The medial prefrontal cortex (mPFC) plays a vital role in the processing of emotional events. It has been shown that activation of the glutamatergic transmission in prelimbic subregion of the mPFC ...(PL-PFC) evoked anxiety-like behavior in rodents. We previously reported that local perfusion of a selective agonist to delta-opioid receptor (DOP), KNT-127, attenuated the veratrine-induced elevation of extracellular glutamate in the PL-PFC and anxiety-like behavior in mice. These results suggested the possibility that KNT-127 suppresses glutamate release from the presynaptic site in the PL-PFC. To examine this possibility directly, we performed whole-cell patch-clamp recording from principal neurons in the PL-PFC and examined the spontaneous and electrically-evoked excitatory postsynaptic currents (EPSC)s. We found that bath application of KNT-127 significantly decreased the frequency of spontaneous and miniature EPSCs. Conversely, amplitude, rise time, and decay time of spontaneous and miniature EPSCs were not affected by bath application of KNT-127. Also, KNT-127 increased paired-pulse ratios of electrically-evoked EPSCs in the PL-PFC principal neurons tested. Further, we analyzed the firing properties of pyramidal neurons in the PL-PFC and found that KNT-127 treatment significantly reduced the number of action potentials and firing threshold. These results suggested that KNT-127 suppresses glutamatergic synaptic transmission by inhibiting glutamate release from the presynaptic site and reduces neuronal excitability in the mouse PL-PFC. We propose the possibility that these suppressing effects of KNT-127 on PL-PFC activity are part of the underlying mechanisms of its anxiolytic-like effects.
•KNT-127 decreases frequency of sEPSC and mEPSCs in the PL-PFC.•KNT-127 increases the paired-pulse ratio of eEPSCs in the PL-PFC.•KNT-127 suppresses action potential firing and increases rheobase in the PL-PFC.•KNT-127 inhibits glutamate release from presynapse via DOP in the PL-PFC.•KNT-127 decreases cellular excitability of principal neuron in the PL-PFC.
Prostate cancer (PCa) is a common malignant tumor among adult males, and convenient intraoperative detection of PCa would reduce the risk of leaving positive surgical margins, especially during ...nerve-sparing procedures. To achieve rapid, fluorescence-based visualization of PCa, we focused on the glutamate carboxypeptidase (CP) activity of prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein that is attracting attention as a PCa biomarker. Based on our finding that aryl glutamate conjugates with an azoformyl linker are recognized by PSMA and have a sufficiently low LUMO (lowest unoccupied molecular orbital) energy level to quench the fluorophore through photoinduced electron transfer, we designed and synthesized a first-in-class activatable fluorescence probe for CP activity of PSMA. The developed probe allowed us to visualize the CP activity of PSMA in living cells and in clinical specimens from PCa patients and is expected to be useful for rapid intraoperative detection and diagnosis of PCa.
Circadian rhythm disturbances are well established in neurological diseases. However, how these disruptions cause homeostatic imbalances remains poorly understood. Brain and muscle aryl hydrocarbon ...receptor nuclear translocator-like protein 1 (Bmal1) is a major circadian clock transcriptional activator, and Bmal1 deficiency in male
mice induced marked astroglial activation without affecting the number of astrocytes in the brain and spinal cord. Bmal1 deletion caused blood-brain barrier (BBB) hyperpermeability with an age-dependent loss of pericyte coverage of blood vessels in the brain. Using Nestin-green fluorescent protein (GFP) transgenic mice, we determined that pericytes are Nestin-GFP
in the adult brain. Bmal1 deletion caused Nestin-GFP
pericyte dysfunction, including the downregulation of platelet-derived growth factor receptor β (PDGFRβ), a protein necessary for maintaining BBB integrity. Knockdown of Bmal1 downregulated PDGFRβ transcription in the brain pericyte cell line. Thus, the circadian clock component Bmal1 maintains BBB integrity via regulating pericytes.
