scholarly journals Cortical diurnal rhythms remain intact with microglial depletion

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Rocio A. Barahona ◽  
Samuel Morabito ◽  
Vivek Swarup ◽  
Kim N. Green
Keyword(s):  
Gene Expression ◽  
Inflammatory Responses ◽  
Brain Regions ◽  
Adult Brain ◽  
Diurnal Rhythms ◽  
Dark Phase ◽  
Perineuronal Nets ◽  
Diurnal Changes ◽  
Cycling Gene ◽  
Diurnal Regulation

AbstractMicroglia are subject to change in tandem with the endogenously generated biological oscillations known as our circadian rhythm. Studies have shown microglia harbor an intrinsic molecular clock which regulates diurnal changes in morphology and influences inflammatory responses. In the adult brain, microglia play an important role in the regulation of condensed extracellular matrix structures called perineuronal nets (PNNs), and it has been suggested that PNNs are also regulated in a circadian and diurnal manner. We sought to determine whether microglia mediate the diurnal regulation of PNNs via CSF1R inhibitor dependent microglial depletion in C57BL/6J mice, and how the absence of microglia might affect cortical diurnal gene expression rhythms. While we observe diurnal differences in microglial morphology, where microglia are most ramified at the onset of the dark phase, we do not find diurnal differences in PNN intensity. However, PNN intensity increases across many brain regions in the absence of microglia, supporting a role for microglia in the regulation of PNNs. Here, we also show that cortical diurnal gene expression rhythms are intact, with no cycling gene changes without microglia. These findings demonstrate a role for microglia in the maintenance of PNNs, but not in the maintenance of diurnal rhythms.

scholarly journals Quantitative RT-PCR analyses of five evolutionary conserved genes in Alligator brains during development

2011 ◽  
Vol 2 (4) ◽  
Author(s):  
Sarah Wilson ◽  
Tianli Zhu ◽  
Rajesh Khanna ◽  
Michael Pritz
Keyword(s):  
Gene Expression ◽  
Brain Area ◽  
Brain Regions ◽  
Adult Brain ◽  
Time Interval ◽  
Conserved Genes ◽  
Mrna Gene ◽  
Alligator Mississipiensis ◽  
Mrna Gene Expression ◽  
Present Gene

AbstractGene expression was investigated in the major brain subdivisions (telencephalon, diencephalon, midbrain and hindbrain) in a representative reptile, Alligator mississipiensis, during the later stages of embryonic development. The following genes were examined: voltage-gated sodium channel isoforms: NaV1.1 and NaV1.2; synaptic vesicle 2a (SV2a); synaptophysin; and calbindin 2. With the exception of synaptophysin, which was only expressed in the telencephalon, all genes were expressed in all brain regions sampled at the time periods examined. For NaV1.1, gene expression varied according to brain area sampled. When compared with NaV1.1, the pattern of NaV1.2 gene expression differed appreciably. The gene expression of SV2a was the most robust of any of the genes examined. Of the other genes examined, although differences were noted, no statistically significant changes were found either between brain part or time interval. Although limited, the present analysis is the first quantitative mRNA gene expression study in any reptile during development. Together with future experiments of a similar nature, the present gene expression results should determine which genes are expressed in major brain areas at which times during development in Alligator. When compared with other amniotes, these results will prove useful for determining how gene expression during development influences adult brain structure.

scholarly journals Diurnal changes in perineuronal nets and parvalbumin neurons in the rat medial prefrontal cortex

2020 ◽  
Author(s):  
John H. Harkness ◽  
Angela E. Gonzalez ◽  
Priyanka N. Bushana ◽  
Emily T. Jorgensen ◽  
Deborah M. Hegarty ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Medial Prefrontal Cortex ◽  
Active Phase ◽  
Autism Spectrum ◽  
Diurnal Rhythms ◽  
Oxidative Stress Marker ◽  
Perineuronal Nets ◽  
Diurnal Changes ◽  
Strong Trend ◽  
Fast Spiking

