Medial Cells Research Articles

Projection motifs and wiring logic of medial pulvinar thalamocortical axons in the marmoset monkey.

The medial pulvinar thalamic nucleus (MPu) is an evolutionary novelty of the primate thalamus, prominently expanded in humans. Piecemeal data from studies in various monkey species indicates that MPu axons reach prefrontal, inferior parietal, cingulate, insular or temporal areas; however, the precise wiring and functional logic of such brain-wide connections remain obscure. In marmoset monkeys (Callithrix jacchus) of both sexes, we visualized the axons originated from specific pulvinar domains by means of biotinylated dextranamine (BDA) microinjections and compared them across multiple cases. In addition, by injecting retrograde tracers in the cortical areas targeted by the pulvinar axons, we investigated the organization of projection cells within MPu and the existence of long-range branched axons. Specific projection motifs reveal a caudal MPu subnucleus that innervates inferior and ventral temporal areas, and a rostral MPu subnucleus that innervates temporal, ventral prefrontal, premotor, inferior posterior parietal and cingulate areas. We demonstrate numerous MPu neurons that innervate through branched axons prefrontal and parietal or prefrontal and temporal areas; other cells with different projection patterns are closely intermingled with them. Our findings support the notion that MPu is a hub of the brain-wide networks that support complex visual and social cognition, sensory-guided reaching, working memory, and attention. Moreover, the finding of long-range branching MPu axons and dense terminal arborizations suggest that MPu cells may regulate functional connectivity among high-level cortical areas at widely different spatial scales. Besides, the anatomical "ground truth" provided by our study is relevant for functional imaging and distributed network modelling studies.Significance statement The medial nucleus of the pulvinar complex is an evolutionary novelty of the primate thalamus and is uniquely expanded in humans. However, its functions are poorly understood, as data on its connections remain incomplete and fragmentary. Using high-resolution connection-labeling methods in marmoset monkeys, we mapped in full the thalamocortical axons arising from specific medial pulvinar domains and analyzed their branching patterns. Projection motifs reveal two main subnuclei, each targeting specific cortical networks. Moreover, we show that some pulvinar neurons simultaneously innervate distant prefrontal and parietal areas or prefrontal and temporal areas. Their connection patterns might allow medial pulvinar cells modulate, at different scales, functional connectivity in the cortical networks supporting object vision, social cognition, attention sensory-guided reaching and working memory.

Impact and mechanism of the TBX-22 gene mutation G874A on the epithelial-mesenchymal transition in medial edge epithelial cells.

Cleft lip and palate (CL/P) are prevalent congenital anomalies with complex genetic causes. The G874A mutation of T-box transcription factor 22 (TBX-22) gene is notably associated with CL/P, while the underlying mechanism remains to be clarified. Studies have shown that the restriction of epithelial-mesenchymal transformation (EMT) process in medial edge epithelial cells (MEEs) is crucial for CL/P development. In our current research, primary MEEs, isolated and cultured from mouse embryos, were genetically introduced the TBX-22 G874A mutation and subsequently treated with TGF-β1. They were then utilized to test the hypothesis that the G874A mutation in TBX22 plays a role in the regulation of the EMT in MEEs. Our findings reveal that TBX22 reduces miR140-5p transcription by binding to its promoter, while miR140-5p downregulates TGFBR1 protein expression by targeting its mRNA 3'-UTR. In other words, TBX22 could indirectly positively regulates TGFBR1 expression post-transcriptionally. Functional cellular assays showed that the G874A mutation of TBX-22 counteracted TGF-β1-induced decrease in proliferation and migration. Western blotting results showed that the G874A mutation of TBX-22 inhibited EMT protein expression (α-SMA and Vimentin) and promoted E-cadherin in TGF-β1-induced MEEs. To summarize, our research reveals that the G874A mutation of TBX22 impedes the progression of EMT in MEEs through the upregulation of miR140-5p and the downregulation of TGFBR1. This highlights TGFBR1 as a viable target for the prevention of CL/P.

Exosome-Mediated Transfer of X-Motif-Tagged Anti-MiR-33a-5p Antagomirs to the Medial Cells of Transduced Rabbit Carotid Arteries.

