scholarly journals Decision letter: State-dependent cell-type-specific membrane potential dynamics and unitary synaptic inputs in awake mice

2018 ◽  
Keyword(s):  
Membrane Potential ◽  
Cell Type ◽  
Synaptic Inputs ◽  
State Dependent ◽  
Dependent Cell ◽  
Cell Type Specific ◽  
Specific Membrane

scholarly journals State-dependent cell-type-specific membrane potential dynamics and unitary synaptic inputs in awake mice

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Aurélie Pala ◽  
Carl CH Petersen
Keyword(s):  
Membrane Potential ◽  
Barrel Cortex ◽  
Field Potential ◽  
Low Frequency ◽  
Inhibitory Neuron ◽  
Single Layer ◽  
Cell Type ◽  
State Dependent ◽  
Layer 2 ◽  
Cell Type Specific

The cellular and synaptic mechanisms driving cell-type-specific function during various cortical network activities and behaviors are poorly understood. Here, we targeted whole-cell recordings to two classes of inhibitory GABAergic neurons in layer 2/3 of the barrel cortex of awake head-restrained mice and correlated spontaneous membrane potential dynamics with cortical state and whisking behavior. Using optogenetic stimulation of single layer 2/3 excitatory neurons we measured unitary excitatory postsynaptic potentials (uEPSPs) across states. During active states, characterized by whisking and reduced low-frequency activity in the local field potential, parvalbumin-expressing neurons depolarized and, albeit in a small number of recordings, received uEPSPs with increased amplitude. In contrast, somatostatin-expressing neurons hyperpolarized and reduced firing rates during active states without consistent change in uEPSP amplitude. These results further our understanding of neocortical inhibitory neuron function in awake mice and are consistent with the hypothesis that distinct genetically-defined cell classes have different state-dependent patterns of activity.

scholarly journals Cell type-specific membrane potential changes in dorsolateral striatum accompanying reward-based sensorimotor learning

Function ◽  
2021 ◽  
Author(s):  
Tanya Sippy ◽  
Corryn Chaimowitz ◽  
Sylvain Crochet ◽  
Carl C H Petersen
Keyword(s):  
Membrane Potential ◽  
Dopamine Receptors ◽  
Cell Types ◽  
Projection Neurons ◽  
Striatal Neurons ◽  
Cell Type ◽  
Indirect Pathway ◽  
Cell Type Specific ◽  
Striatal Membrane ◽  
Sensory Evoked

Abstract The striatum integrates sensorimotor and motivational signals, likely playing a key role in reward-based learning of goal-directed behavior. However, cell type-specific mechanisms underlying reinforcement learning remain to be precisely determined. Here, we investigated changes in membrane potential dynamics of dorsolateral striatal neurons comparing naïve mice and expert mice trained to lick a reward spout in response to whisker deflection. We recorded from three distinct cell types: i) direct pathway striatonigral neurons, which express type 1 dopamine receptors; ii) indirect pathway striatopallidal neurons, which express type 2 dopamine receptors; and iii) tonically active, putative cholinergic, striatal neurons. Task learning was accompanied by cell type-specific changes in the membrane potential dynamics evoked by the whisker deflection and licking in successfully-performed trials. Both striatonigral and striatopallidal types of striatal projection neurons showed enhanced task-related depolarization across learning. Striatonigral neurons showed a prominent increase in a short latency sensory-evoked depolarization in expert compared to naïve mice. In contrast, the putative cholinergic striatal neurons developed a hyperpolarizing response across learning, driving a pause in their firing. Our results reveal cell type-specific changes in striatal membrane potential dynamics across the learning of a simple goal-directed sensorimotor transformation, helpful for furthering the understanding of the various potential roles of different basal ganglia circuits.

scholarly journals Cell-type specific arousal-dependent modulation of thalamic activity in the lateral geniculate nucleus

2021 ◽  
Author(s):  
Benedek Molnár ◽  
Péter Sere ◽  
Sándor Bordé ◽  
Krisztián Koós ◽  
Péter Horváth ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Lateral Geniculate Nucleus ◽  
Visual Information ◽  
Neuronal Membrane ◽  
Intracellular Recordings ◽  
Lateral Geniculate ◽  
State Dependent ◽  
Cell Type Specific ◽  
Evoked Activity ◽  
Corticothalamic Feedback