ABSTRACTPerineuronal nets (PNNs) surrounding fast-spiking, parvalbumin (PV) inhibitory interneurons are vital for providing excitatory:inhibitory balance within cortical circuits, and this balance is impaired in disorders such as schizophrenia, autism spectrum disorder, and substance use disorders. These disorders are also associated with altered diurnal rhythms, yet few studies have examined the diurnal rhythms of PNNs or PV cells. We measured the intensity and number of PV cells and PNNs labeled with Wisteria floribunda agglutinin (WFA) in the rat prelimbic medial prefrontal cortex (mPFC) at Zeitgeber times (ZT) ZT0, 6, 12, and 18. We also measured the oxidative stress marker 8-oxo-deoxyguanosine (8-oxo-dG). Relative to ZT0, the intensities of PNN and PV staining were increased in the dark (active) phase compared with the light (inactive) phase. The intensity of 8-oxo-dG was decreased from ZT0 at all time points (ZT6,12,18), in both PV cells and non-PV cells. To examine corresponding changes in inhibitory and excitatory inputs, we measured GAD 65/67 and vGlut1 puncta apposed to PV cells with and without PNNs. Relative to ZT6, there were more excitatory puncta on PV cells surrounded by PNNs at ZT18, but no changes in PV cells devoid of PNNs. No changes in inhibitory puncta were observed. Whole-cell slice recordings in fast-spiking (PV) cells with PNNs showed an increased ratio of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor:N-methyl-D-aspartate receptor (AMPA:NMDA) at ZT18 vs. ZT6. The number of PV cells and co-labeled PV/PNN cells containing the transcription factor orthodenticle homeobox 2 (OTX2), which maintains PNNs, showed a strong trend toward an increase from ZT6 to ZT18. These diurnal fluctuations in PNNs and PV cells are expected to alter cortical excitatory:inhibitory balance and provide new insights into treatment approaches for diseases impacted by imbalances in sleep and circadian rhythms.

scholarly journals 014 Diurnal changes in perineuronal nets and parvalbumin neurons in the rat medial prefrontal cortex

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A7-A8
Author(s):  
Barbara Sorg ◽  
John Harkness ◽  
Angela Gonzalez ◽  
Priyanka Bushana ◽  
Emily Jorgensen ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Medial Prefrontal Cortex ◽  
Diurnal Rhythms ◽  
Oxidative Stress Marker ◽  
Perineuronal Nets ◽  
Diurnal Changes ◽  
Strong Trend ◽  
Fast Spiking ◽  
Diurnal Fluctuations ◽  
Alcohol And Drug Abuse

Abstract Introduction Perineuronal nets (PNNs) surrounding fast-spiking, parvalbumin (PV) interneurons provide excitatory:inhibitory balance within cortical circuits. This balance is impaired in several disorders that are also associated with altered diurnal rhythms, yet few studies examined diurnal rhythms of PNNs or PV cells. Methods We measured the intensity and number of PV cells and PNNs labeled with Wisteria floribunda agglutinin (WFA) and also the oxidative stress marker 8-oxo-deoxyguanosine (8-oxo-dG) in rat prelimbic medial prefrontal cortex (mPFC) at Zeitgeber times (ZT) ZT0, 6, 12, and 18. To examine changes in inhibitory and excitatory inputs to PV cells, we measured GAD 65/67 and vGLUT1 puncta apposed to PV cells with and without PNNs. Whole-cell slice recordings in fast-spiking (PV) cells with PNNs was conducted to determine the ratio of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor:N-methyl-D-aspartate receptor (AMPA:NMDA) at ZT18 vs. ZT6. Finally, the number of PV cells and PV/PNN cells containing orthodenticle homeobox 2 (OTX2), which maintains PNNs, was also assessed. Results Relative to ZT0, the intensities of PNN and PV labeling were increased in the dark compared with the light phase. The intensity of 8-oxo-dG was decreased from ZT0 at all times. There were more excitatory puncta on PV cells with PNNs at ZT18 vs. ZT6, but no changes in PV cells without PNNs and no changes in inhibitory puncta. There was an increased AMPA:NMDA ratio at ZT18 vs. ZT6. The number of PV cells and PV/PNN cells containing OTX2 showed a strong trend toward an increase from ZT6 to ZT18, with no differences in non-PV-containing cells. Conclusion Diurnal fluctuations in PNNs and PV cells alter cortical excitatory:inhibitory balance. Detailed understanding of how these fluctuations are regulated should provide new insights into treatments for diseases impacted by disturbances in sleep and circadian rhythms. Ongoing studies are examining diurnal fluctuations in downstream signaling after PNN removal. Support (if any) Washington State University Alcohol and Drug Abuse Research Program, NIH GM134789 (JHH); NIH DA033404 (BAS), DA040965 (BAS, TEB, SAA); NIH NS078498 (JPW); NIH P30 NS061800 (SAA); and Agence Nationale de la Recherche ANR-18-CE16-0013-01 (AP and AAD).

