scholarly journals Hypothalamic Molecular Changes Underlying Natural Reproductive Senescence in the Female Rat

Endocrinology ◽  
2014 ◽  
Vol 155 (9) ◽  
pp. 3597-3609 ◽  
Author(s):  
Bailey A. Kermath ◽  
Penny D. Riha ◽  
Michael J. Woller ◽  
Andrew Wolfe ◽  
Andrea C. Gore
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
Steroid Hormone Receptors ◽  
Female Rats ◽  
Mrna Levels ◽  
Female Rat ◽  
Aged Rats ◽  
Middle Aged ◽  
Reproductive Senescence ◽  
Periventricular Nucleus

Abstract The role of the hypothalamus in female reproductive senescence is unclear. Here we identified novel molecular neuroendocrine changes during the natural progression from regular reproductive cycles to acyclicity in middle-aged female rats, comparable with the perimenopausal progression in women. Expression of 48 neuroendocrine genes was quantified within three hypothalamic regions: the anteroventral periventricular nucleus, the site of steroid positive feedback onto GnRH neurons; the arcuate nucleus (ARC), the site of negative feedback and pulsatile GnRH release; and the median eminence (ME), the site of GnRH secretion. Surprisingly, the majority of changes occurred in the ARC and ME, with few effects in anteroventral periventricular nucleus. The overall pattern was increased mRNA levels with chronological age and decreases with reproductive cycle status in middle-aged rats. Affected genes included transcription factors (Stat5b, Arnt, Ahr), sex steroid hormone receptors (Esr1, Esr2, Pgr, Ar), steroidogenic enzymes (Sts, Hsd17b8), growth factors (Igf1, Tgfa), and neuropeptides (Kiss1, Tac2, Gnrh1). Bionetwork analysis revealed region-specific correlations between genes and hormones. Immunohistochemical analyses of kisspeptin and estrogen receptor-α in the ARC demonstrated age-related decreases in kisspeptin cell numbers as well as kisspeptin-estrogen receptor-α dual-labeled cells. Taken together, these results identify unexpectedly strong roles for the ME and ARC during reproductive decline and highlight fundamental differences between middle-aged rats with regular cycles and all other groups. Our data provide evidence of decreased excitatory stimulation and altered hormone feedback with aging and suggest novel neuroendocrine pathways that warrant future study. Furthermore, these changes may impact other neuroendocrine systems that undergo functional declines with age.

scholarly journals Estradiol Dose-Dependent Regulation of Membrane Estrogen Receptor-α, Metabotropic Glutamate Receptor-1a, and Their Complexes in the Arcuate Nucleus of the Hypothalamus in Female Rats

Endocrinology ◽  
2013 ◽  
Vol 154 (9) ◽  
pp. 3251-3260 ◽  
Author(s):  
Matthew Mahavongtrakul ◽  
Martha P. Kanjiya ◽  
Maribel Maciel ◽  
Shrey Kanjiya ◽  
Kevin Sinchak
Keyword(s):  
Estrogen Receptor ◽  
Glutamate Receptor ◽  
Arcuate Nucleus ◽  
Metabotropic Glutamate Receptor ◽  
Estradiol Benzoate ◽  
Estrogen Receptor Α ◽  
Female Rats ◽  
Female Rat ◽  
Metabotropic Glutamate ◽  
Dose Dependent

Sexual receptivity in the female rat is dependent on dose and duration of estradiol exposure. A 2 μg dose of estradiol benzoate (EB) primes reproductive behavior circuits without facilitating lordosis. However, 50 μg EB facilitates lordosis after 48 hours. Both EB doses activate membrane estrogen receptor-α (mERα) that complexes with and signals through metabotropic glutamate receptor-1a (mGluR1a). This mERα-mGluR1a signaling activates a multisynaptic lordosis-inhibiting circuit in the arcuate nucleus (ARH) that releases β-endorphin in the medial preoptic nucleus (MPN), activating μ-opioid receptors (MOP). MPN MOP activation is maintained, inhibiting lordosis for 48 hours by 2 μg EB, whereas 50 μg EB at 48 hours deactivates MPN MOP, facilitating lordosis. We hypothesized that 50 μg EB down-regulates ERα and mERα-mGluR1a complexes in the ARH to remove mERα-mGluR1a signaling. In experiment I, 48 hours after 2 μg or 50 μg EB, the number of ARH ERα-immunopositive cells was reduced compared with controls. In experiment II, compared with oil controls, total ARH ERα protein was decreased 48 hours after 50 μg EB, but the 2 μg dose was not. These results indicate that both EB doses reduced the total number of cells expressing ERα, but 2 μg EB may have maintained or increased ERα expressed per cell, whereas 50 μg EB appeared to reduce total ERα per cell. In experiment III, coimmunoprecipitation and Western blot revealed that total mERα and coimmunoprecipitated mERα with mGluR1a were greater 48 hours after 2 μg EB treatment vs rats receiving 50 μg EB. These results indicate 2 μg EB maintains but 50 μg EB down-regulates mERα-mGluR1a to regulate the lordosis circuit activity.

