The Role of Glutamate in Maintaining Muscle Spindle Afferent Excitability in Adult Mice

Abstract Toll-like receptor 4 (TLR4) is best known for its role in bacteria-produced lipopolysaccharide recognition. Regarding female reproduction, TLR4 is expressed by murine cumulus cells and participates in ovulation and in cumulus–oocyte complex (COC) expansion, maternal–fetal interaction and preterm labour. Despite these facts, the role of TLR4 in ovarian physiology is not fully understood. Therefore, the aim of the present study was to investigate the effects of TLR4 genetic ablation on mice folliculogenesis and female fertility, through analysis of reproductive crosses, ovarian responsiveness and follicular quantification in TLR4−/− (n = 94) and C57BL/6 mice [wild type (WT), n = 102]. TLR4-deficient pairs showed a reduced number of pups per litter (P = 0.037) compared with WT. TLR4−/− mice presented more primordial, primary, secondary and antral follicles (P < 0.001), however there was no difference in estrous cyclicity (P > 0.05). A lower (P = 0.006) number of COC was recovered from TLR4−/− mice oviducts after superovulation, and in heterozygous pairs, TLR4−/− females also showed a reduction in the pregnancy rate and in the number of fetuses per uterus (P = 0.007) when compared with WT. Altogether, these data suggest that TLR4 plays a role in the regulation of murine folliculogenesis and in determining ovarian endowment. TLR4 deficiency may affect ovulation and pregnancy rates, potentially decreasing fertility, therefore the potential side effects of its blockade have to be carefully investigated.

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Inhibition of mTOR during a postnatal critical sensitive window rescues deficits in GABAergic PV cell connectivity and social behavior caused by loss of TSC1

10.1101/2020.03.29.014563 ◽

2020 ◽

Author(s):

Mayukh Choudhury ◽

Clara A. Amegandjin ◽

Vidya Jadhav ◽

Josianne Nunes Carriço ◽

Ariane Quintal ◽

...

Keyword(s):

Social Behavior ◽

Time Course ◽

Cell Types ◽

Developmental Time ◽

Adult Mice ◽

Mtorc1 Signaling ◽

Pv Cell ◽

Mechanistic Basis

ABSTRACTMutations in regulators of the Mechanistic Target Of Rapamycin Complex 1 (mTORC1), such as Tsc1/2, lead to neurodevelopmental disorders associated with autism, intellectual disabilities and epilepsy. Whereas the effects of mTORC1 signaling dysfunction within diverse cell types are likely critical for the onset of the diverse neurological symptoms associated with mutations in mTORC1 regulators, they are not well understood. In particular, the effects of mTORC1 dys-regulation in specific types of inhibitory interneurons are unclear.Here, we showed that Tsc1 haploinsufficiency in parvalbumin (PV)-positive GABAergic interneurons either in cortical organotypic cultures or in vivo caused a premature increase in their perisomatic innervations, followed by a striking loss in adult mice. This effects were accompanied by alterations of AMPK-dependent autophagy in pre-adolescent but not adult mice. PV cell-restricted Tsc1 mutant mice showed deficits in social behavior. Treatment with the mTOR inhibitor Rapamycin restricted to the third postnatal week was sufficient to permanently rescue deficits in both PV cell innervation and social behavior in adult conditional haploinsufficient mice. All together, these findings identify a novel role of Tsc1-mTORC1 signaling in the regulation of the developmental time course and maintenance of cortical PV cell connectivity and provide a mechanistic basis for the targeted rescue of autism-related behaviors in disorders associated with deregulated mTORC1 signaling.

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Gonadal expression of c-kit encoded at the W locus of the mouse

Development ◽

10.1242/dev.110.4.1057 ◽

1990 ◽

Vol 110 (4) ◽

pp. 1057-1069 ◽

Cited By ~ 26

Author(s):

K. Manova ◽

K. Nocka ◽

P. Besmer ◽

R.F. Bachvarova

Keyword(s):