Relationship between AMPK and the transcriptional balance of clock-related genes in skeletal muscle

2008 ◽  
Vol 295 (5) ◽  
pp. E1032-E1037 ◽  
Author(s):  
Elaine Vieira ◽  
Elisabeth C. Nilsson ◽  
Annika Nerstedt ◽  
Mattias Ormestad ◽  
Yun Chau Long ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Environmental Changes ◽  
Energy Utilization ◽  
Dark Phase ◽  
Diurnal Changes ◽  
Wild Type ◽  
Orphan Nuclear Receptors ◽  
Basal Expression ◽  
Amp Activated Protein Kinase

Circadian clocks coordinate physiological, behavioral, and biochemical events with predictable daily environmental changes by a self-sustained transcriptional feedback loop. CLOCK and ARNTL are transcriptional activators that regulate Per and Cry gene expression. PER and CRY inhibit their own transcription, and their turnover allows this cycle to restart. The transcription factors BHLHB2 and BHLHB3 repress Per activation, whereas orphan nuclear receptors of the NR1D and ROR families control Arntl expression. Here we show the AMP-activated protein kinase (AMPK)γ3 subunit is involved in the regulation of peripheral circadian clock function. AMPKγ3 knockout ( Prkag3−/−) mice or wild-type littermates were injected with saline or an AMPK activator, 5-amino-4-imidazole-carboxamide riboside (AICAR), and white glycolytic gastrocnemius muscle was removed for gene expression analysis. Genes involved in the regulation of circadian rhythms ( Cry2, Nr1d1, and Bhlhb2) were differentially regulated in response to AICAR in wild-type mice but remained unaltered in Prkag3−/− mice. Basal expression of Per1 was higher in Prkag3−/− mice compared with wild-type mice. Distinct diurnal changes in the respiratory exchange ratio (RER) between the light and dark phase of the day were observed in wild-type mice but not Prkag3−/− mice. In summary, the expression profile of clock-related genes in skeletal muscle in response to AICAR, as well as the diurnal shift in energy utilization, is impaired in AMPKγ3 subunit knockout mice. Our results indicate AMPK heterotrimeric complexes containing the AMPKγ3 subunit may play a specific role in linking circadian oscillators and energy metabolism in skeletal muscle.

scholarly journals Differential transcript usage unravels gene expression alterations in Alzheimer’s disease human brains

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Diego Marques-Coelho ◽  
◽  
Lukas da Cruz Carvalho Iohan ◽  
Ana Raquel Melo de Farias ◽  
Amandine Flaig ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Differential Expression ◽  
Cell Types ◽  
Brain Regions ◽  
Adult Brain ◽  
Gene Transcript ◽  
Comprehensive Overview ◽  
Gene Expression Alterations

AbstractAlzheimer’s disease (AD) is the leading cause of dementia in aging individuals. Yet, the pathophysiological processes involved in AD onset and progression are still poorly understood. Among numerous strategies, a comprehensive overview of gene expression alterations in the diseased brain could contribute for a better understanding of the AD pathology. In this work, we probed the differential expression of genes in different brain regions of healthy and AD adult subjects using data from three large transcriptomic studies: Mayo Clinic, Mount Sinai Brain Bank (MSBB), and ROSMAP. Using a combination of differential expression of gene and isoform switch analyses, we provide a detailed landscape of gene expression alterations in the temporal and frontal lobes, harboring brain areas affected at early and late stages of the AD pathology, respectively. Next, we took advantage of an indirect approach to assign the complex gene expression changes revealed in bulk RNAseq to individual cell types/subtypes of the adult brain. This strategy allowed us to identify previously overlooked gene expression changes in the brain of AD patients. Among these alterations, we show isoform switches in the AD causal gene amyloid-beta precursor protein (APP) and the risk gene bridging integrator 1 (BIN1), which could have important functional consequences in neuronal cells. Altogether, our work proposes a novel integrative strategy to analyze RNAseq data in AD and other neurodegenerative diseases based on both gene/transcript expression and regional/cell-type specificities.

scholarly journals Schizotypy-related magnetization of cortex in healthy adolescence is co-located with expression of schizophrenia-related genes

2018 ◽  
Author(s):  
Rafael Romero-Garcia ◽  
Jakob Seidlitz ◽  
Kirstie J Whitaker ◽  
Sarah E Morgan ◽  
Peter Fonagy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Magnetization Transfer ◽  
Gene Expression Pattern ◽  
Structural Mri ◽  
Brain Regions ◽  
Posterior Cingulate Cortex ◽  
Genomic Variation ◽  
Adult Brain ◽  
Brain Gene Expression ◽  
Histological Data