ABSTRACTState dependent thalamocortical activity is important for sensory coding, oscillations and cognition. The lateral geniculate nucleus (LGN) relays visual information to the cortex, but the state dependent spontaneous and visually evoked activity of LGN neurons in awake behaving animals remains controversial. Using a combination of pupillometry, extracellular and intracellular recordings from identified LGN neurons we show that thalamocortical neurons and interneurons are distinctly correlated to arousal forming two complementary coalitions. Intracellular recordings indicated that the membrane potential of LGN TC neurons was tightly correlated to fluctuations in pupil size. Inactivating the corticothalamic feedback to the LGN suppressed the arousal dependency of LGN neurons. Taken together our results show that LGN neuronal membrane potential and action potential output are dynamically linked to arousal dependent brain states in awake mice and this might have important functional implications.

scholarly journals Identification of the promoter and a transcriptional enhancer of the gene encoding L-CAM, a calcium-dependent cell adhesion molecule

1993 ◽  
Vol 90 (23) ◽  
pp. 11356-11360 ◽  
Author(s):  
B C Sorkin ◽  
F S Jones ◽  
B A Cunningham ◽  
G M Edelman
Keyword(s):  
Cell Adhesion ◽  
Cell Adhesion Molecule ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Cell Type ◽  
Cis Acting ◽  
Calcium Dependent ◽  
Dependent Cell ◽  
Cell Type Specific ◽  
Lmh Cells

L-CAM is a calcium-dependent cell adhesion molecule that is expressed in a characteristic place-dependent pattern during development. Previous studies of ectopic expression of the chicken L-CAM gene under the control of heterologous promoters in transgenic mice suggested that cis-acting sequences controlling the spatiotemporal expression patterns of L-CAM were present within the gene itself. We have now examined the L-CAM gene for sequences that control its expression and have found an enhancer within the second intron of the gene. A 2.5-kb Kpn I-EcoRI fragment from the intron acted as an enhancer of a simian virus 40 minimal promoter driving a chloramphenicol acetyltransferase (CAT) reporter gene and produced 14.0-fold induction of CAT activity in MDCK cells. To narrow down the region responsible for enhancer activity and to determine whether the enhancer could function in a cell type-specific manner, a number of smaller restriction fragments from the intron were tested for activity in two chicken cell lines, the LMH hepatoma line, which produces high levels of L-CAM, and the SL-29 fibroblast line, which produces little, if any, L-CAM. Four L-CAM enhancer plasmids containing shorter segments derived from the intron showed enhanced CAT activity levels (between 9.4- and 16.5-fold) in extracts from transfected LMH cells but not from SL-29 cells. DNA sequence analysis of the L-CAM enhancer region revealed putative binding sites for the transcription factors SP1, E2A, and AP-2. In addition, LE-9, the smallest L-CAM enhancer segment (310 bp), contained a consensus binding site for the liver-enriched POU-homeodomain transcription factor, HNF-1. Tests of upstream sequences showed that a 630-bp fragment, corresponding to nearly the entire intergenic region between L-CAM and its neighboring CAM gene, K-CAM, could function as a promoter. In combination with the L-CAM enhancer, this fragment directed cell type-specific expression of the CAT reporter gene in LMH cells at a level comparable to that observed with enhancer constructs using the simian virus 40 minimal promoter. These combined observations define a promoter and an enhancer for the chicken L-CAM gene. They raise the possibility that these cis-acting regulatory sequences may be instrumental in directing specific place-dependent expression of the L-CAM gene in the chicken.

scholarly journals Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer’s disease brains

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Julio Barrera ◽  
Lingyun Song ◽  
Julia E. Gamache ◽  
Melanie E. Garrett ◽  
Alexias Safi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Unmet Need ◽  
Chromatin Accessibility ◽  
Cell Type ◽  
Neuronal Nuclei ◽  
Dependent Cell ◽  
A Cell ◽  
Cell Type Specific

