scholarly journals Dendritic GABAergic inhibition controlled by Shh signaling-dependent stellate cell pool is critical for motor learning

2021 ◽  
Author(s):  
Wen Li ◽  
Lei Chen ◽  
Jonathan T Fleming ◽  
Emily Y Brignola ◽  
Kirill Zavalin ◽  
...  
Keyword(s):  
Motor Learning ◽  
Neural Circuit ◽  
Stellate Cell ◽  
Eyeblink Conditioning ◽  
Molecular Layer ◽  
Inhibitory Synapses ◽  
Shh Signaling ◽  
Shh Pathway ◽  
Pathway Activation

Cerebellar inhibitory interneurons are important regulators of neural circuit activity for diverse motor and non-motor functions. The molecular layer interneurons (MLI), consisting of basket cells (BCs) and stellate cells (SCs), are generated sequentially from Pax2+ immature interneurons which migrate from the prospective white matter to the ML of the cortex. However, little is known as to how MLI subtype identities and pool sizes are determined, nor are their contributions to motor learning well-understood. Here, we show that GABAergic progenitors fated to generate BCs and SCs transiently respond to the Shh signal. Conditional abrogation of Shh signaling reduced the number of Pax2+ cells, whereas persistent Shh pathway activation increased their numbers. These changes did not affect BC numbers but selectively altered the SC pool size. Moreover, genetic depletion of GABAergic progenitors when BCs are generated resulted in a specific reduction of SCs, suggesting that the specification of MLI subtypes is independent of their birth order and occurs after Pax2+ cells settle into their final laminar positions. Mutant mice with reduced SC numbers displayed decreased dendritic inhibitory synapses and neurotransmission onto Purkinje cells, resulting in an impaired acquisition of eyeblink conditioning. These findings reveal an essential role of Shh signaling-dependent SCs in regulating inhibitory dendritic synapses and motor learning.

scholarly journals Differences in chloride gradients allow for three distinct types of synaptic modulation by endocannabinoids

2016 ◽  
Vol 116 (2) ◽  
pp. 619-628 ◽  
Author(s):  
Yanqing Wang ◽  
Brian D. Burrell
Keyword(s):  
Neural Circuit ◽  
Critical Role ◽  
Low Frequency ◽  
Inhibitory Synapses ◽  
Primary Role ◽  
Synaptic Modulation ◽  
Hirudo Verbana ◽  
Frequency Stimulation ◽  
Circuit Output

Endocannabinoids can elicit persistent depression of excitatory and inhibitory synapses, reducing or enhancing (disinhibiting) neural circuit output, respectively. In this study, we examined whether differences in Cl−gradients can regulate which synapses undergo endocannabinoid-mediated synaptic depression vs. disinhibition using the well-characterized central nervous system (CNS) of the medicinal leech, Hirudo verbana. Exogenous application of endocannabinoids or capsaicin elicits potentiation of pressure (P) cell synapses and depression of both polymodal (Npoly) and mechanical (Nmech) nociceptive synapses. In P synapses, blocking Cl−export prevented endocannabinoid-mediated potentiation, consistent with a disinhibition process that has been indicated by previous experiments. In Nmechneurons, which are depolarized by GABA due to an elevated Cl−equilibrium potentials (ECl), endocannabinoid-mediated depression was prevented by blocking Cl−import, indicating that this decrease in synaptic signaling was due to depression of excitatory GABAergic input (disexcitation). Npolyneurons are also depolarized by GABA, but endocannabinoids elicit depression in these synapses directly and were only weakly affected by disruption of Cl−import. Consequently, the primary role of elevated EClmay be to protect Npolysynapses from disinhibition. All forms of endocannabinoid-mediated plasticity required activation of transient potential receptor vanilloid (TRPV) channels. Endocannabinoid/TRPV-dependent synaptic plasticity could also be elicited by distinct patterns of afferent stimulation with low-frequency stimulation (LFS) eliciting endocannabinoid-mediated depression of Npolysynapses and high-frequency stimulus (HFS) eliciting endocannabinoid-mediated potentiation of P synapses and depression of Nmechsynapses. These findings demonstrate a critical role of differences in Cl−gradients between neurons in determining the sign, potentiation vs. depression, of synaptic modulation under normal physiological conditions.

scholarly journals Arl13b regulates ciliogenesis and the dynamic localization of Shh signaling proteins

