57; p = 0.83). The risk of TB was increased in patients with RA. Anti-TNF therapy was an identified risk factor.

Tackling challenges in care of Alzheimer's disease and other dementias amid the COVID-19 pandemic, now and in the future.

We have provided an overview on the profound impact of COVID-19 upon older people with Alzheimer's disease and other dementias and the challenges encountered in our management of dementia in different health-care settings, including hospital, out-patient, care homes, and the community during the COVID-19 pandemic. We have also proposed a conceptual framework and practical suggestions for health-care providers in tackling these challenges, which can also apply to the care of older people in general, with or without other neurological diseases, such as stroke or parkinsonism. We believe this review will provide strategic directions and set standards for health-care leaders in dementia, including governmental bodies around the world in coordinating emergency response plans for protecting and caring for older people with dementia amid the COIVD-19 outbreak, which is likely to continue at varying severity in different regions around the world in the medium term.

Reduced lysosomal clearance of autophagosomes promotes survival and colonization of Helicobacter pylori.

Evasion of autophagy is key for intracellular survival of bacteria in host cells, but its involvement in persistent infection by Helicobacter pylori, a bacterium identified to invade gastric epithelial cells, remains obscure. The aim of this study was to functionally characterize the role of autophagy in H. pylori infection. Autophagy was assayed in H. pylori-infected human gastric epithelium and the functional role of autophagy was determined via genetic or pharmacological ablation of autophagy in mouse and cell line models of H. pylori infection. Here, we showed that H. pylori inhibited lysosomal function and thereby promoted the accumulation of autophagosomes in gastric epithelial cells. Importantly, inhibiting autophagosome formation by pharmacological inhibitors or genetic ablation of BECN1 or ATG5 reduced H. pylori intracellular survival, whereas inhibition of lysosomal functions exerted an opposite effect. Further experiments demonstrated that H. pylori inhibited lysosomal acidification and the retrograde trafficking of mannose-6-phosphate receptors, both of which are known to positively regulate lysosomal function. We conclude that H. pylori subverts autophagy into a pro-survival mechanism through inhibition of lysosomal clearance of autophagosomes. Disruption of autophagosome formation offers a novel strategy to reduce H. pylori colonization in human stomachs. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The emergence of functional microcircuits in visual cortex.

Sensory processing occurs in neocortical microcircuits in which synaptic connectivity is highly structured and excitatory neurons form subnetworks that process related sensory information. However, the developmental mechanisms underlying the formation of functionally organized connectivity in cortical microcircuits remain unknown. Here we directly relate patterns of excitatory synaptic connectivity to visual response properties of neighbouring layer 2/3 pyramidal neurons in mouse visual cortex at different postnatal ages, using two-photon calcium imaging in vivo and multiple whole-cell recordings in vitro. Although neural responses were already highly selective for visual stimuli at eye opening, neurons responding to similar visual features were not yet preferentially connected, indicating that the emergence of feature selectivity does not depend on the precise arrangement of local synaptic connections. After eye opening, local connectivity reorganized extensively: more connections formed selectively between neurons with similar visual responses and connections were eliminated between visually unresponsive neurons, but the overall connectivity rate did not change. We propose a sequential model of cortical microcircuit development based on activity-dependent mechanisms of plasticity whereby neurons first acquire feature preference by selecting feedforward inputs before the onset of sensory experience--a process that may be facilitated by early electrical coupling between neuronal subsets--and then patterned input drives the formation of functional subnetworks through a redistribution of recurrent synaptic connections.

Morphological Diversity, Protein Adsorption, and Cellular Uptake of Polydopamine-Coated Gold Nanoparticles.

Polydopamine (PDA)-coated nanoparticles are adhesive bionanomaterials widely utilized in intracellular applications, yet how their adhesiveness affects their colloidal stability and their interactions with serum proteins and mammalian cells remain unclear. In this work, we systematically investigate the combined effects of dopamine (DA) concentration and polymerization time (both reaction parameters spanning 2 orders of magnitude) on the morphological diversity of PDA-coated nanoparticles by coating PDA onto gold nanoparticle cores. Independent of the DA concentration, Au@PDA NPs remain largely aggregated upon several hours of limited polymerization; interestingly, extended polymerization for 2 days or longer yield randomly aggregated NPs, nearly monodisperse NPs, or worm-like NP chains in the ascending order of DA concentration. Upon exposure to serum proteins, the specific type of proteins adsorbed to the Au@PDA NPs strongly depends upon the DA concentration. As DA concentration increases, less albumin and more hemoglobin subunits adhere. Moreover, cellular uptake is a strong function of polymerization time. Serum-stabilized Au@PDA NPs prepared by limited polymerization enter Neuro-2a and HeLa cancer cells more abundantly than those prepared by extended polymerization. Our data underscore the importance of DA concentration and polymerization time for tuning the morphology and degree of intracellular delivery of PDA-coated nanostructures.

Functional specificity of local synaptic connections in neocortical networks.

Neuronal connectivity is fundamental to information processing in the brain. Therefore, understanding the mechanisms of sensory processing requires uncovering how connection patterns between neurons relate to their function. On a coarse scale, long-range projections can preferentially link cortical regions with similar responses to sensory stimuli. But on the local scale, where dendrites and axons overlap substantially, the functional specificity of connections remains unknown. Here we determine synaptic connectivity between nearby layer 2/3 pyramidal neurons in vitro, the response properties of which were first characterized in mouse visual cortex in vivo. We found that connection probability was related to the similarity of visually driven neuronal activity. Neurons with the same preference for oriented stimuli connected at twice the rate of neurons with orthogonal orientation preferences. Neurons responding similarly to naturalistic stimuli formed connections at much higher rates than those with uncorrelated responses. Bidirectional synaptic connections were found more frequently between neuronal pairs with strongly correlated visual responses. Our results reveal the degree of functional specificity of local synaptic connections in the visual cortex, and point to the existence of fine-scale subnetworks dedicated to processing related sensory information.

5-HT3a Receptors Modulate Hippocampal Gamma Oscillations by Regulating Synchrony of Parvalbumin-Positive Interneurons.

Gamma-frequency oscillatory activity plays an important role in information integration across brain areas. Disruption in gamma oscillations is implicated in cognitive impairments in psychiatric disorders, and 5-HT3 receptors (5-HT3Rs) are suggested as therapeutic targets for cognitive dysfunction in psychiatric disorders. Using a 5-HT3aR-EGFP transgenic mouse line and inducing gamma oscillations by carbachol in hippocampal slices, we show that activation of 5-HT3aRs, which are exclusively expressed in cholecystokinin (CCK)-containing interneurons, selectively suppressed and desynchronized firings in these interneurons by enhancing spike-frequency accommodation in a small conductance potassium (SK)-channel-dependent manner. Parvalbumin-positive interneurons therefore received diminished inhibitory input leading to increased but desynchronized firings of PV cells. As a consequence, the firing of pyramidal neurons was desynchronized and gamma oscillations were impaired. These effects were independent of 5-HT3aR-mediated CCK release. Our results therefore revealed an important role of 5-HT3aRs in gamma oscillations and identified a novel crosstalk among different types of interneurons for regulation of network oscillations. The functional link between 5-HT3aR and gamma oscillations may have implications for understanding the cognitive impairments in psychiatric disorders.