scholarly journals Neuroendocrine Aging in the Female Rat: The Changing Relationship of Hypothalamic Gonadotropin-Releasing Hormone Neurons and N-Methyl-d-Aspartate Receptors**Preliminary versions of this work were presented at the 28th and 29th Annual Meetings of the Society for Neuroscience (Abstracts 110.11 and 777.10). This work was supported by the Brookdale Foundation (to A.C.G.), NIH Grant 1-PO1-AG16765–01 (to A.C.G. and J.H.M.).

Endocrinology ◽  
2000 ◽  
Vol 141 (12) ◽  
pp. 4757-4767 ◽  
Author(s):  
Andrea C. Gore ◽  
Glendy Yeung ◽  
John H. Morrison ◽  
Twethida Oung
Keyword(s):  
Critical Role ◽  
Reproductive Status ◽  
Female Rats ◽  
Mrna Levels ◽  
Female Rat ◽  
Messenger Rnas ◽  
Middle Aged ◽  
Medial Basal Hypothalamus ◽  
Aging Rats ◽  
Gnrh Neurons

Abstract The reproductive axis undergoes alterations during aging, resulting in acyclicity and the loss of reproductive function. In the hypothalamus, changes intrinsic to GnRH neurons may play a critical role in this process, as may changes in inputs to GnRH neurons from neurotransmitters such as glutamate. We investigated the effects of age and reproductive status on neuroendocrine glutamatergic NMDA receptors (NRs), their regulation of GnRH neurons, and their expression on GnRH neurons, in female rats. First, we quantified NR subunit messenger RNAs (mRNAs) in preoptic area-anterior hypothalamus (POA-AH) and medial basal hypothalamus (MBH), the sites of GnRH perikarya and neuroterminals, respectively. In POA-AH, NR1 mRNA levels varied little with age or reproductive status. NR2a and NR2b mRNA levels decreased significantly between cycling and acyclic rats. In MBH, NR mRNAs all increased with aging, particularly in acyclic animals. Second, we tested the effects of N-methyl-d,l-aspartate (NMA) on GnRH mRNA levels in POA-AH of aging rats. NMA elevated GnRH mRNA levels in young rats, but decreased them in middle-aged rats. Third, we quantified expression of the NR1 subunit on GnRH perikarya in aging rats using double label immunocytochemistry. NR1 expression on GnRH cell bodies varied with age and reproductive status, with 30%, 19%, and 46% of GnRH somata double labeled with NR1 in young proestrous, middle-aged proestrous, and middle-aged persistent estrous rats, respectively. Thus, 1) the expression of hypothalamic NR subunit mRNAs correlates with reproductive status; 2) changes in NR subunit mRNA levels, if reflected by changes in protein levels, may result in alterations in the stoichiometry of the NR during aging, with possible physiological consequences; 3) the effects of NR activation on GnRH mRNA switches from stimulatory to inhibitory during reproductive aging; and 4) expression of the NR1 subunit on GnRH perikarya changes with reproductive status. These molecular, physiological, and cellular neuroendocrine changes are proposed to be involved in the transition to acyclicity in aging female rats.

