Although cerebellar alterations have been implicated in stress symptoms, the exact contribution of the cerebellum to stress symptoms remains to be elucidated. Here, we demonstrated the crucial role ...of cerebellar neurons projecting to the ventral tegmental area (VTA) in the development of chronic stress-induced behavioral alterations in mice. Chronic chemogenetic activation of inhibitory Purkinje cells in crus I suppressed c-Fos expression in the DN and an increase in immobility in the tail suspension test or forced swimming test, which were triggered by chronic stress application. The combination of adeno-associated virus-based circuit mapping and electrophysiological recording identified network connections from crus I to the VTA via the dentate nucleus (DN) of the deep cerebellar nuclei. Furthermore, chronic inhibition of specific neurons in the DN that project to the VTA prevented stressed mice from showing such depression-like behavior, whereas chronic activation of these neurons alone triggered behavioral changes that were comparable with the depression-like behaviors triggered by chronic stress application. Our results indicate that the VTA-projecting cerebellar neurons proactively regulate the development of depression-like behavior, raising the possibility that cerebellum may be an effective target for the prevention of depressive disorders in human.
The 3D curvature gaps (3D-gaps) between the 3D-dummy and 3D-body curved surface shapes of adult males and females (a total of 2,528 models) were automatically extracted using the four curvature angle ...values in each of the 10 areas regardless of size. The 3D-gap values were useful common information data for the 3D custom-made garment design and sewing in both models. In the case of tight-fitting garment design based on the 3D-dummy, the 3D-gap features of the four curvature values represented differences between the female- and male-dominated clusters in the chest, abdomen, and buttocks areas. In the female-dominated clusters, the 3D-gap in the chest areas tends to be high, while the 3D-gaps in the abdomen and buttocks areas tend to be high in the male-dominated clusters. The 3D-gap features in the slightly older female-dominated clusters show more complexity in many areas. The slightly younger male-dominated clusters extracted the 3D-gap features in each area. Although the number of both models was few, the 3D-gap in the back area was high in the older male and female common clusters. Using the 3D-gaps, we were able to numerically extract differences in the 3D-body curved surface shapes in the garment design.
An important feature of long-term synaptic plasticity is the prolonged maintenance of plastic changes in synaptic transmission. The trafficking of AMPA-type glutamate receptors (AMPARs) is involved ...in the expression of many forms of synaptic plasticity, yet the subsequent events accomplishing the maintenance of plastic changes in synaptic AMPAR numbers are not fully understood. Here, we find that maintenance of cerebellar long-term depression results from a reduction in the number of AMPARs residing within endocytic recycling pathways. We then develop a genetically encoded, photosensitive inhibitor of late endosome sorting and use this to discover that initial maintenance of long-term depression relies on timely regulated late endosome sorting, which exhibits a threshold as well as switch-like behavior. Thus, our results indicate that recycling AMPAR numbers are reduced by a switching machinery of transient late endosome sorting, and that this process enables the transition from basal synaptic transmission to long-term depression maintenance.Long term depression (LTD) of the cerebellum is known to be mediated by postsynaptic trafficking of glutamate receptor AMPAR. Here, Kim and colleagues show that early- to late-endosomal sorting of AMPAR represents the switch from expression to maintenance phase of cerebellar LTD.
As cerebellar granule cells (GCs) coordinate the formation of regular cerebellar networks during postnatal development, molecules in GCs are expected to be involved. Here, we test the effects of the ...knockdown (KD) of multiple epidermal growth factor-like domains protein 11 (MEGF11), which is a homolog of proteins mediating astrocytic phagocytosis but is substantially increased at the later developmental stages of GCs on cerebellar development. MEGF11-KD in GCs of developing mice results in abnormal cerebellar structures, including extensively ectopic Purkinje cell (PC) somas, and in impaired motor functions. MEGF11-KD also causes abnormally asynchronous synaptic release from GC axons, parallel fibers, before the appearance of abnormal cerebellar structures. Interestingly, blockade of this abnormal synaptic release restores most of the cerebellar structures. Thus, apart from phagocytic functions of its related homologs in astrocytes, MEGF11 in GCs promotes proper PC development and cerebellar network formation by regulating immature synaptic transmission.
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•Abnormal PC structures are observed as a result of MEGF11 knockdown in developing GCs•The requirement of MEGF11 in GCs is primarily limited to the developmental stage•MEGF11 knockdown leads to abnormally asynchronous evoked synaptic release from PFs•Blockade of synaptic release restores abnormal PC structures induced by MEGF11 knockdown
Molecules expressed in cerebellar granule cells are expected to play important roles in network formation during postnatal development. Jun et al. show that multiple epidermal growth factor-like domains protein 11 indeed regulates Purkinje cell maturation and synaptic formation by controlling appropriate synaptic transmission from parallel fibers.