Circadian rhythm disturbances may play a role in neurodegenerative disorders, such as Alzheimer's disease. Our results revealed that one of the circadian clock components maintains the integrity of the blood-brain barrier (BBB) by regulating vascular-embedded pericytes. These cells were recently identified as a vital component for the control of BBB permeability and cerebral blood flow. Our present study demonstrates the involvement of circadian clock component Bmal1 in BBB homeostasis and highlights the role of Bmal1 dysfunction in multiple neurological diseases.
The evaluation of tactile sensitivity involving frictional behavior via computational models can further accelerate the development of industrial products in terms of usability. This study aimed to ...confirm the capability of a previously proposed mechano-neurophysiological model, representing the basic mechanical (i.e., finger skin deformation) and neurophysiological (i.e., neural activities of slowly adapting type-1 (SA1) afferents) functions in the tactile sensation process, for simulating tactile responses during Braille reading under multiple frictional conditions. A previous psychophysical experiment on tactile recognition during Braille reading reported that the misread rate was significantly higher at frictional coefficient (μ) = 2.62 than at μ = 0.56, whereas no significant differences were observed between the misread rates at μ = 0.25 and 0.77. The Braille reading experiment was simulated using the mechano-neurophysiological model to achieve the present aim. The simulation results revealed marginal differences in the SA1 responses between μ = 0.25 and 0.77, and the correlation coefficients between the SA1 responses and Braille patterns were 0.98 at μ = 0.25 and 0.96 at μ = 0.77, suggesting a limited influence of friction on Braille recognition. However, the SA1 responses varied considerably between μ = 0.56 and 2.62, and the correlation coefficients were 0.97 at μ = 0.56 and 0.49 at μ = 2.62, implying a relatively strong influence of friction. The simulation results supported the above-mentioned findings of the previous psychophysical experiment, thereby demonstrating that the mechano-neurophysiological model qualitatively determined the tendency of influence of friction on Braille recognition.
The Polycomb-group (PcG) repressive complex-1 (PRC1) forms microscopically visible clusters in nuclei; however, the impact of this cluster formation on transcriptional regulation and the underlying ...mechanisms that regulate this process remain obscure. Here, we report that the sterile alpha motif (SAM) domain of a PRC1 core component Phc2 plays an essential role for PRC1 clustering through head-to-tail macromolecular polymerization, which is associated with stable target binding of PRC1/PRC2 and robust gene silencing activity. We propose a role for SAM domain polymerization in this repression by two distinct mechanisms: first, through capturing and/or retaining PRC1 at the PcG targets, and second, by strengthening the interactions between PRC1 and PRC2 to stabilize transcriptional repression. Our findings reveal a regulatory mechanism mediated by SAM domain polymerization for PcG-mediated repression of developmental loci that enables a robust yet reversible gene repression program during development.
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•PRC1 forms visible subnuclear clusters at its target loci in mouse primary cells•The polymerization of the Phc2 SAM domain is required for PRC1 clustering•Clustering of PRC1 links to chromatin condensation and gene silencing•PRC1 clustering associates with stable binding of PRC1/PRC2 at its target loci
Gene silencing by the Polycomb-repressive complex-1 (PRC1) is crucial for embryogenesis. Isono et al. show that subnuclear PRC1 clustering at its target genes is mediated by the polymerization capacity of the Phc2 SAM domain and associates with stable PRC1/PRC2 binding, trimethylation of histone H3 Lys27, and robust gene silencing.
Oxytocin (OXT) neurons project to various brain regions and its receptor expression is widely distributed. Although it has been reported that OXT administration affects cognitive function, it is ...unclear how endogenous OXT plays roles in cognitive function. The present study examined the role of endogenous OXT in mice cognitive function. OXT neurons were specifically activated by OXT neuron-specific excitatory Designer Receptors Exclusively Activated by Designer Drug expression system and following administration of clozapine-N-oxide (CNO). Object recognition memory was assessed with the novel object recognition task (NORT). Moreover, we observed the expression of c-Fos via immunohistochemical staining to confirm neuronal activity. In NORT, the novel object exploration time percentage significantly increased in CNO-treated mice. CNO-treated mice showed a significant increase in the number of c-Fos-positive cells in the supramammillary nucleus (SuM). In addition, we found that the OXT-positive fibers from paraventricular hypothalamic nucleus (PVN) were identified in the SuM. Furthermore, mice injected locally with CNO into the SuM to activate OXTergic axons projecting from the PVN to the SuM showed significantly increased percentage time of novel object exploration. Taken together, we proposed that object recognition memory in mice could be modulated by OXT neurons in the PVN projecting to the SuM.
