scholarly journals Dopamine neurons drive fear extinction learning by signaling the omission of expected aversive outcomes

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Ximena I Salinas-Hernández ◽  
Pascal Vogel ◽  
Sebastian Betz ◽  
Raffael Kalisch ◽  
Torfi Sigurdsson ◽  
...  
Keyword(s):  
Fear Extinction ◽  
Dopamine Neurons ◽  
Cell Type ◽  
Extinction Learning ◽  
Neuronal Mechanisms ◽  
The Us ◽  
Neuronal Signal ◽  
Cell Type Specific ◽  
Dopamine Signal

Extinction of fear responses is critical for adaptive behavior and deficits in this form of safety learning are hallmark of anxiety disorders. However, the neuronal mechanisms that initiate extinction learning are largely unknown. Here we show, using single-unit electrophysiology and cell-type specific fiber photometry, that dopamine neurons in the ventral tegmental area (VTA) are activated by the omission of the aversive unconditioned stimulus (US) during fear extinction. This dopamine signal occurred specifically during the beginning of extinction when the US omission is unexpected, and correlated strongly with extinction learning. Furthermore, temporally-specific optogenetic inhibition or excitation of dopamine neurons at the time of the US omission revealed that this dopamine signal is both necessary for, and sufficient to accelerate, normal fear extinction learning. These results identify a prediction error-like neuronal signal that is necessary to initiate fear extinction and reveal a crucial role of DA neurons in this form of safety learning.

The role of CpG methylation in cell type-specific expression of the aquaporin-5 gene

2007 ◽  
Vol 353 (4) ◽  
pp. 1017-1022 ◽  
Author(s):  
Johji Nomura ◽  
Akinori Hisatsune ◽  
Takeshi Miyata ◽  
Yoichiro Isohama
Keyword(s):  
Cpg Methylation ◽  
Cell Type ◽  
Aquaporin 5 ◽  
Specific Expression ◽  
Cell Type Specific Expression ◽  
Cell Type Specific

scholarly journals Cell type-specific pharmacology of NMDA receptors using masked MK801

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Yunlei Yang ◽  
Peter Lee ◽  
Scott M Sternson
Keyword(s):  
Synaptic Plasticity ◽  
Ion Channels ◽  
Signaling Pathways ◽  
Drug Addiction ◽  
Neuronal Population ◽  
Dopamine Neurons ◽  
Synaptic Potentiation ◽  
Cell Type ◽  
Brain Circuits ◽  
Cell Type Specific

N-Methyl-D-aspartate receptors (NMDA-Rs) are ion channels that are important for synaptic plasticity, which is involved in learning and drug addiction. We show enzymatic targeting of an NMDA-R antagonist, MK801, to a molecularly defined neuronal population with the cell-type-selectivity of genetic methods and the temporal control of pharmacology. We find that NMDA-Rs on dopamine neurons are necessary for cocaine-induced synaptic potentiation, demonstrating that cell type-specific pharmacology can be used to dissect signaling pathways within complex brain circuits.

scholarly journals Target-specific M1 inputs to infragranular S1 pyramidal neurons

2016 ◽  
Vol 116 (3) ◽  
pp. 1261-1274 ◽  
Author(s):  
Amanda K. Kinnischtzke ◽  
Erika E. Fanselow ◽  
Daniel J. Simons
Keyword(s):  
Primary Motor Cortex ◽  
Pyramidal Neurons ◽  
Projection Neurons ◽  
Cell Type ◽  
Intrinsic Properties ◽  
Subcortical Structures ◽  
Medial Nucleus ◽  
Cell Type Specific ◽  
Posterior Medial Nucleus