Atherosclerosis is caused by the accumulation of cholesterol within intimal smooth muscle cells (SMCs) and macrophages. However, the transporter ATP-binding cassette subfamily A, member 1 (ABCA1), can remove cholesterol from these intimal, cells reducing atherosclerosis. Antagomir-mediated inhibition of miR-33a-5p, a microRNA that represses ABCA1 translation, promotes ABCA1-dependent cholesterol efflux and may impede atherosclerosis development. In our previous work, transducing cultured endothelial cells (ECs) with a helper-dependent adenoviral vector (HDAd) that expresses X-motif-tagged anti-miR-33a-5p enhanced antagomir packaging into EC-derived exosomes, which delivered the antagomir to cultured SMCs and macrophages. In this present study, we tested whether in vivo transduction of rabbit carotid artery endothelium can deliver an X-motif-tagged anti-miR-33a-5p to subendothelial cells. Rabbit carotid endothelial cells were transduced in vivo with an HDAd expressing anti-miR-33a-5p either with or without the X-motif (n = 11 arteries per vector). Contralateral carotids received HDAd that express scrambled oligonucleotides. Three days after transduction, the antagomir-without the X-motif-was detected in the intima but not in the media of transduced carotids (p = 0.062). The X-motif antagomir was detected in 82% of the intimal extracts (9 out of 11 carotids) and 27% of medial samples (3 out of 11 carotids, p = 0.031). However, the X-motif did not significantly enhance antagomir delivery to the media (p = 0.214 vs. non-X-motif antagomir). Expression of the antagomirs-with and without the X-motif-was sub-stoichiometric in ECs and SMCs. No antagomir-related changes in miR-33a-5p or ABCA1 expressions were detected. Despite its potential as a therapeutic strategy, our exosome-targeted gene transfer system requires further improvements to enhance antagomir expression and delivery to the subendothelial cells.

Radioanatomical evaluation of the subtympanic sinus in children under five years old and its clinical implications - high resolution computed tomography study.

This study aimed to evaluate subtympanic sinus (STS) and its vicinity in high-resolution computed tomography (HRCT) scans of children under five years old with non-diseased temporal bones. We divided the whole group into children under 24 months of age (first stage of pneumatisation development) and between 25 and 60 (second stage). We have determined the width of the entrance to STS, depth of the STS, type in relation to facial nerve according to Anschuetz classification, the pneumatisation of posterior and medial air cell tracts, and jugular bulb position. All the HRCTs (280 temporal bones) were analyzed according to the multiplanar reconstruction protocol with symmetrization. STS's mean width and depth were 2.71 ± 0.60mm and 3.26 ± 1.11mm, respectively. The most common STS type was type A (59.3%), followed by type B (30.7%) and type C (10%). The posterior air cell tract (retrofacial cells) was present in 39.3%. The medial air cell tract (hypotympanic cells) was present in 30.7% The jugular bulb position affected the final shape of STS in 17.5%. The results support the necessity of the classification for the STS. Our study may help with surgical planning regarding endoscopic ear procedures and gives a broader understanding of how pneumatization or jugular bulb might correlate with the final shape of the retrotympanum. The historical remarks track the term's origin for clarity in research and respect for earlier investigators.

Modification of pre-ictal cortico-hippocampal oscillations by medial ganglionic eminence precursor cells grafting in the pilocarpine model of epilepsy

Cell replacement therapies using medial ganglionic eminence (MGE)-derived GABAergic precursors reduce seizures by restoring inhibition in animal models of epilepsy. However, how MGE-derived cells affect abnormal neuronal networks and consequently brain oscillations to reduce ictogenesis is still under investigation. We performed quantitative analysis of pre-ictal local field potentials (LFP) of cortical and hippocampal CA1 areas recorded in vivo in the pilocarpine rat model of epilepsy, with or without intrahippocampal MGE-precursor grafts (PILO and PILO+MGE groups, respectively). The PILO+MGE animals had a significant reduction in the number of seizures. The quantitative analysis of pre-ictal LFP showed decreased power of cortical and hippocampal delta, theta and beta oscillations from the 5 min. interictal baseline to the 20 s. pre-ictal period in both groups. However, PILO+MGE animals had higher power of slow and fast oscillations in the cortex and lower power of slow and fast oscillations in the hippocampus compared to the PILO group. Additionally, PILO+MGE animals exhibited decreased cortico-hippocampal synchrony for theta and gamma oscillations at seizure onset and lower hippocampal CA1 synchrony between delta and theta with slow gamma oscillations compared to PILO animals. These findings suggest that MGE-derived cell integration into the abnormally rewired network may help control ictogenesis.

