scholarly journals Different Roles for VIP Neurons in the Neonatal and Adult Suprachiasmatic Nucleus

2020 ◽  
Vol 35 (5) ◽  
pp. 465-475 ◽  
Author(s):  
Cristina Mazuski ◽  
Samantha P. Chen ◽  
Erik D. Herzog
Keyword(s):  
Suprachiasmatic Nucleus ◽  
Daily Activity ◽  
Locomotor Behavior ◽  
Circadian Period ◽  
Circadian Gene ◽  
Daily Rhythms ◽  
Apoptotic Pathway ◽  
Adult Mice ◽  
Genetic Deletion

The suprachiasmatic nucleus (SCN) drives circadian rhythms in locomotion through coupled, single-cell oscillations. Global genetic deletion of the neuropeptide Vip or its receptor Vipr2 results in profound deficits in daily synchrony among SCN cells and daily rhythms in locomotor behavior and glucocorticoid secretion. To test whether this phenotype depends on vasoactive intestinal polypeptide (VIP) neurons in the SCN, we ablated VIP SCN neurons in vivo in adult male mice through Caspase3-mediated induction of the apoptotic pathway in cre-expressing VIP neurons. We found that ablation of VIP SCN neurons in adult mice caused a phenotype distinct from Vip- and Vipr2-null mice. Mice lacking VIP neurons retained rhythmic locomotor activity with a shortened circadian period, more variable onsets, and decreased duration of daily activity. Circadian hormonal outputs, specifically corticosterone rhythms, were severely dampened. In contrast, deletion of neonatal SCN VIP neurons dramatically reduced circadian gene expression in the cultured SCN, mimicking the effects of global deletion of Vip or Vipr2. These results suggest that SCN VIP neurons play a role in lengthening circadian period and stimulating the daily surge in glucocorticoids in adults and in synchronizing and sustaining daily rhythms among cells in the developing SCN.

scholarly journals Adult mice lacking VIP SCN neurons retain circadian locomotor behavior but exhibit dampened daily glucocorticoid rhythms

2020 ◽  
Author(s):  
Cristina Mazuski ◽  
Samantha P. Chen ◽  
Erik D. Herzog
Keyword(s):  
Gene Expression ◽  
Circadian Rhythms ◽  
Daily Activity ◽  
Locomotor Behavior ◽  
Circadian Period ◽  
Circadian Gene ◽  
Daily Rhythms ◽  
Apoptotic Pathway ◽  
Adult Mice ◽  
Genetic Deletion

AbstractThe suprachiasmatic nucleus (SCN) drives circadian rhythms in locomotion through coupled, single-cell oscillations. Global genetic deletion of the neuropeptide, Vip or its receptor Vipr2, results in profound deficits in daily synchrony among SCN cells and daily rhythms in locomotor behavior and glucocorticoid secretion. To test whether this phenotype depends on VIP neurons in the SCN, we ablated VIP SCN neurons in vivo in adult mice through Caspase3-mediated induction of the apoptotic pathway in cre-expressing VIP neurons. We found that ablation of VIP SCN neurons in adult mice caused a phenotype distinct from Vip- and Vipr2- null mice. Mice lacking VIP neurons retained rhythmic locomotor activity with a shortened circadian period, more variable onsets and decreased duration of daily activity. Circadian hormonal outputs, specifically corticosterone rhythms were severely dampened. In contrast, deletion of neonatal SCN VIP neurons dramatically reduced circadian gene expression in the cultured SCN, mimicking the effects of global deletion of Vip or Vipr2. These results suggest that SCN VIP neurons play a role in lengthening circadian period and stimulating the daily surge in glucocorticoids in adults and in synchronizing and sustaining daily rhythms among cells in the developing SCN.Significance StatementThe importance of the neuropeptide, VIP, for circadian rhythms has been described in mice lacking the gene for Vip or its receptor, Vipr2. This study found that ablation of VIP neurons only in the adult SCN reproduced the loss of circadian rhythms in glucocorticoids, but not the loss of circadian locomotor behavior, seen with global loss of VIP signaling. We conclude that VIP SCN neurons play two roles: one in adulthood lengthening circadian period and regulating circadian outputs, and one in development coordinating synchrony among circadian cells.