Stress increases the risk of neuropsychiatric disorders, such as major depression. Exposure to stress has been reported to induce various neuronal changes, such as alterations in synaptic ...transmission and structure. However, a causal link between stress-induced neural circuit alterations and changes in emotional behaviours is not well understood. In the present study, we focused on a projection pathway from the orbitofrontal cortex (OFC) to the basolateral nucleus of the amygdala (BLA) as a crucial circuit for negative emotions and examined the effect of stress on OFC-BLA excitatory synaptic transmission using optogenetic and whole-cell patch-clamp methods in mice. As a stress-inducing procedure, we used repeated tail-shock, which increased stress-related behaviours. We found greater α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/N-methyl-D-aspartate current ratios and insertion of calcium-permeable AMPA receptors (AMPARs) in the OFC-BLA synapse after stress. These stress-induced synaptic and behavioural changes were reduced by a blockade of protein kinase A, which plays a principal role in stress-induced targeting of AMPARs into the synaptic membrane. To examine a possible causal relationship between alterations in synaptic transmission in the OFC-BLA pathway and stress-related behaviour, we performed optogenetic activation or chemogenetic inactivation of OFC-BLA transmission in mice. We found that optogenetic activation and chemogenetic inactivation of OFC-BLA transmission increased and decreased stress-related behaviour, respectively. In conclusion, we have demonstrated that stress altered the postsynaptic properties of the OFC-BLA pathway. These synaptic changes might be one of the underlying mechanisms of stress-induced behavioural alterations.
The thymus, a primary lymphoid organ of the immune system, undergoes several changes due to a variety of reasons, ranging from aging to pathological conditions. These changes can make distinguishing ...between benign and neoplastic changes in the thymus challenging, thereby complicating the histopathological diagnoses of thymic tumors. Moreover, most patients with thymic tumors are asymptomatic at the time of diagnosis. Therefore, imaging plays an extremely important role in the evaluation of thymic lesions. In this review, we introduced the imaging characteristics of the thymus, ranging from benign findings, such as normal maturation and benign lesions, to neoplasms.
•Vicarious social defeat stress diminishes cell survival rate in the hippocampus.•Vicarious social defeat stress produces no effect on cell proliferation rate.•Psychological stress influences ...new-born neuronal cell survival in the hippocampus.•Antidepressant fluoxetine rescues deficiencies in social behaviors and neurogenesis.•Validities of vicarious social defeat stress as a depression model is reinforced.
Increasing evidence has shown that adult hippocampal neurogenesis is closely related to the pathophysiological condition of depressive disorders. Recently, chronic social defeat stress paradigms have been regarded as important animal models of depression, accompanied with neural plastic changes in the hippocampus. However, little is known about influences of non-physical stress on neurogenesis. In the present study, we focused on the chronic vicarious social defeat stress paradigm and examined the effect of psychological stress on mouse hippocampal neurogenesis. Immediately after the chronic psychological stress, the cell survival rate in the dentate gyrus of the hippocampus was significantly diminished without modifying the cell proliferation rate. The decreased ratio in cell survival persisted for 4 weeks after the stress-loading period, while the differentiation and maturity of new-born neurons were identical to control groups. Furthermore, treatment with the chronic antidepressant fluoxetine reversed the social behavioral deficits and promoted new-born neurons survival. These results demonstrate that emotional stress in the vicarious social defeat stress paradigm influences neuronal cell survival in the hippocampus, which reinforces its validity as an animal model of depression.
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