Estrous Cycle Modulation of Feeding and Relaxin-3/Rxfp3 mRNA Expression - Implications for Estradiol

2020 ◽  
Author(s):  
Camila de Ávila ◽  
Sandrine Chometton ◽  
Juliane Calvez ◽  
Geneviève Guèvremont ◽  
Alan Kania ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Food Intake ◽  
Estrous Cycle ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Female Rats ◽  
Type I ◽  
Mrna Levels ◽  
Female Rat ◽  
Relaxin Family

Introduction: Food intake varies during the ovarian hormone/estrous cycle in humans and rodents, an effect mediated mainly by estradiol. A potential mediator of the central anorectic effects of estradiol is the neuropeptide relaxin-3 (RLN3) synthetised in the nucleus incertus (NI) and acting via the relaxin-family peptide-3 receptor (RXFP3). Methods: We investigated the relationship of RLN3/RXFP3 signaling and feeding behavior across the female rat estrous cycle. We used in situ hybridization to investigate expression patterns of Rln3 mRNA in NI and Rxfp3 mRNA in the hypothalamic paraventricular nucleus (PVN), lateral hypothalamic area (LHA), medial preoptic area (MPA), and bed nucleus of the stria terminalis (BNST), across the estrous cycle. We identified expression of estrogen receptors in the NI using droplet digital polymerase-chain reaction and assessed the electrophysiological responsiveness of NI neurons to estradiol in brain slices. Results: Rln3 mRNA reached the lowest levels in the NI pars compacta during proestrus. Rxfp3 mRNA levels varied across the estrous cycle in a region-specific manner, with changes observed in the perifornical LHA, magnocellular PVN, dorsal BNST, and MPA, but not in the parvocellular PVN or lateral LHA. G protein-coupled estrogen receptor-1 (Gper1) mRNA was the most abundant estrogen receptor transcript in the NI. Estradiol inhibited 33% of type I NI neurons, including RLN3-positive cells. Conclusion: These findings demonstrate that the RLN3/RXFP3 system is modulated by the estrous cycle and although further studies are required to better elucidate the cellular and molecular mechanisms of estradiol signaling, current results implicate the involvement of RLN3/RXFP3 system in food intake fluctuations observed across the estrous cycle in female rats.

scholarly journals Hypothalamic Insulin-Like Growth Factor-I Receptors Are Necessary for Hormone-Dependent Luteinizing Hormone Surges: Implications for Female Reproductive Aging

Endocrinology ◽  
2010 ◽  
Vol 151 (3) ◽  
pp. 1356-1366 ◽  
Author(s):  
Brigitte J. Todd ◽  
Zaher O. Merhi ◽  
Jun Shu ◽  
Anne M. Etgen ◽  
Genevieve S. Neal-Perry
Keyword(s):  
Young Adult ◽  
Third Ventricle ◽  
Female Rats ◽  
Aged Rats ◽  
Gnrh Neuron ◽  
Middle Aged ◽  
Reproductive Senescence ◽  
Lh Surge ◽  
Neuron Activation ◽  
Igf I

Brain IGF-I receptors are required for maintenance of estrous cycles in young adult female rats. Circulating and hypothalamic IGF-I levels decrease with aging, suggesting a role for IGF-I in the onset of reproductive senescence. Therefore, the present study investigated potential mechanisms of action of brain IGF-I receptors in the regulation of LH surges in young adult and middle-aged rats. We continuously infused IGF-I, the selective IGF-I receptor antagonist JB-1, or vehicle into the third ventricle of ovariectomized young adult and middle-aged female rats primed with estradiol and progesterone. Pharmacological blockade of IGF-I receptors attenuated and delayed the LH surge in young adult rats, reminiscent of the LH surge pattern that heralds the onset of reproductive senescence in middle-aged female rats. Infusion of IGF-I alone had no effect on the LH surge but reversed JB-1 attenuation of the surge in young females. In middle-aged rats, infusion of low doses of IGF-I partially restored LH surge amplitude, and infusion of JB-1 completely obliterated the surge. Intraventricular infusion of IGF-I or JB-1 did not modify pituitary sensitivity to exogenous GnRH or GnRH peptide content in the anterior or mediobasal hypothalamus in either young or middle-aged rats. These findings support the hypothesis that brain IGF-I receptor signaling is necessary for GnRH neuron activation under estrogen-positive feedback conditions and that decreased brain IGF-I signaling in middle-aged females contributes, in part, to LH surge dysfunction by disrupting estradiol-sensitive processes that affect GnRH neuron activation and/or GnRH release.