Abstract Background In the post-GWAS era, there is an unmet need to decode the underpinning genetic etiologies of late-onset Alzheimer’s disease (LOAD) and translate the associations to causation. Methods We conducted ATAC-seq profiling using NeuN sorted-nuclei from 40 frozen brain tissues to determine LOAD-specific changes in chromatin accessibility landscape in a cell-type specific manner. Results We identified 211 LOAD-specific differential chromatin accessibility sites in neuronal-nuclei, four of which overlapped with LOAD-GWAS regions (±100 kb of SNP). While the non-neuronal nuclei did not show LOAD-specific differences, stratification by sex identified 842 LOAD-specific chromatin accessibility sites in females. Seven of these sex-dependent sites in the non-neuronal samples overlapped LOAD-GWAS regions including APOE. LOAD loci were functionally validated using single-nuclei RNA-seq datasets. Conclusions Using brain sorted-nuclei enabled the identification of sex-dependent cell type-specific LOAD alterations in chromatin structure. These findings enhance the interpretation of LOAD-GWAS discoveries, provide potential pathomechanisms, and suggest novel LOAD-loci. Graphical Abstract

scholarly journals Cell-Type Specific Changes in DNA Methylation of SNCA Intron 1 in Synucleinopathy Brains

2021 ◽  
Vol 15 ◽  
Author(s):  
Jeffrey Gu ◽  
Julio Barrera ◽  
Young Yun ◽  
Susan K. Murphy ◽  
Thomas G. Beach ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Frontal Cortex ◽  
Cpg Island ◽  
Cell Type ◽  
Neuronal Nuclei ◽  
Intron 1 ◽  
Significant Difference ◽  
Dependent Cell ◽  
A Cell ◽  
Cell Type Specific

Parkinson’s disease (PD) and dementia with Lewy body (DLB) are the most common synucleinopathies. SNCA gene is a major genetic risk factor for these diseases group, and dysregulation of its expression has been implicated in the genetic etiologies of several synucleinopathies. DNA methylation at CpG island (CGI) within SNCA intron 1 has been suggested as a regulatory mechanism of SNCA expression, and changes in methylation levels at this region were associated with PD and DLB. However, the role of DNA methylation in the regulation of SNCA expression in a cell-type specific manner and its contribution to the pathogenesis of PD and DLB remain poorly understood, and the data are conflicting. Here, we employed a bisulfite pyrosequencing technique to profile the DNA methylation across SNCA intron 1 CGI in PD and DLB compared to age- and sex-matched normal control subjects. We analyzed homogenates of bulk post-mortem frozen frontal cortex samples and a subset of neuronal and glia nuclei sorted by the fluorescence-activated nuclei sorting (FANS) method. Bulk brain tissues showed no significant difference in the overall DNA methylation across SNCA intron 1 CGI region between the neuropathological groups. Sorted neuronal nuclei from PD frontal cortex showed significant lower levels of DNA methylation at this region compared to normal controls, but no differences between DLB and control, while sorted glia nuclei exhibited trends of decreased overall DNA methylation in DLB only. In conclusion, our data suggested disease-dependent cell-type specific differential DNA methylation within SNCA intron 1 CGI. These changes may affect SNCA dysregulation that presumably mediates disease-specific risk. Our results can be translated into the development of the SNCA intron 1 CGI region as an attractive therapeutics target for gene therapy in patients who suffer from synucleinopathies due to SNCA dysregulation.

scholarly journals Cell-Type Specific Arousal-Dependent Modulation of Thalamic Activity in the Lateral Geniculate Nucleus

2021 ◽  
Author(s):  
Benedek Molnár ◽  
Péter Sere ◽  
Sándor Bordé ◽  
Krisztián Koós ◽  
Nikolett Zsigri ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Lateral Geniculate Nucleus ◽  
Visual Information ◽  
Neuronal Membrane ◽  
Intracellular Recordings ◽  
Lateral Geniculate ◽  
State Dependent ◽  
Cell Type Specific ◽  
Brain States ◽  
Corticothalamic Feedback

Abstract State dependent thalamocortical activity is important for sensory coding, oscillations and cognition. The lateral geniculate nucleus (LGN) relays visual information to the cortex, but the state dependent spontaneous activity of LGN neurons in awake behaving animals remains controversial. Using a combination of pupillometry, extracellular and intracellular recordings from identified LGN neurons in behaving mice we show that thalamocortical neurons and interneurons are distinctly correlated to arousal forming two complementary coalitions. Intracellular recordings indicated that the membrane potential of LGN TC neurons was tightly correlated to fluctuations in pupil size. Inactivating the corticothalamic feedback to the LGN suppressed the arousal dependency of LGN neurons. Taken together our results show that LGN neuronal membrane potential and action potential output are dynamically linked to arousal dependent brain states in awake mice, and this might have important functional implications.

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