2011 ◽  
Vol 22 (23) ◽  
pp. 4694-4703 ◽  
Author(s):  
Christine E. Larkins ◽  
Gladys D. Gonzalez Aviles ◽  
Michael P. East ◽  
Richard A. Kahn ◽  
Tamara Caspary
Keyword(s):  
Sonic Hedgehog ◽  
Protein Localization ◽  
Signaling Proteins ◽  
Shh Signaling ◽  
Dynamic Localization ◽  
Shh Pathway ◽  
Ciliary Protein ◽  
Adp Ribosylation Factor

Arl13b, a ciliary protein within the ADP-ribosylation factor family and Ras superfamily of GTPases, is required for ciliary structure but has poorly defined ciliary functions. In this paper, we further characterize the role of Arl13b in cilia by examining mutant cilia in vitro and determining the localization and dynamics of Arl13b within the cilium. Previously, we showed that mice lacking Arl13b have abnormal Sonic hedgehog (Shh) signaling; in this study, we show the dynamics of Shh signaling component localization to the cilium are disrupted in the absence of Arl13b. Significantly, we found Smoothened (Smo) is enriched in Arl13b-null cilia regardless of Shh pathway stimulation, indicating Arl13b regulates the ciliary entry of Smo. Furthermore, our analysis defines a role for Arl13b in regulating the distribution of Smo within the cilium. These results suggest that abnormal Shh signaling in Arl13b mutant embryos may result from defects in protein localization and distribution within the cilium.

scholarly journals Sonic hedgehog pathway activation increases mitochondrial abundance and activity in hippocampal neurons

2017 ◽  
Vol 28 (3) ◽  
pp. 387-395 ◽  
Author(s):  
Pamela J. Yao ◽  
Uri Manor ◽  
Ronald S. Petralia ◽  
Rebecca D. Brose ◽  
Ryan T. Y. Wu ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Hippocampal Neurons ◽  
Mitochondrial Fission ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Shh Signaling ◽  
Shh Pathway ◽  
Pathway Activation ◽  
Peptide Hydrogen ◽  
And Function

Mitochondria are essential organelles whose biogenesis, structure, and function are regulated by many signaling pathways. We present evidence that, in hippocampal neurons, activation of the Sonic hedgehog (Shh) signaling pathway affects multiple aspects of mitochondria. Mitochondrial mass was increased significantly in neurons treated with Shh. Using biochemical and fluorescence imaging analyses, we show that Shh signaling activity reduces mitochondrial fission and promotes mitochondrial elongation, at least in part, via suppression of the mitochondrial fission protein dynamin-like GTPase Drp1. Mitochondria from Shh-treated neurons were more electron-dense, as revealed by electron microscopy, and had higher membrane potential and respiratory activity. We further show that Shh protects neurons against a variety of stresses, including the mitochondrial poison rotenone, amyloid β-peptide, hydrogen peroxide, and high levels of glutamate. Collectively our data suggest a link between Shh pathway activity and the physiological properties of mitochondria in hippocampal neurons.

scholarly journals Ixazomib Improves Bone Remodeling and Counteracts Sonic Hedgehog Signaling Inhibition Mediated by Myeloma Cells

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 323 ◽  
Author(s):  
Daniele Tibullo ◽  
Anna Longo ◽  
Nunzio Vicario ◽  
Alessandra Romano ◽  
Alessandro Barbato ◽  
...  
Keyword(s):  
Osteogenic Differentiation ◽  
Bone Remodeling ◽  
Sonic Hedgehog ◽  
Bone Disease ◽  
Human Mscs ◽  
Bone Homeostasis ◽  
Shh Signaling ◽  
Shh Pathway ◽  
Pathway Activation ◽  
Osteolytic Bone Disease