Transcriptomic analysis of the human habenula in schizophrenia.

Transcriptomic analysis of the human habenula and identification of molecular changes associated with schizophrenia risk and illness state.

Molecular anatomy of emerging Xenopus left-right organizer at successive developmental stages.

Vertebrate left-right symmetry breaking is preceded by formation of left-right organizer. In Amphibian, this structure is formed by gastrocoel roof plate, which emerges from superficial suprablastoporal cells. GRP is subdivided into medial area, which generates leftward flow by rotating monocilia and lateral Nodal1 expressing areas, which are involved in sensing of the flow. After successful symmetry breaking, medial cells are incorporated into a deep layer where they contribute to the axial mesoderm, while lateral domains join somitic mesoderm. Here, we performed detailed analysis of spatial and temporal gene expression of important markers and the corresponding morphology of emerging GRP. Endodermal marker Sox17 and markers of superficial mesoderm display complementary patterns at all studied stages. At early stages, GRP forms Tekt2 positive epithelial domain clearly separated from underlying deep layers, while at later stages, this separation disappears. Marker of early somitic mesoderm MyoD1 was absent in emerging GRP and was induced together with Nodal1 during early neurulation. Decreasing morphological separation is accompanied by lateral to medial covering of GRP by endoderm. Our data supports continuous link between superficial mesoderm at the start of gastrulation and mature GRP and suggests late induction of somitic fate in lateral GRP.

Age-related alterations in efferent medial olivocochlear-outer hair cell and primary auditory ribbon synapses in CBA/J mice.

Hearing decline stands as the most prevalent single sensory deficit associated with the aging process. Giving compelling evidence suggesting a protective effect associated with the efferent auditory system, the goal of our study was to characterize the age-related changes in the number of efferent medial olivocochlear (MOC) synapses regulating outer hair cell (OHC) activity compared with the number of afferent inner hair cell ribbon synapses in CBA/J mice over their lifespan. Organs of Corti of 3-month-old CBA/J mice were compared with mice aged between 10 and 20 months, grouped at 2-month intervals. For each animal, one ear was used to characterize the synapses between the efferent MOC fibers and the outer hair cells (OHCs), while the contralateral ear was used to analyze the ribbon synapses between inner hair cells (IHCs) and type I afferent nerve fibers of spiral ganglion neurons (SGNs). Each cochlea was separated in apical, middle, and basal turns, respectively. The first significant age-related decline in afferent IHC-SGN ribbon synapses was observed in the basal cochlear turn at 14 months, the middle turn at 16 months, and the apical turn at 18 months of age. In contrast, efferent MOC-OHC synapses in CBA/J mice exhibited a less pronounced loss due to aging which only became significant in the basal and middle turns of the cochlea by 20 months of age. This study illustrates an age-related reduction on efferent MOC innervation of OHCs in CBA/J mice starting at 20 months of age. Our findings indicate that the morphological decline of efferent MOC-OHC synapses due to aging occurs notably later than the decline observed in afferent IHC-SGN ribbon synapses.

Liver-specific Bmal1 deletion in mice leads to increased aortic stiffness and altered vascular remodeling