The functional role of input from the primary motor cortex (M1) to primary somatosensory cortex (S1) is unclear; one key to understanding this pathway may lie in elucidating the cell-type specific microcircuits that connect S1 and M1. Recently, we discovered that a subset of pyramidal neurons in the infragranular layers of S1 receive especially strong input from M1 (Kinnischtzke AK, Simons DJ, Fanselow EE. Cereb Cortex 24: 2237–2248, 2014), suggesting that M1 may affect specific classes of pyramidal neurons differently. Here, using combined optogenetic and retrograde labeling approaches in the mouse, we examined the strengths of M1 inputs to five classes of infragranular S1 neurons categorized by their projections to particular cortical and subcortical targets. We found that the magnitude of M1 synaptic input to S1 pyramidal neurons varies greatly depending on the projection target of the postsynaptic neuron. Of the populations examined, M1-projecting corticocortical neurons in L6 received the strongest M1 inputs, whereas ventral posterior medial nucleus-projecting corticothalamic neurons, also located in L6, received the weakest. Each population also possessed distinct intrinsic properties. The results suggest that M1 differentially engages specific classes of S1 projection neurons, thereby regulating the motor-related influence S1 exerts over subcortical structures.

scholarly journals Conditional ablation and conditional rescue models for Casq2 elucidate the role of development and of cell-type specific expression of Casq2 in the CPVT2 phenotype

2018 ◽  
Vol 27 (9) ◽  
pp. 1533-1544 ◽  
Author(s):  
Daniel J Flores ◽  
ThuyVy Duong ◽  
Luke O Brandenberger ◽  
Apratim Mitra ◽  
Aditya Shirali ◽  
...  
Keyword(s):  
Cell Type ◽  
Specific Expression ◽  
Cell Type Specific Expression ◽  
Cell Type Specific

scholarly journals Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice

2018 ◽  
Vol 115 (20) ◽  
pp. 5253-5258 ◽  
Author(s):  
Hideyuki Yanai ◽  
Shiho Chiba ◽  
Sho Hangai ◽  
Kohei Kometani ◽  
Asuka Inoue ◽  
...  
Keyword(s):  
Immune Cell ◽  
Cell Types ◽  
Type I ◽  
Type I Ifn ◽  
Cell Type ◽  
Gene Ablation ◽  
Cell Type Specific

IFN regulatory factor 3 (IRF3) is a transcription regulator of cellular responses in many cell types that is known to be essential for innate immunity. To confirm IRF3’s broad role in immunity and to more fully discern its role in various cellular subsets, we engineered Irf3-floxed mice to allow for the cell type-specific ablation of Irf3. Analysis of these mice confirmed the general requirement of IRF3 for the evocation of type I IFN responses in vitro and in vivo. Furthermore, immune cell ontogeny and frequencies of immune cell types were unaffected when Irf3 was selectively inactivated in either T cells or B cells in the mice. Interestingly, in a model of lipopolysaccharide-induced septic shock, selective Irf3 deficiency in myeloid cells led to reduced levels of type I IFN in the sera and increased survival of these mice, indicating the myeloid-specific, pathogenic role of the Toll-like receptor 4–IRF3 type I IFN axis in this model of sepsis. Thus, Irf3-floxed mice can serve as useful tool for further exploring the cell type-specific functions of this transcription factor.

scholarly journals Auxins and Cytokinins—The Role of Subcellular Organization on Homeostasis

2018 ◽  
Vol 19 (10) ◽  
pp. 3115 ◽  
Author(s):  
Vladimír Skalický ◽  
Martin Kubeš ◽  
Richard Napier ◽  
Ondřej Novák
Keyword(s):  
Plant Growth ◽  
Growth And Development ◽  
Recent Progress ◽  
Plant Hormone ◽  
Cell Type ◽  
Plant Growth And Development ◽  
Master Regulators ◽  
Cell Type Specific ◽  
Structural Levels