scholarly journals Acute Knockdown of Kv4.1 Regulates Repetitive Firing Rates and Clock Gene Expression in the Suprachiasmatic Nucleus and Daily Rhythms in Locomotor Behavior

eNeuro ◽  
2017 ◽  
Vol 4 (3) ◽  
pp. ENEURO.0377-16.2017 ◽  
Author(s):  
Tracey O. Hermanstyne ◽  
Daniel Granados-Fuentes ◽  
Rebecca L. Mellor ◽  
Erik D. Herzog ◽  
Jeanne M. Nerbonne
Keyword(s):  
Gene Expression ◽  
Suprachiasmatic Nucleus ◽  
Clock Gene ◽  
Locomotor Behavior ◽  
Repetitive Firing ◽  
Daily Rhythms ◽  
Firing Rates ◽  
Clock Gene Expression

scholarly journals Gestational low-dose BPA exposure impacts suprachiasmatic nucleus neurogenesis and circadian activity with transgenerational effects

2021 ◽  
Vol 7 (22) ◽  
pp. eabd1159
Author(s):  
Dinushan Nesan ◽  
Kira M. Feighan ◽  
Michael C. Antle ◽  
Deborah M. Kurrasch
Keyword(s):  
Social Interactions ◽  
Suprachiasmatic Nucleus ◽  
Low Dose ◽  
Ex Vivo ◽  
Neural Progenitors ◽  
Fetal Exposure ◽  
Circadian Activity ◽  
Adult Mice ◽  
Physiological Processes

Critical physiological processes such as sleep and stress that underscore health are regulated by an intimate interplay between the endocrine and nervous systems. Here, we asked how fetal exposure to the endocrine disruptor found in common plastics, bisphenol A (BPA), causes lasting effects on adult animal behaviors. Adult mice exposed to low-dose BPA during gestation displayed notable disruption in circadian activity, social interactions, and associated neural hyperactivity, with some phenotypes maintained transgenerationally. Gestational BPA exposure increased vasopressin+ neurons in the suprachiasmatic nucleus (SCN), the region that regulates circadian rhythms, of F1 and F3 generations. Mechanistically, BPA increased proliferation of hypothalamic neural progenitors ex vivo and caused precocious neurogenesis in vivo. Co-antagonism of both estrogen and androgen receptors was necessary to block BPA’s effects on hypothalamic neural progenitors, illustrating a dual role for these endocrine targets. Together, gestational BPA exposure affects development of circadian centers, with lasting consequences across generations.

scholarly journals Circadian clock neurons mediate time-of-day dependent responses to light

2018 ◽  
Author(s):  
Jeff R. Jones ◽  
Tatiana Simon ◽  
Lorenzo Lones ◽  
Erik D. Herzog
Keyword(s):  
Suprachiasmatic Nucleus ◽  
Time Of Day ◽  
Light Cycle ◽  
Hormone Release ◽  
Daily Rhythms ◽  
Light Responses ◽  
And Behavior

ABSTRACTCircadian (~24 h) rhythms influence nearly all aspects of physiology, including sleep/wake, metabolism, and hormone release. The suprachiasmatic nucleus (SCN) synchronizes these daily rhythms to the external light cycle, but the mechanisms by which this occurs is unclear. The neuropeptide vasoactive intestinal peptide (VIP) is the predominant contributor to synchrony within the SCN and is important for circadian light responses, but the role of VIP neurons themselves is unclear. Thus, we tested the hypothesis that rhythmic SCN VIP neurons mediate circadian light responses. Using in vivo fiber photometry recording of SCN VIP neurons we found daily rhythms in spontaneous calcium events that peaked during the subjective day and in light-evoked calcium events that exhibited the greatest response around subjective dusk. These rhythms were correlated with spontaneous and NMDA-evoked VIP release from SCN VIP neurons in vitro. Finally, in vivo hyperpolarization of VIP neurons attenuated light-induced shifts of daily rhythms in locomotion. We conclude that SCN VIP neurons are circadian and depolarize to light to modulate entrainment of daily rhythms in the SCN and behavior.