In Situ Hybridization ◽

Germ Cells ◽

Leydig Cells ◽

Interstitial Tissue ◽

Type B ◽

Age Dependence ◽

Oocyte Growth ◽

Adult Mice

Recently, it has been shown that the c-kit proto-oncogene is encoded at the white spotting (W) locus in mice. Mutations of this gene cause depletion of germ cells, some hematopoietic cells and melanocytes. In order to define further the role of c-kit in gametogenesis, we have examined its expression in late fetal and postnatal ovaries and in postnatal testis. By RNA blot analysis, c-kit transcripts were not detected in late fetal ovaries but appeared at birth. The relative amount reached a maximum in ovaries of juvenile mice, and decreased in adult ovaries. c-kit transcripts were present in increasing amounts in isolated primordial, growing and full-grown oocytes, as well as in ovulated eggs. Little was detected in early 2-cell embryos and none in blastocysts. In situ hybridization revealed c-kit transcripts in a few oocytes of late fetal ovaries and in all oocytes (from primordial to full-grown) in ovaries from juvenile and adult mice. Expression was also observed in ovarian interstitial tissue from 14 days of age onward. Using indirect immunofluorescence, the c-kit protein was detected on the surface of primordial, growing and full-grown oocytes, as well as on embryos at the 1- and 2-cell stages; little remained in blastocysts. In situ hybridization analysis of testes from mice of different ages demonstrated expression in spermatogonia from 6 days of age onward. Using information provided by determining the stage of the cycle of the seminiferous epithelium for a given tubule and by following the age dependence of labeling, it was concluded that the period of expression of c-kit extends from at least as early as type A2 spermatogonia through type B spermatogonia and into preleptotene spermatocytes. Leydig cells were labelled at all ages examined. The expression pattern in oocytes correlates most strongly with oocyte growth and in male germ cells with gonial proliferation.

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The role of Smad2 and Smad3 in regulating homeostatic functions of fibroblasts in vitro and in adult mice

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ◽

10.1016/j.bbamcr.2020.118703 ◽

2020 ◽

Vol 1867 (7) ◽

pp. 118703 ◽

Cited By ~ 1

Author(s):

Shuaibo Huang ◽

Bijun Chen ◽

Claudio Humeres ◽

Linda Alex ◽

Anis Hanna ◽

...

Keyword(s):

Adult Mice

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DLK1 Expressed in Mouse Orexin Neurons Modulates Anxio-Depressive Behavior but Not Energy Balance

Brain Sciences ◽

10.3390/brainsci10120975 ◽

2020 ◽

Vol 10 (12) ◽

pp. 975

Author(s):

Tatiyana Harris ◽

Raluca Bugescu ◽

Jaylyn Kelly ◽

Anna Makela ◽

Morgan Sotzen ◽

...

Keyword(s):

Body Weight ◽

Energy Balance ◽

Ingestive Behavior ◽

Hypothalamic Area ◽

Disease States ◽

Adult Mice ◽

Plus Maze ◽

And Behavior ◽

Physiologic Role

Lateral hypothalamic area (LHA) neurons expressing the neuropeptide orexin (OX) are implicated in obesity and anxio-depression. However, these neurons release OX as well as a host of other proteins that might contribute to normal physiology and disease states. We hypothesized that delta-like homolog 1 (DLK1), a protein reported to be co-expressed by all OX neurons, contributes to the regulation of energy balance and/or anxio-depression. Consistent with previous reports, we found that all rat OX neurons co-express DLK1. Yet, in mice and humans only a subset of OX neurons co-expressed DLK1. Since human OX-DLK1 distribution is more similar to mice than rats, mice are a comparable model to assess the human physiologic role of DLK1. We therefore used a viral lesion strategy to selectively delete DLK1 within the LHA of adult mice (DLK1Null) to reveal its role in body weight and behavior. Adult-onset DLK1 deletion had no impact on body weight or ingestive behavior. However, DLK1Null mice engaged in more locomotor activity than control mice and had decreased anxiety and depression measured via the elevated plus maze and forced swim tests. These data suggest that DLK1 expression via DLK1-expressing OX neurons primarily contributes to anxio-depression behaviors without impacting body weight.

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Vulnerable and resilient cognitive performance related to early life stress: The potential mediating role of dopaminergic receptors in the medial prefrontal cortex of adult mice

International Journal of Developmental Neuroscience ◽

10.1002/jdn.10004 ◽

2020 ◽

Vol 80 (1) ◽

pp. 13-27

Author(s):

Saulo G. Tractenberg ◽

Rodrigo Orso ◽

Kerstin C. Creutzberg ◽

Luiza M. C. Malcon ◽

Francisco S. Lumertz ◽

...