Plant hormones are master regulators of plant growth and development. Better knowledge of their spatial signaling and homeostasis (transport and metabolism) on the lowest structural levels (cellular and subcellular) is therefore crucial to a better understanding of developmental processes in plants. Recent progress in phytohormone analysis at the cellular and subcellular levels has greatly improved the effectiveness of isolation protocols and the sensitivity of analytical methods. This review is mainly focused on homeostasis of two plant hormone groups, auxins and cytokinins. It will summarize and discuss their tissue- and cell-type specific distributions at the cellular and subcellular levels.

scholarly journals NF-κB/Rel Transcription Factors in Pancreatic Cancer: Focusing on RelA, c-Rel, and RelB

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 937 ◽  
Author(s):  
Derya Kabacaoglu ◽  
Dietrich A. Ruess ◽  
Jiaoyu Ai ◽  
Hana Algül
Keyword(s):  
Transcription Factors ◽  
Ductal Adenocarcinoma ◽  
Cell Type ◽  
Dual Nature ◽  
Ability To Act ◽  
Cell Type Specific ◽  
Additional Tumor ◽  
Light Chain Enhancer ◽  
Oncogenic Function

Regulation of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/Rel transcription factors (TFs) is extremely cell-type-specific owing to their ability to act disparately in the context of cellular homeostasis driven by cellular fate and the microenvironment. This is also valid for tumor cells in which every single component shows heterogenic effects. Whereas many studies highlighted a per se oncogenic function for NF-κB/Rel TFs across cancers, recent advances in the field revealed their additional tumor-suppressive nature. Specifically, pancreatic ductal adenocarcinoma (PDAC), as one of the deadliest malignant diseases, shows aberrant canonical-noncanonical NF-κB signaling activity. Although decades of work suggest a prominent oncogenic activity of NF-κB signaling in PDAC, emerging evidence points to the opposite including anti-tumor effects. Considering the dual nature of NF-κB signaling and how it is closely linked to many other cancer related signaling pathways, it is essential to dissect the roles of individual Rel TFs in pancreatic carcinogenesis and tumor persistency and progression. Here, we discuss recent knowledge highlighting the role of Rel TFs RelA, RelB, and c-Rel in PDAC development and maintenance. Next to providing rationales for therapeutically harnessing Rel TF function in PDAC, we compile strategies currently in (pre-)clinical evaluation.

scholarly journals Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility

2018 ◽  
Vol 115 (5) ◽  
pp. 1111-1116 ◽  
Author(s):  
Mitra Heshmati ◽  
Hossein Aleyasin ◽  
Caroline Menard ◽  
Daniel J. Christoffel ◽  
Meghan E. Flanigan ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Cell Type ◽  
Dopamine D2 ◽  
Disease States ◽  
Specific Effects ◽  
Chronic Social Defeat Stress ◽  
Cell Type Specific ◽  
Stress Susceptibility ◽  
Cell Adhesion Proteins

Behavioral coping strategies are critical for active resilience to stress and depression; here we describe a role for neuroligin-2 (NLGN-2) in the nucleus accumbens (NAc). Neuroligins (NLGN) are a family of neuronal postsynaptic cell adhesion proteins that are constituents of the excitatory and inhibitory synapse. Importantly, NLGN-3 and NLGN-4 mutations are strongly implicated as candidates underlying the development of neuropsychiatric disorders with social disturbances such as autism, but the role of NLGN-2 in neuropsychiatric disease states is unclear. Here we show a reduction in NLGN-2 gene expression in the NAc of patients with major depressive disorder. Chronic social defeat stress in mice also decreases NLGN-2 selectively in dopamine D1-positive cells, but not dopamine D2-positive cells, within the NAc of stress-susceptible mice. Functional NLGN-2 knockdown produces bidirectional, cell-type-specific effects: knockdown in dopamine D1-positive cells promotes subordination and stress susceptibility, whereas knockdown in dopamine D2-positive cells mediates active defensive behavior. These findings establish a behavioral role for NAc NLGN-2 in stress and depression; provide a basis for targeted, cell-type specific therapy; and highlight the role of active behavioral coping mechanisms in stress susceptibility.

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