scholarly journals The cell-autonomous clock of VIP receptor VPAC2 cells drives circadian behaviour

2020 ◽  
Author(s):  
Ryan Hamnett ◽  
Johanna E. Chesham ◽  
Elizabeth S. Maywood ◽  
Michael H. Hastings
Keyword(s):  
Vasoactive Intestinal Peptide ◽  
Suprachiasmatic Nucleus ◽  
Ex Vivo ◽  
Cell Types ◽  
Feedback Loops ◽  
Target Cells ◽  
Circadian Pacemaker ◽  
Circadian Period ◽  
Daily Rhythms ◽  
Cognate Receptor

AbstractCircadian (∼daily) rhythms pervade mammalian behaviour. They are generated by cell-autonomous, transcriptional/translational feedback loops (TTFL), active in all tissues. This distributed clock network is co-ordinated by the principal circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN). Its robust and accurate time-keeping arises from circuit-level interactions that bind its individual cellular clocks into a coherent time-keeper. Cells that express the neuropeptide vasoactive intestinal peptide (VIP) mediate retinal entrainment of the SCN, and in the absence of VIP, or its cognate receptor VPAC2, circadian behaviour is compromised because SCN cells cannot synchronise. The contributions to SCN pacemaking and circadian behaviour of other cell types, not least the VPAC2-expressing target cells of VIP, are, however, not understood. We therefore employed intersectional genetics to manipulate the cell-autonomous TTFL of VPAC2-expressing cells, creating temporally chimaeric mice. We could then determine whether and how VPAC2-expressing cells (a minority ∼35% of SCN cells) contribute to SCN time-keeping. Lengthening of the intrinsic TTFL period of VPAC2 cells by deletion of the CK1εTau allele concomitantly lengthened the period of circadian behavioural rhythms. It also increased the variability of the circadian period of bioluminescent TTFL rhythms in SCN slices recorded ex vivo. Abrogation of circadian competence in VPAC2 cells by deletion of Bmal1 severely disrupted circadian behavioural rhythms and compromised TTFL time-keeping in the corresponding SCN slices. Thus, VPAC2-expressing cells are a distinct, functionally powerful subset of the SCN circuit, contributing to computation of ensemble period and maintenance of circadian robustness. These findings extend our understanding of SCN circuit topology.

scholarly journals Ovarian Accumulation of Nanoemulsions: Impact of Mice Age and Particle Size

2021 ◽  
Vol 22 (15) ◽  
pp. 8283
Author(s):  
Eike Folker Busmann ◽  
Julia Kollan ◽  
Karsten Mäder ◽  
Henrike Lucas
Keyword(s):  
Particle Size ◽  
Ex Vivo ◽  
Reticuloendothelial System ◽  
Systematic Investigation ◽  
Measured Signal ◽  
Reproductive Aging ◽  
Sex Steroid Hormone ◽  
Adult Mice ◽  
Radiant Efficiency

Nanotechnology in the field of drug delivery comes with great benefits due to the unique physicochemical properties of newly developed nanocarriers. However, they may come as well with severe toxicological side effects because of unwanted accumulation in organs outside of their targeted site of actions. Several studies showed an unintended accumulation of various nanocarriers in female sex organs, especially in the ovaries. Some led to inflammation, fibrosis, or decreasing follicle numbers. However, none of these studies investigated ovarian accumulation in context to both reproductive aging and particle size. Besides the influences of particle size, the biodistribution profile may be altered as well by reproductive aging because of reduced capacities of the reticuloendothelial system (RES), changes in sex steroid hormone levels as well as altering ovarian stromal blood flow. This systematic investigation of the biodistribution of intravenously (i.v) injected nanoemulsions revealed significant dependencies on the two parameters particle size and age starting from juvenile prepubescent to senescent mice. Using fluorescent in vivo and ex vivo imaging, prepubescent mice showed nearly no accumulation of nanoemulsion in their uteri and ovaries, but high accumulations in the organs of the RES liver and spleen independently of the particle size. In fertile adult mice, the accumulation increased significantly in the ovaries with an increased particle size of the nanoemulsions by nearly doubling the portion of the average radiant efficiency (PARE) to ~10% of the total measured signal of all excised organs. With reproductive aging and hence loss of fertility in senescent mice, the accumulation decreased again to moderate levels, again independently of the particle size. In conclusion, the ovarian accumulation of these nanocarriers depended on both the age plus the particle size during maturity.