Keyword(s):

Prefrontal Cortex ◽

Cognitive Performance ◽

Medial Prefrontal Cortex ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Dopaminergic Receptors ◽

Mediating Role ◽

Adult Mice

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The role of brachial muscle spindle signals in assignment of visual direction

Journal of Neurophysiology ◽

10.1152/jn.1993.70.4.1578 ◽

1993 ◽

Vol 70 (4) ◽

pp. 1578-1584 ◽

Cited By ~ 17

Author(s):

P. DiZio ◽

C. E. Lathan ◽

J. R. Lackner

Keyword(s):

Apparent Motion ◽

Muscle Spindle ◽

Target Location ◽

Biceps Brachii ◽

Visual Target ◽

Visual Direction ◽

Muscle Vibration ◽

Illusory Motion ◽

The Stability

1. In the oculobrachial illusion, a target light attached to the unseen stationary hand is perceived as moving and changing spatial position when illusory motion of the forearm is elicited by brachial muscle vibration. Our goal was to see whether we could induce apparent motion and displacement of two retinally fixed targets in opposite directions by the use of oculobrachial illusions. 2. We vibrated both biceps brachii, generating illusory movements of the two forearms in opposite directions, and measured any associated changes in perceived distance between target lights on the unseen stationary hands. The stability of visual fixation of one of the targets was also measured. 3. The seen distance between the stationary targets increased significantly when vibration induced an illusory increase in felt distance between the hands, both with binocular and monocular viewing. 4. Subjects maintained fixation accuracy equally well during vibration-induced illusory increases in visual target separation and in a no-vibration control condition. Fixation errors were not correlated with the extent or direction of illusory visual separation. 5. These findings indicate that brachial muscle spindle signals can contribute to an independent representation of felt target location in head-centric coordinates that can be interrelated with a visual representation of target location generated by retinal and oculomotor signals. 6. A model of how these representations are interrelated is proposed, and its relation to other intersensory interactions is discussed.

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Gene delivery of medium chain acyl-coenzyme A dehydrogenase induces physiological cardiac hypertrophy and protects against pathological remodelling

Clinical Science ◽

10.1042/cs20171269 ◽

2018 ◽

Vol 132 (3) ◽

pp. 381-397 ◽

Cited By ~ 8

Author(s):

Bianca C. Bernardo ◽

Kate L. Weeks ◽

Thawin Pongsukwechkul ◽

Xiaoming Gao ◽

Helen Kiriazis ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Coenzyme A ◽

Healthy Adult ◽

Capillary Density ◽

Medium Chain ◽

Adult Mice ◽

Physiological Cardiac Hypertrophy ◽

Chain Acyl ◽

Acyl Coenzyme A

We previously showed that medium chain acyl-coenzyme A dehydrogenase (MCAD, key regulator of fatty acid oxidation) is positively modulated in the heart by the cardioprotective kinase, phosphoinositide 3-kinase (PI3K(p110α)). Disturbances in cardiac metabolism are a feature of heart failure (HF) patients and targeting metabolic defects is considered a potential therapeutic approach. The specific role of MCAD in the adult heart is unknown. To examine the role of MCAD in the heart and to assess the therapeutic potential of increasing MCAD in the failing heart, we developed a gene therapy tool using recombinant adeno-associated viral vectors (rAAV) encoding MCAD. We hypothesised that increasing MCAD expression may recapitulate the cardioprotective properties of PI3K(p110α). rAAV6:MCAD or rAAV6:control was delivered to healthy adult mice and to mice with pre-existing pathological hypertrophy and cardiac dysfunction due to transverse aortic constriction (TAC). In healthy mice, rAAV6:MCAD induced physiological hypertrophy (increase in heart size, normal systolic function and increased capillary density). In response to TAC (~15 weeks), heart weight/tibia length increased by ~60% in control mice and ~45% in rAAV6:MCAD mice compared with sham. This was associated with an increase in cardiomyocyte cross-sectional area in both TAC groups which was similar. However, hypertrophy in TAC rAAV6:MCAD mice was associated with less fibrosis, a trend for increased capillary density and a more favourable molecular profile compared with TAC rAAV6:control mice. In summary, MCAD induced physiological cardiac hypertrophy in healthy adult mice and attenuated features of pathological remodelling in a cardiac disease model.

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