AbstractBackgroundGenetic risk is thought to drive clinical variation on a spectrum of schizophrenia-like traits but the underlying changes in brain structure that mechanistically link genomic variation to schizotypal experience and behaviour are unclear.MethodsWe assessed schizotypy using a self-reported questionnaire, and measured magnetization transfer (MT), as a putative micro-structural MRI marker of intra-cortical myelination, in 68 brain regions, in 248 healthy young people (aged 14-25 years). We used normative adult brain gene expression data, and partial least squares (PLS) analysis, to find the weighted gene expression pattern that was most co-located with the cortical map of schizotypy-related magnetization (SRM).ResultsMagnetization was significantly correlated with schizotypy in bilateral posterior cingulate cortex and precuneus (and for disorganized schizotypy also in medial prefrontal cortex; all FDR-corrected P < 0.05), which are regions of the default mode network specialized for social and memory functions. The genes most positively weighted on the whole genome expression map co-located with SRM were enriched for genes that were significantly down-regulated in two prior case-control histological studies of brain gene expression in schizophrenia. Conversely, the most negatively weighted genes were enriched for genes that were transcriptionally up-regulated in schizophrenia. Positively weighted (down-regulated) genes were enriched for neuronal, specifically inter-neuronal, affiliations and coded a network of proteins comprising a few highly interactive “hubs” such as parvalbumin and calmodulin.ConclusionsMicrostructural MRI maps of intracortical magnetization can be linked to both the behavioural traits of schizotypy and to prior histological data on dysregulated gene expression in schizophrenia.

scholarly journals Molecular Atlas of the Adult Mouse Brain

2019 ◽  
Author(s):  
Cantin Ortiz ◽  
Jose Fernandez Navarro ◽  
Aleksandra Jurek ◽  
Antje Märtin ◽  
Joakim Lundeberg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Brain ◽  
Spatial Organization ◽  
Adult Mouse ◽  
Brain Regions ◽  
Adult Brain ◽  
Adult Mouse Brain ◽  
Whole Brain ◽  
Systematic Classification ◽  
Molecular Code

AbstractBrain maps are essential for integrating information and interpreting the structure-function relationship of circuits and behavior. We aimed to generate a systematic classification of the adult mouse brain organization based on unbiased extraction of spatially-defining features. Applying whole-brain spatial transcriptomics, we captured the gene expression signatures to define the spatial organization of molecularly discrete subregions. We found that the molecular code contained sufficiently detailed information to directly deduce the complex spatial organization of the brain. This unsupervised molecular classification revealed new area- and layer-specific subregions, for example in isocortex and hippocampus, and a new division of striatum. The whole-brain molecular atlas further supports the identification of the spatial origin of single neurons using their gene expression profile, and forms the foundation to define a minimal gene set - a brain palette – that is sufficient to spatially annotate the adult brain. In summary, we have established a new molecular atlas to formally define the identity of brain regions, and a molecular code for mapping and targeting of discrete neuroanatomical domains.

scholarly journals Differential transcript usage unravels gene expression alterations in Alzheimer’s disease human brains

2020 ◽  
Author(s):  
Diego Marques-Coelho ◽  
Lukas Iohan da Cruz Carvalho ◽  
Ana Raquel Melo de Farias ◽  
Jean-Charles Lambert ◽  
Marcos Romualdo Costa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Differential Expression ◽  
Brain Regions ◽  
Adult Brain ◽  
Gene Transcript ◽  
Cell Type ◽  
Comprehensive Overview ◽  
Gene Expression Alterations

AbstractAlzheimer’s disease (AD) is the leading cause of dementia in aging individuals. However pathophysiological processes involved in the brain are still poorly understood. Among numerous strategies, a comprehensive overview of gene expression alterations in the diseased brain has been proposed to help for a better understanding of the disease processes. In this work, we probed the differential expression of genes in different brain regions of healthy and AD adult subjects using data from three large studies: MAYO Clinic; Mount Sinai Brain Bank (MSBB) and ROSMAP. Using a combination of differential expression of gene (DEG) and isoform switch analyses we provide a detailed landscape of gene expression alterations in the temporal and frontal lobes, harboring brain areas affected at early and late stages of the AD pathology, respectively. Next, we took advantage of an indirect approach to assign the complex gene expression changes revealed in bulk RNAseq to individual cell types of the adult brain. This strategy allowed us to identify cell type/subtype specific isoform switches in AD brains previously overlooked. This was the case, for example, for the AD causal gene APP and the risk gene BIN1, which presented isoform switches with potential functional consequences in neuronal cells. Altogether, our work proposes a novel integrative strategy to analyze RNAseq data in AD based on both gene/transcript expression and regional/cell-type specificities.