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of plasma cells (PC) in the bone marrow (BM), leading to bone loss and BM failure. Osteolytic bone disease is a common manifestation observed in MM patients and represents the most severe cause of morbidity, leading to progressive skeletal damage and disabilities. Pathogenetic mechanisms of MM bone disease are closely linked to PCs and osteoclast (OCs) hyperactivity, coupled with defective osteoblasts (OBs) function that is unable to counteract bone resorption. The aim of the present study was to investigate the effects of Ixazomib, a third-generation proteasome inhibitor, on osteoclastogenesis and osteogenic differentiation. We found that Ixazomib was able to reduce differentiation of human monocytes into OCs and to inhibit the expression of OC markers when added to the OC medium. Concurrently, Ixazomib was able to stimulate osteogenic differentiation of human mesenchymal stromal cells (MSCs), increasing osteogenic markers, either alone or in combination with the osteogenic medium. Given the key role of Sonic Hedgehog (SHH) signaling in bone homeostasis, we further investigated Ixazomib-induced SHH pathway activation. This set of experiments showed that Ixazomib, but not Bortezomib, was able to bind the Smoothened (SMO) receptor leading to nuclear translocation of GLI1 in human MSCs. Moreover, we demonstrated that PCs act as GLI1 suppressors on MSCs, thus reducing the potential of MSCs to differentiate in OBs. In conclusion, our data demonstrated that Ixazomib regulates bone remodeling by decreasing osteoclastogenesis and prompting osteoblast differentiation via the canonical SHH signaling pathway activation, thus, representing a promising therapeutic option to improve the complex pathological condition of MM patients.

scholarly journals Activation of Sonic Hedgehog Leads to Survival Enhancement of Astrocytes via the GRP78-Dependent Pathway in Mice Infected withAngiostrongylus cantonensis

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Kuang-Yao Chen ◽  
Chien-Ju Cheng ◽  
Lian-Chen Wang
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Glial Fibrillary Acidic Protein ◽  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Angiostrongylus Cantonensis ◽  
Shh Signaling ◽  
Shh Pathway ◽  
Dependent Pathway

Angiostrongylus cantonensisinfection may cause elevation of ROS and antioxidants in the CSF of infected mice. Astrocytes may protect the surrounding neurons from oxidative stress-induced cell death by secreting Sonic hedgehog (Shh) via the PI3-K/AKT/Bcl-2 pathway. This study was conducted to determine the role of the Shh signaling pathway inA. cantonensis-infected BABL/c mice by coculturing astrocytes with living fifth-stage larvae or soluble antigens. The Shh pathway was activated with corresponding increases in the level of the Shh. Glial fibrillary acidic protein (GFAP) and Shh were increased in astrocyte cocultured with living fifth-stage larvae or soluble antigens. The survival of astrocytes pretreated with Shh was significantly elevated in cocultures with the antigens but reduced by its inhibitor cyclopamine. The expression of GRP78 and Bcl-2 was significantly higher in astrocytes pretreated with recombinant Shh. These findings suggest that the expression of Shh may inhibit cell death by activating Bcl-2 through a GRP78-dependent pathway.

scholarly journals Complement C3-dependent glutamatergic synapse elimination in the developing hippocampus is region- and synapse-specific

2020 ◽  
Author(s):  
Eric W. Salter ◽  
Gang Lei ◽  
Sun-Lim Choi ◽  
Liam T. Ralph ◽  
Lijia Zhang ◽  
...  
Keyword(s):  
Molecular Layer ◽  
Stratum Radiatum ◽  
Complement C3 ◽  
Inhibitory Synapses ◽  
Complement Cascade ◽  
Synapse Elimination ◽  
Immune Pathway ◽  
Innate Immune Pathway ◽  
Stratum Lacunosum Moleculare

SummaryThe complement cascade is an innate immune pathway that, in addition to host defense against pathogens, actively maintains tissue homeostasis. Complement is necessary for synaptic pruning during development and drives aberrant synapse loss in a number of neurodegenerative disorders that affect the hippocampus. However, the physiological function of complement in hippocampal synapse development is unknown. To address this, we investigated C3−/− mice at P16-18. We found that VGLUT2+ synapses were increased in the CA1 stratum lacunosum moleculare (SLM) and dentate gyrus molecular layer (DGML) of C3−/− mice compared to wildtype. Conversely, VGLUT1+ synapses, inhibitory synapses and myelin were not affected in the CA1 stratum radiatum (SR), SLM or DGML of C3−/− mice. Finally, we found that there was a decrease in microglial phagocytic activity only in VGLUT2+ regions and this correlated with the amount of VGLUT2+ synapses. Our study elucidates a role of the complement cascade in regulating hippocampus synapse number with exceptional specificity for VGLUT2-containing synapses during development.

scholarly journals Lhx2 is a progenitor-intrinsic modulator of Sonic Hedgehog signaling during early retinal neurogenesis