Circadian rhythms have an important role in cardiovascular physiology. Circadian clock genes are critical for vascular homeostasis. Global loss of the circadian clock gene Bmal1 increases aortic stiffness with impaired vascular function and blood pressure rhythm in mice. We previously found that hepatocyte-specific Bmal1 deletion (HBK) in the liver changes perivascular adipose tissue-mediated vascular function in young adult mice, indicating that liver circadian clock disruption distally affects function in another tissue and potential cross-talk between the liver and vasculature. We hypothesized that liver-specific Bmal1 deletion leads to aortic stiffness and pathological vascular remodeling. Studies were performed in 4- to 6- month old male HBK and flox control mice. Aortic stiffness, measured by pulse wave velocity, was significantly elevated in HBK mice compared to flox control mice (Flox: 1.84 ± 0.1 m/s; HBK: 2.9 ± 0.2 m/s; n = 5, p < 0.01). Systolic blood pressure (tail-cuff) in the light phase was similar in both flox control and HBK mice (Flox: 101 ± 1 mm Hg; HBK: 103 ± 2 mm Hg; n = 3-5, p = 0.35). Aortas and plasma were collected at ZT2 for histological analysis and metabolite measurements. MetaMorph software analysis of Masson’s Trichrome-stained aortic sections revealed significantly increased aortic wall fibrosis in HBK mice (% fibrosis per area, Flox 17.0% ± 3.3%, HBK 27.4% ± 2.1%, p=0.03). The medial cell number in H&E stained-aortic sections was increased in HBK mice compared to flox control mice (Flox: 534.6 ± 31.9; HBK: 1069 ± 90.1; p < 0.01). TUNEL stained apoptotic cells were also counted and more apoptotic cells were observed in young HBK mice aortas compared to flox controls (Flox: 224.4 ± 56.1; HBK: 408.4 ± 20.8; p = 0.02). Aortic wall thickness was not different in young adult HBK mice compared to flox control mice. Aortic levels of the lipid peroxidation marker vascular 4-hydroxynonenal (4-HNE), a measure of oxidative stress, were similar between flox control and HBK mice. In plasma, the oxidative stress marker, 8-hydroxy-2’-deoxyguanosine (8-OHdG), a DNA damage product, and plasminogen activator inhibitor-1 (PAI-1) were not different between genotypes. In conclusion, our findings indicate that liver circadian clock disruption increases aortic stiffness and fibrosis with higher cell numbers as well as aortic apoptosis. These data suggest that altered vascular remodeling in HBK mice may contribute to aortic stiffness resulting in cardiovascular disease. Funded by P01HL136267 to JSP, R21AA026906 to SMB, and AHA 856877 to PP. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

PDGFRALPHA ACTIVATION LEADS TO BLOOD PRESSURE INCREASE AND SMALL ARTERIES MEDIAL HYPERTROPHY IN MALE MICE

Objective: Arterial remodeling is associated with vascular function alteration and with hypertension development. This remodeling is due to cells reorganization within the vascular wall and in some cases to smooth muscle cells proliferation. PDGF (Platelet-derived Growth Factor) is a major regulator of arterial remodeling and some studies suggest that PDGFRα, one of its receptors, could be activated during hypertension. Our aim is to determine the role of PDGFRα and of PDGFRα-expressing progenitor cells in vascular remodeling. Design and method: We used a tamoxifen-inducible genetic mouse model of PDGFRα constitutive activation. Blood pressure was measured by the tail-cuff method and by carotid catheter. Small mesenteric arteries reactivity was studied using ex vivo arteriography. Vascular remodeling was analyzed by immunofluorescence. Results: PDGFRα constitutive activation for 6 weeks led to a 25% increase in blood pressure (p<0.05) and a 25% decrease in cardiac output in male mice (p<0.05), without changes in other cardiac parameters. In these mice, small mesenteric arteries showed no alteration in contractility or endothelium-dependent and independent relaxation but an increase of media thickness, whereas larger vessels did not show structure or function alteration. Echo-doppler analyses showed an increased resistivity index of the renal artery (+13% p<0.05) but not of the aorta suggesting an increased resistance of small renal arteries. The remodeling of small mesenteric arteries was characterized by an early proliferation of perivascular cells at 4 days but not of medial cells followed by the production of new smooth muscle cells after 2 weeks. Female mice did not show blood pressure increase following induction of PDGFRα constitutive activation for 6 weeks. Small mesenteric arteries showed a reduced contractility with alteration of endothelium-dependent and independent relaxation. Conclusions: These results suggest that PDGFRα activation could participate in arterial hypertension development by leading to increased media thickness and stiffness in small arteries in males. Our results suggest that in females the increased resistance of small vessels is compensated by a decreased contractility.