scholarly journals Lack of WWC2 Protein Leads to Aberrant Angiogenesis in Postnatal Mice

2021 ◽  
Vol 22 (10) ◽  
pp. 5321
Author(s):  
Viktoria Constanze Brücher ◽  
Charlotte Egbring ◽  
Tanja Plagemann ◽  
Pavel I. Nedvetsky ◽  
Verena Höffken ◽  
...  
Keyword(s):  
Signalling Pathway ◽  
Control Group ◽  
Knock Out ◽  
Ocular Angiogenesis ◽  
Sprouting Angiogenesis ◽  
Adult Mice ◽  
Upstream Regulator ◽  
Knock Out Mice ◽  
Hippo Signalling

The WWC protein family is an upstream regulator of the Hippo signalling pathway that is involved in many cellular processes. We examined the effect of an endothelium-specific WWC1 and/or WWC2 knock-out on ocular angiogenesis. Knock-outs were induced in C57BL/6 mice at the age of one day (P1) and evaluated at P6 (postnatal mice) or induced at the age of five weeks and evaluated at three months of age (adult mice). We analysed morphology of retinal vasculature in retinal flat mounts. In addition, in vivo imaging and functional testing by electroretinography were performed in adult mice. Adult WWC1/2 double knock-out mice differed neither functionally nor morphologically from the control group. In contrast, the retinas of the postnatal WWC knock-out mice showed a hyperproliferative phenotype with significantly enlarged areas of sprouting angiogenesis and a higher number of tip cells. The branching and end points in the peripheral plexus were significantly increased compared to the control group. The deletion of the WWC2 gene was decisive for these effects; while knocking out WWC1 showed no significant differences. The results hint strongly that WWC2 is an essential regulator of ocular angiogenesis in mice. As an activator of the Hippo signalling pathway, it prevents excessive proliferation during physiological angiogenesis. In adult animals, WWC proteins do not seem to be important for the maintenance of the mature vascular plexus.

scholarly journals Identification of the MuRF1 skeletal muscle ubiquitylome through quantitative proteomics

Function ◽  
2021 ◽  
Author(s):  
Leslie M Baehr ◽  
David C Hughes ◽  
Sarah A Lynch ◽  
Delphi Van Haver ◽  
Teresa Mendes Maia ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Potential Role ◽  
Ubiquitin Proteasome System ◽  
In Vivo Electroporation ◽  
Adult Mice ◽  
Expression Of Genes ◽  
Regulation Of Metabolism ◽  
Ubiquitin Proteasome

Abstract MuRF1 (TRIM63) is a muscle-specific E3 ubiquitin ligase and component of the ubiquitin proteasome system. MuRF1 is transcriptionally upregulated under conditions that cause muscle loss, in both rodents and humans, and is a recognized marker of muscle atrophy. In this study, we used in vivo electroporation to determine if MuRF1 overexpression alone can cause muscle atrophy and, in combination with ubiquitin proteomics, identify the endogenous MuRF1 substrates in skeletal muscle. Overexpression of MuRF1 in adult mice increases ubiquitination of myofibrillar and sarcoplasmic proteins, increases expression of genes associated with neuromuscular junction instability, and causes muscle atrophy. A total of 169 ubiquitination sites on 56 proteins were found to be regulated by MuRF1. MuRF1-mediated ubiquitination targeted both thick and thin filament contractile proteins, as well as, glycolytic enzymes, deubiquitinases, p62, and VCP. These data reveal a potential role for MuRF1 in not only the breakdown of the sarcomere, but also the regulation of metabolism and other proteolytic pathways in skeletal muscle.

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