2021 ◽  
Author(s):  
Xiaodong Li ◽  
Patrick J Gordon ◽  
John A Gaynes ◽  
Alexandra W Fuller ◽  
Randy Ringuette ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Signaling Pathways ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Sonic Hedgehog Signaling ◽  
Shh Signaling ◽  
Downstream Targets ◽  
Shh Pathway ◽  
Pathway Activation ◽  
Retinal Neurogenesis

An important question in organogenesis is how tissue-specific transcription factors interact with signaling pathways. In some cases, transcription factors define the context for how signaling pathways elicit tissue- or cell-specific responses, and in others, they influence signaling through transcriptional regulation of signaling components or accessory factors. We previously showed that during optic vesicle patterning, the Lim-homeodomain transcription factor Lhx2 has a contextual role by linking the Sonic Hedgehog (Shh) pathway to downstream targets without regulating the pathway itself. Here, we show that during early retinal neurogenesis, Lhx2 is a multilevel regulator of Shh signaling. Specifically, Lhx2 acts cell autonomously to control the expression of pathway genes required for efficient activation and maintenance of signaling in retinal progenitor cells. The Shh co-receptors Cdon and Gas1 are candidate direct targets of Lhx2 that mediate pathway activation, whereas Lhx2 directly or indirectly promotes the expression of other pathway components important for activation and sustained signaling. We also provide genetic evidence suggesting that Lhx2 has a contextual role by linking the Shh pathway to downstream targets. Through these interactions, Lhx2 establishes the competence for Shh signaling in retinal progenitors and the context for the pathway to promote early retinal neurogenesis. The temporally distinct interactions between Lhx2 and the Shh pathway in retinal development illustrate how transcription factors and signaling pathways adapt to meet stage-dependent requirements of tissue formation.

scholarly journals The Role of Sonic Hedgehog Pathway in the Development of the Central Nervous System and Aging-Related Neurodegenerative Diseases

2021 ◽  
Vol 8 ◽  
Author(s):  
Chen Yang ◽  
Yan Qi ◽  
Zhitang Sun
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Neural Patterning ◽  
Shh Signaling ◽  
Shh Pathway ◽  
The Central Nervous System

The Sonic hedgehog (SHH) pathway affects neurogenesis and neural patterning during the development of the central nervous system. Dysregulation of the SHH pathway in the brain contributes to aging-related neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. At present, the SHH signaling pathway can be divided into the canonical signaling pathway and non-canonical signaling pathway, which directly or indirectly mediates other related pathways involved in the development of neurodegenerative diseases. Hence, an in-depth knowledge of the SHH signaling pathway may open an avenue of possibilities for the treatment of neurodegenerative diseases. Here, we summarize the role and mechanism of the SHH signaling pathway in the development of the central nervous system and aging-related neurodegenerative diseases. In this review, we will also highlight the potential of the SHH pathway as a therapeutic target for treating neurodegenerative diseases.

Concurrent Electrodermal and Eyeblink Conditioning With Masked and Unmasked Stimuli

2021 ◽  
Vol 35 (1) ◽  
pp. 35-42
Author(s):  
José Luis Marcos ◽  
Azahara Marcos
Keyword(s):  
Unconditioned Stimulus ◽  
Strong Evidence ◽  
Eyeblink Conditioning ◽  
Noise Burst ◽  
Conditioning Phase ◽  
Contingency Awareness ◽  
Blank Screen ◽  
Neutral Face ◽  
Fearful Face

Abstract. The aim of this study was to determine if contingency awareness between the conditioned (CS) and unconditioned stimulus (US) is necessary for concurrent electrodermal and eyeblink conditioning to masked stimuli. An angry woman’s face (CS+) and a fearful face (CS−) were presented for 23 milliseconds (ms) and followed by a neutral face as a mask. A 98 dB noise burst (US) was administered 477 ms after CS+ offset to elicit both electrodermal and eyeblink responses. For the unmasking conditioning a 176 ms blank screen was inserted between the CS and the mask. Contingency awareness was assessed using trial-by-trial ratings of US-expectancy in a post-conditioning phase. The results showed acquisition of differential electrodermal and eyeblink conditioning in aware, but not in unaware participants. Acquisition of differential eyeblink conditioning required more trials than electrodermal conditioning. These results provided strong evidence of the causal role of contingency awareness on differential eyeblink and electrodermal conditioning.

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