Computed Tomographic Study of Frontal Sinus Cells and Opacification as Per the International Frontal Sinus Anatomy Classification.

International frontal sinus anatomy classification (IFAC) was introduced in 2016 to standardize the nomenclature of the cells in the frontal recess region, facilitate better communication between surgeons and precision in surgical planning, and improve surgical teaching. This study aims to estimate the radiological prevalence of the different frontal recess cells according to the IFAC and to evaluate the relationship of these cells with the frontal sinus opacification in patients with chronic rhinosinusitis. In this study, 90 participants diagnosed with chronic rhinosinusitis (CRS) who underwent computed tomogram (CT) of the para nasal sinuses were enrolled consecutively. The CT images were were studied in detail using RadiAnt DICOM viewer. The frontal recess cells were grouped as per the IFAC guidelines and their respective prevalence was calculated. The frontal recess cells were grouped as per the Opacification or mucosal thickening within these cells and the frontal sinuses were noted. A multivariate logistic regression analysis was done to evaluate the association between frontal sinus opacification and presence of various IFAC cells. A total of 640 IFAC cells were documented in 180 sides, of which 326 were anterior cells, 263 were posterior cells and 51 were medial cells. The most prevalent cell was the agger nasi cells(ANC), present in 91.7% of 180 sides, the supra agger nasi cells(SANC), Supra agger nasi frontal cells(SAFC), supra bulla cells(SBC), supra bulla frontal cells(SBFC), supra orbital ethmoidal cells(SOEC) and frontal septal cells(FSC) were present in 47.8%,37.8%, 65.6%,28.9%, 51.1% and 28.3% respectively. There was no significant association of presence of IFAC cells and frontal sinus opacification except for SBFC(p = 0.038). A significantly higher number of diseased frontal recess cells were seen with involved frontal sinuses when compared with non-involved frontal sinuses across all types of IFAC cells. The ANC were the most prevalent among all the IFAC cells and the FSC were the least prevalent. There was no significant association with the presence of different types of IFAC cells and frontal sinus opacification except for SBFC. However, there was a significantly higher number of diseased IFAC cells associated with frontal sinus opacification than in those without frontal sinus opacification.

Treadmill exercise pretreatment ameliorated structural synaptic plasticity impairments of medial prefrontal cortex in vascular dementia rat and improved recognition memory

This study aimed to investigate structural synaptic plasticity in the medial prefrontal cortex of rats under treadmill exercise pretreatment or naive conditions in a vascular dementia model, followed by recognition memory performance in a novel object recognition task. In this study, 24 Sprague–Dawley rats were obtained and randomly assigned into 4 groups as follows: control group (Con group, n = 6), vascular dementia (VD group, n = 6), exercise and vascular dementia group (Exe + VD group, n = 6), and exercise group (Exe group, n = 6). Initially, 4 weeks of treadmill exercise intervention was administered to the rats in the Exe + VD and Exe groups. Then, to establish the vascular dementia model, the rats both in the VD and Exe + VD groups were subjected to bilateral common carotids arteries surgery. One week later, open-field task and novel recognition memory task were adopted to evaluate anxiety-like behavior and recognition memory in each group. Then, immunofluorescence and Golgi staining were used to evaluate neuronal number and spine density in the rat medial prefrontal cortex. Transmission electron microscopy was used to observe the synaptic ultrastructure. Finally, microdialysis coupled with high-performance liquid chromatography was used to assess the levels of 5-HT and dopamine in the medial prefrontal cortex. The behavior results showed that 4 weeks of treadmill exercise pretreatment significantly alleviated recognition memory impairment and anxiety-like behavior in VD rats (P < 0.01), while the rats in VD group exhibited impaired recognition memory and anxiety-like behavior when compared with the Con group (P < 0.001). Additionally, NeuN immunostaining results revealed a significant decrease of NeuN-marked neuron in the VD group compared to Con group (P < 0.01), but a significantly increase in this molecular marker was found in the Exe + VD group compared to the Con group (P < 0.01). Golgi staining results showed that the medial prefrontal cortex neurons in the VD group displayed fewer dendritic spines than those in the Con group (P < 0.01), and there were more spines on the dendrites of medial prefrontal cortex cells in Exe + VD rats than in VD rats (P < 0.01). Transmission electron microscopy further revealed that there was a significant reduction of synapses intensity in the medial prefrontal cortex of rats in the VD group when compared with the Con group(P < 0.01), but physical exercise was found to significantly increased synapses intensity in the VD model (P < 0.01). Lastly, the levels of dopamine and 5-HT in the medial prefrontal cortex of rats in the VD group was significantly lower compared to the Con group (P < 0.01), and treadmill exercise was shown to significantly increased the levels of dopamine and 5-HT in the VD rats (P < 0.05). Treadmill exercise pretreatment ameliorated structural synaptic plasticity impairments of medial prefrontal cortex in VD rat and improved recognition memory.