scholarly journals Diurnal expression of functional and clock-related genes throughout the rat HPA axis: system-wide shifts in response to a restricted feeding schedule

2009 ◽  
Vol 296 (4) ◽  
pp. E888-E897 ◽  
Author(s):  
Milena Girotti ◽  
Marc S. Weinberg ◽  
Robert L. Spencer
Keyword(s):  
Gene Expression ◽  
Food Availability ◽  
Hpa Axis ◽  
Clock Gene ◽  
Brain Regions ◽  
The Body ◽  
Diurnal Rhythms ◽  
Restricted Feeding ◽  
Dark Cycle ◽  
Clock Gene Expression

The diurnal rhythm of glucocorticoid secretion depends on the suprachiasmatic (SCN) and dorsomedial (putative food-entrainable oscillator; FEO) nuclei of the hypothalamus, two brain regions critical for coordination of physiological responses to photoperiod and feeding cues, respectively. In both cases, time keeping relies upon diurnal oscillations in clock gene ( per1, per2, and bmal) expression. Glucocorticoids may play a key role in synchronization of the rest of the body to photoperiod and food availability. Thus glucocorticoid secretion may be both a target and an important effector of SCN and FEO output. Remarkably little, however, is known about the functional diurnal rhythms of the individual components of the hypothalamic-pituitary-adrenal (HPA) axis. We examined the 24-h pattern of hormonal secretion (ACTH and corticosterone), functional gene expression (c- fos, crh, pomc, star), and clock gene expression ( per1, per2 and bmal) in each compartment of the HPA axis under a 12:12-h light-dark cycle and compared with relevant SCN gene expression. We found that each anatomic component of the HPA axis has a unique circadian signature of functional and clock gene expression. We then tested the susceptibility of these measures to nonphotic entrainment cues by restricting food availability to only a portion of the light phase of a 12:12-h light-dark cycle. Restricted feeding is a strong zeitgeber that can dramatically alter functional and clock gene expression at all levels of the HPA axis, despite ongoing photoperiod cues and only minor changes in SCN clock gene expression. Thus the HPA axis may be an important mediator of the body entrainment to the FEO.

scholarly journals Systematic investigation of imprinted gene expression and enrichment in the mouse brain explored at single-cell resolution

2020 ◽  
Author(s):  
M. J. Higgs ◽  
M. J. Hill ◽  
R. M. John ◽  
A. R. Isles
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Gene Networks ◽  
Cell Types ◽  
Brain Regions ◽  
Systematic Investigation ◽  
Adult Brain ◽  
Imprinted Genes ◽  
Imprinted Gene ◽  
The Brain

AbstractAlthough a number of imprinted genes are known to be highly expressed in the brain, and in certain brain regions in particular, whether they are truly over-represented in the brain has never been formally tested. Using fifteen single-cell RNA sequencing datasets we take a systematic approach to investigate imprinted gene over-representation at the organ, brain region, and cell-specific levels. We establish that imprinted genes are indeed over-represented in the adult brain, and in neurons particularly compared to other brain cell-types. We then examine brain-wide datasets to examine enrichment within distinct regions of the brain and demonstrate over-representation of imprinted genes in the hypothalamus, ventral midbrain, pons and medulla. Finally, using datasets focusing on these regions of enrichment, we were able to identify hypothalamic neuroendocrine populations and the monoaminergic hindbrain neurons as specific hotspots of imprinted gene expression. These analyses provide the first robust assessment of the neural systems on which imprinted genes converge. Moreover, the unbiased approach, with each analysis informed by the findings of the previous level, permits highly informed inferences about the functions on which imprinted genes converge. Our findings indicate the neuronal regulation of motivated behaviours such as feeding, parental behaviour and sleep as functional hotspots for imprinting, thus adding statistically rigour to prior assumptions and providing testable predictions for novel neural and behavioural phenotypes associated with specific genes and imprinted gene networks. In turn, this work sheds further light on the potential evolutionary drivers of genomic imprinting in the brain.

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