The cerebellum has a long history in terms of research on its network structures and motor functions, yet our understanding of them has further advanced in recent years owing to technical ...developments, such as viral tracers, optogenetic and chemogenetic manipulation, and single cell gene expression analyses. Specifically, it is now widely accepted that the cerebellum is also involved in non-motor functions, such as cognitive and psychological functions, mainly from studies that have clarified neuronal pathways from the cerebellum to other brain regions that are relevant to these functions. The techniques to manipulate specific neuronal pathways were effectively utilized to demonstrate the involvement of the cerebellum and its pathways in specific brain functions, without altering motor activity. In particular, the cerebellar efferent pathways that have recently gained attention are not only monosynaptic connections to other brain regions, including the periaqueductal gray and ventral tegmental area, but also polysynaptic connections to other brain regions, including the non-primary motor cortex and hippocampus. Besides these efferent pathways associated with non-motor functions, recent studies using sophisticated experimental techniques further characterized the historically studied efferent pathways that are primarily associated with motor functions. Nevertheless, to our knowledge, there are no articles that comprehensively describe various cerebellar efferent pathways, although there are many interesting review articles focusing on specific functions or pathways. Here, we summarize the recent findings on neuronal networks projecting from the cerebellum to several brain regions. We also introduce various techniques that have enabled us to advance our understanding of the cerebellar efferent pathways, and further discuss possible directions for future research regarding these efferent pathways and their functions.
A new spirocyclized rhodol-based fluorescent probe has been developed for detecting mitochondrial Cu(+). Alkylation of the hydroxy group of a xanthene moiety with a tris(2-pyridylmethyl)amine-based ...ligand induced the formation of a non-fluorescent spirocyclic structure. The reaction with Cu(+) in the presence of submillimolar concentrations of glutathione at physiological pH resulted in the elimination of the ligand together with an increase in the fluorescence of the rhodol fluorophore. This probe was used to visualize mitochondrial Cu(+) in copper supplemented cells.
The 3D-dummy curved surface shape for the 3D custom-made garment design was automatically generated by using the 3D convex hulling method by Legendre transformation in the 3D-body of adult females (N ...= 1,471 and ages of 18 to 84). The 3D curvature gaps represent the different curvature values between the 3D-dummy and the 3D-body for the four curvatures using the concentrated Gaussian curvature Kc (Σ + Kc and Σ - Kc) and concentrated mean curvature Hc (Σ + Hc and Σ - Hc) in each of the 10 areas. Using the four 3D curvature gap values and the color maps in the 10 areas, the special information of the 3D-dummy curved surface shapes for making and designing garments, which are different from 3D-body curved surface shapes, were extracted. The mean values of the 3D-dummy shape were lower than those of the 3D-body shape in most areas, while the mean values of the convex Σ + Hc 3D curvature gaps in the lower areas of the 3D-dummy were higher than those of the 3D-body. The 3D curvature gap types of the 3D-dummy were extracted from the 9 clusters of the 30s, early 40s, elder 40s, and 50s groups. However, the 3D curvature gaps between the buttocks of both the 3D-dummy and the 3D-body were low values in the older age groups.
We described here a coumarin-based dual-excitation ratiometric probe for cadmium, CadMQ. This fluorescence sensor has high quantum yields of 0.59 and 0.70 in the metal-free and Cd2+-bound forms, ...respectively, and has a dissociation constant of 0.16 nM for Cd2+. CadMQ is cell permeable and locates within the acidic compartments of the cells. We further show that CadMQ is a useful tool to ratiometrically probe the change in the intracellular Cd2+ levels with the use of two excited wavelengths.
The well-organized cerebellar structures and neuronal networks are likely crucial for their functions in motor coordination, motor learning, cognition, and emotion. Such cerebellar structures and ...neuronal networks are formed during developmental periods through orchestrated mechanisms, which include not only cell-autonomous programs but also interactions between the same or different types of neurons. Cerebellar granule cells (GCs) are the most numerous neurons in the brain and are generated through intensive cell division of GC precursors (GCPs) during postnatal developmental periods. While GCs go through their own developmental processes of proliferation, differentiation, migration, and maturation, they also play a crucial role in cerebellar development. One of the best-characterized contributions is the enlargement and foliation of the cerebellum through massive proliferation of GCPs. In addition to this contribution, studies have shown that immature GCs and GCPs regulate multiple factors in the developing cerebellum, such as the development of other types of cerebellar neurons or the establishment of afferent innervations. These studies have often found impairments of cerebellar development in animals lacking expression of certain molecules in GCs, suggesting that the regulations are mediated by molecules that are secreted from or present in GCs. Given the growing recognition of GCs as regulators of cerebellar development, this review will summarize our current understanding of cerebellar development regulated by GCs and molecules in GCs, based on accumulated studies and recent findings, and will discuss their potential further contributions.
SARS-CoV-2 enters host cells when the viral spike protein is cleaved by transmembrane protease serine 2 (TMPRSS2) after binding to the host angiotensin-converting enzyme 2 (ACE2). Since ACE2 and ...TMPRSS2 are expressed in the tongue and gingival mucosa, the oral cavity is a potential entry point for SARS-CoV-2. This study evaluated the inhibitory effects of general ingredients of toothpastes and mouthwashes on the spike protein-ACE2 interaction and the TMPRSS2 protease activity using an in vitro assay. Both assays detected inhibitory effects of sodium tetradecene sulfonate, sodium N-lauroyl-N-methyltaurate, sodium N-lauroylsarcosinate, sodium dodecyl sulfate, and copper gluconate. Molecular docking simulations suggested that these ingredients could bind to inhibitor-binding site of ACE2. Furthermore, tranexamic acid exerted inhibitory effects on TMPRSS2 protease activity. Our findings suggest that these toothpaste and mouthwash ingredients could help prevent SARS-CoV-2 infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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