Two new species and new material of the family Evaniidae (Hymenoptera: Evanioidea) from the mid-Cretaceous amber of Northern Myanmar

Two new species, Sorellevania rara Li, Shih & Ren, sp. nov. and Iberoevania nova Li, Shih & Ren, sp. nov., and a new specimen of Cretevania bechlyi Jennings, Krogmann & Mew, 2013 are described and illustrated respectively from two male and one female specimens preserved in the mid-Cretaceous Kachin amber. Sorellevania rara sp. nov. is the third species of the genus Sorellevania Engel, 2006. The placement of the new specimen in the latter genus is supported by its small body size, its elbowed antenna, and its forewing venation (e.g., the shape of the medial cells). Iberoevania nova sp. nov. is assigned to Iberoevania based on its forewing with five enclosed cells, the crossveins 2r-m, and 2m-cu absent while 1rs-m is present, and its long petiole (about half the length of the gaster). A map of the deposits yielding Evaniidae during the Cretaceous and a histogram of Evaniidae species and genus diversity during the Cretaceous and Cenozoic are provided.

The effects of hydration on the topographical and mechanical properties of corneocytes

It is well established that the biomechanical properties of the Stratum Corneum (SC) are influenced by both moisture-induced plasticization and the lipid content. This study employs Atomic Force Microscopy to investigate how hydration affects the surface topographical and elasto-viscoplastic characteristics of corneocytes from two anatomical sites. Volar forearm cells underwent swelling when immersed in water with a 50% increase in thickness and volume. Similarly, medial heel cells demonstrated significant swelling in volume, accompanied by increased cell area and reduced cell roughness. Furthermore, as the water activity was increased, they exhibited enhanced compliance, leading to a decreased Young's modulus, hardness, and relaxation times. Moreover, the swollen cells also displayed a greater tolerance to strain before experiencing permanent deformation. Despite the greater predominance of immature cornified envelopes in plantar skin, the comparable Young's modulus of medial heel and forearm corneocytes suggests that cell stiffness primarily relies on the keratin matrix rather than on the cornified envelope. The Young's moduli of the cells in distilled water are similar to those reported for the SC, which suggests that the corneodesmosomes and intercellular lamellae lipids junctions that connect the corneocytes are able to accommodate the mechanical deformations of the SC.

Sex-specific metabolic adaptations from in utero exposure to particulate matter derived from combustion of petrodiesel and biodiesel fuels

Maternal exposure to particulate matter derived from diesel exhaust has been shown to cause metabolic dysregulation, neurological problems, and increased susceptibility to diabetes in the offspring. Diesel exhaust is a major source of air pollution and the use of biodiesel (BD) and its blends have been progressively increasing throughout the world; however, studies on the health impact of BD vs. petrodiesel combustion-generated exhaust have been controversial in part, due to differences in the chemical and physical nature of the associated particulate matter (PM). To explore the long-term impact of prenatal exposure, pregnant mice were exposed to PM generated by combustion of petrodiesel (B0) and a 20% soy BD blend (B20) by intratracheal instillation during embryonic days 9–17 and allowed to deliver. Offspring were then followed for 52 weeks. We found that mother's exposure to B0 and B20 PM manifested in striking sex-specific phenotypes with respect to metabolic adaptation, maintenance of glucose homeostasis, and medial hypothalamic glial cell makeup in the offspring. The data suggest PM exposure limited to a narrower critical developmental window may be compensated for by the mother and/or the fetus by altered metabolic programming in a marked sex-specific and fuel-derived PM-specific manner, leading to sex-specific risk for diseases related to environmental exposure later in life.

Characterisation of topographical, biomechanical and maturation properties of corneocytes with respect to anatomical location.

The Stratum Corneum (SC) is the first barrier of the skin. The properties of individual cells are crucial in understanding how the SC at different anatomical regions maintains a healthy mechanical barrier. The aim of the current study is to present a comprehensive description of the maturation and mechanical properties of superficial corneocytes at different anatomical sites in the nominal dry state. Corneocytes were collected from five anatomical sites: forearm, cheek, neck, sacrum and medial heel of 10 healthy young participants. The surface topography was analysed using Atomic Force Microscopy (AFM) and Scanning Electron Microscopy (SEM). The level of positive-involucrin cornified envelopes (CEs) and desmoglein-1 (Dsg1) were used as indirect measures of immature CEs and corneodesmosomes, respectively. In addition, AFM nanoindentation and stress-relaxation experiments were performed to characterise the mechanical properties. Volar forearm, neck and sacrum corneocytes presented similar topographies (ridges and valleys) and levels of Dsg1 (13-37%). In contrast, cheek cells exhibited circular nano-objects, while medial heel cells were characterized by villi-like structures. Additionally, medial heel samples also showed the greatest level of immature CEs (32-56%, p<0.001) and Dsg1 (59-78%, p<0.001). A large degree of inter-subject variability was found for the Young's moduli of the cells (0.19-2.03GPa), which was correlated with the level of immature CEs at the cheek, neck and sacrum (p<0.05). It is concluded that a comprehensive study of the mechanical and maturation properties of corneocytes may be used to understand the barrier functions of the SC at different anatomical sites.

Severe arterial injury heals with a complex clonal structure involving a large fraction of surviving smooth muscle cells

Background and aimsSmooth muscle cell (SMC) lineage cells in atherosclerosis and flow cessation-induced neointima are oligoclonal, being recruited from a tiny fraction of medial SMCs that modulate and proliferate. The present study aimed to investigate the clonal structure of SMC lineage cells healing more severe arterial injury. MethodsArterial injury (wire, stretch, and partial ligation) was inflicted on the right carotid artery in mice with homozygous, SMC-restricted, stochastically recombining reporter transgenes that produced mosaic expression of 10 distinguishable fluorescent phenotypes for clonal tracking. Healed arteries and contra-lateral controls were analyzed after 3 weeks. Additional analysis of cell death and proliferation after injury was performed in wildtype mice. ResultsThe total number of SMC lineage cells in healed arteries was comparable to normal arteries but comprised significantly fewer fluorescent phenotypes. The population had a complex, intermixed, clonal structure. By statistical analysis of expected versus observed fractions of fluorescent phenotypes and visual inspection of coherent groups of same-colored cells, we concluded that >98% of SMC lineage cells in healed arteries belonged to a detectable clone, indicating that nearly all surviving SMCs after severe injury at some point undergo proliferation. This was consistent with serial observations in the first week after injury, which showed severe loss of medial cells followed by widespread proliferation. ConclusionsAfter severe arterial injury, many surviving SMCs proliferate to repair the media and form a neointima. This indicates that the fraction of medial SMCs that are mobilized to repair arteries increases with the level of injury.

Do Place Cells Dream of Deceptive Moves in a Signaling Game?

We consider the possibility of applying game theory to analysis and modeling of neurobiological systems. Specifically, the basic properties and features of information asymmetric signaling games are considered and discussed as having potential to explain diverse neurobiological phenomena; we focus on neuronal action potential discharge that can represent cognitive variables in memory and purposeful behavior. We begin by arguing that there is a pressing need for conceptual frameworks that can permit analysis and integration of information and explanations across many scales of biological function including gene regulation, molecular and biochemical signaling, cellular and metabolic function, neuronal population, and systems level organization to generate plausible hypotheses across these scales. Developing such integrative frameworks is crucial if we are to understand cognitive functions like learning, memory, and perception. The present work focuses on systems neuroscience organized around the connected brain regions of the entorhinal cortex and hippocampus. These areas are intensely studied in rodent subjects as model neuronal systems that undergo activity-dependent synaptic plasticity to form neuronal circuits and represent memories and spatial knowledge used for purposeful navigation. Examples of cognition-related spatial information in the observed neuronal discharge of hippocampal place cell populations and medial entorhinal head-direction cell populations are used to illustrate possible challenges to information maximization concepts. It may be natural to explain these observations using the ideas and features of information asymmetric signaling games.

Adolescent Alcohol Exposure Produces Sex-Specific Long-term Hyperalgesia via Changes in Central Amygdala Circuit Function

BackgroundExposure to alcohol during adolescence produces many effects that last well into adulthood. Acute alcohol use is analgesic, and people living with pain report drinking alcohol to reduce pain, but chronic alcohol use produces increases in pain sensitivity. MethodsWe tested the acute and lasting effects of chronic adolescent intermittent ethanol (AIE) exposure on pain-related behavioral and brain changes in male and female rats. We also tested the long-term effects of AIE on synaptic transmission in midbrain (ventrolateral periaqueductal gray [vlPAG])-projecting central amygdala (CeA) neurons using whole-cell electrophysiology. Finally, we used circuit-based approaches (DREADDs [designer receptors exclusively activated by designer drugs]) to test the role of vlPAG-projecting CeA neurons in mediating AIE effects on pain-related outcomes. ResultsAIE produced long-lasting hyperalgesia in male, but not female, rats. Similarly, AIE led to a reduction in synaptic strength of medial CeA cells that project to the vlPAG in male, but not female, rats. Challenge with an acute painful stimulus (i.e., formalin) in adulthood produced expected increases in pain reactivity, and this effect was exaggerated in male rats with a history of AIE. Finally, CeA-vlPAG circuit activation rescued AIE-induced hypersensitivity in male rats. ConclusionsOur findings are the first, to our knowledge, to show long-lasting sex-dependent effects of adolescent alcohol exposure on pain-related behaviors and brain circuits in adult animals. This work has implications for understanding the long-term effects of underage alcohol drinking on pain-related behaviors in humans.

Dominance status modulates activity in medial amygdala cells with projections to the bed nucleus of the stria terminalis

The medial amygdala (MeA) controls several types of social behavior via its projections to other limbic regions. Cells in the posterior dorsal and posterior ventral medial amygdala (MePD and MePV, respectively) project to the bed nucleus of the stria terminalis (BNST) and these pathways respond to chemosensory cues and regulate aggressive and defensive behavior. Because the BNST is also essential for the display of stress-induced anxiety, a MePD/MePV-BNST pathway may modulate both aggression and responses to stress. In this study we tested the hypothesis that dominant animals would show greater neural activity than subordinates in BNST-projecting MePD and MePV cells after winning a dominance encounter as well as after losing a social defeat encounter. We created dominance relationships in male and female Syrian hamsters (Mesocricetus auratus), used cholera toxin b (CTB) as a retrograde tracer to label BNST-projecting cells, and collected brains for c-Fos staining in the MePD and MePV. We found that c-Fos immunoreactivity in the MePD and MePV was positively associated with aggression in males, but not in females. Also, dominant males showed a greater proportion of c-Fos+ /CTB+ double-labeled cells compared to their same-sex subordinate counterparts. Another set of animals received social defeat stress after acquiring a dominant or subordinate social status and we stained for stress-induced c-Fos expression in the MePD and MePV. We found that dominant males showed a greater proportion of c-Fos+ /CTB+ double-labeled cells in the MePD after social defeat stress compared to subordinates. Also, dominants showed a longer latency to submit during social defeat than subordinates. Further, in males, latency to submit was positively associated with the proportion of c-Fos+ /CTB+ double-labeled cells in the MePD and MePV. These findings indicate that social dominance increases neural activity in BNST-projecting MePD and MePV cells and activity in this pathway is also associated with proactive responses during social defeat stress. In sum, activity in a MePD/MePV-BNST pathway contributes to status-dependent differences in stress coping responses and may underlie experience-dependent changes in stress resilience.