Effect of Fetal and Neonatal Hypothyroidism on Glucose Tolerance in Middle-Aged Female Rats

2020 ◽  
Vol 20 ◽  
Author(s):  
Sajad Jeddi ◽  
Saeedeh Khalifi ◽  
Mahboubeh Ghanbari ◽  
Asghar Ghasemi
Keyword(s):  
Glucose Tolerance ◽  
Plasma Glucose ◽  
Female Offspring ◽  
Female Rats ◽  
Control Group ◽  
Female Rat ◽  
Middle Aged ◽  
Intravenous Glucose ◽  
Neonatal Hypothyroidism ◽  
Glucose Levels

Background and objective: The effects of hypothyroidism during pregnancy and lactation on carbohydrate metabolism have been mostly studied in male animals. The aim of this study is therefore to investigate effect of fetal and neonatal hypothyroidism (FH and NH) on the glucose tolerance in middle-aged female rat offspring. Methods: Pregnant female rats were divided into three groups: Rats in the control group consumed tap water, while those in the FH and NH groups consumed 250 mg/L of 6-propyl-2-thiouracil (PTU) in their drinking water during gestation or lactation periods, respectively. After weaning, the female offspring were separated and divided into 3 groups (n=8/group): Control, FH, and NH. Body weight was recorded monthly and intravenous glucose tolerance test (IVGTT) was performed at month 12. Results: Compared to controls, female rats in the FH group had significantly higher plasma glucose levels than controls throughout the IVGTT except at min 60. Values at min 5 of the FH and control group were 196.1±1.9 and 155.3±5.9 mg/dL, respectively (P<0.05). In the NH group, plasma glucose levels were significantly higher only at min 5 (185.7±14.1 vs. 155.3±5.9 mg/dL, P<0.05). Conclusion: Hypothyroidism during fetal or neonatal periods caused glucose intolerance in middle-aged female offspring rats.

scholarly journals Age-Related Effects on Right Femoral Bone of Male Wistar Rats: A Morphometric and Biomechanical Study

2021 ◽  
Author(s):  
Sheila Martins Puelker ◽  
Sonia Regina Ribeiro de Castro ◽  
Romeu Rodrigues de Souza ◽  
Laura Beatriz Mesiano Maifrino ◽  
Ricardo Aparecido Baptista Nucci ◽  
...  
Keyword(s):  
Cortical Thickness ◽  
Wistar Rats ◽  
Female Rats ◽  
Male Rats ◽  
Aged Rats ◽  
Femoral Bone ◽  
Middle Aged ◽  
Left Femur ◽  
Bone Stiffness ◽  
The Right

Abstract Introduction Study of the variations of bone characteristics with age in different animal models is important to design musculoskeletal studies. Thus, this study aimed to evaluate the bone mass, dimensions, and biomechanical parameters of the femur in young, middle-aged, and aged Wistar rats. Materials and Methods Thirty male rats (Rattus norvegicus) were divided in three groups (n = 10 per group)—3-month-old young rats, 12-month-old middle-aged rats, and 18-months-old aged rats. The right femurs were subjected sequentially to morphometric study (bone weight, cortical thickness) and biomechanical tests (maximum resistance strength and bone stiffness). Results We observed a significant increase in femur histological (cortical thickness) and biomechanical (maximum strength and bone stiffness) parameters with aging when compared with young animals. Conclusions With the advancing age, the right femoral bone of middle-aged and old animals had greater variations when compared with young animals. However, further studies with the aid of a comparison between right and left femur and other long bones in both male and female rats are needed to corroborate with our findings.

Glutamine synthetase induction by glucocorticoids is preserved in skeletal muscle of aged rats

1996 ◽  
Vol 271 (6) ◽  
pp. E1061-E1066 ◽  
Author(s):  
D. Meynial-Denis ◽  
M. Mignon ◽  
A. Miri ◽  
J. Imbert ◽  
E. Aurousseau ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glutamine Synthetase ◽  
Skeletal Muscles ◽  
Female Rats ◽  
Mrna Levels ◽  
Aged Rats ◽  
Adult Rats ◽  
Adult Age ◽  
Slow Twitch ◽  
Fast Twitch

Glutamine synthetase (GS) is a glucocorticoid-inducible enzyme that has a key role for glutamine synthesis in muscle. We hypothesized that the glucocorticoid induction of GS could be altered in aged rats, because alterations in the responsiveness of some genes to glucocorticoids were reported in aging. We compared the glucocorticoid-induced GS in fast-twitch and slow-twitch skeletal muscles (tibialis anterior and soleus, respectively) and heart from adult (age 6-8 mo) and aged (age 22 mo) female rats. All animals received dexamethasone (Dex) in their drinking water (0.77 +/- 0.10 and 0.80 +/- 0.08 mg/day per adult and aged rat, respectively) for 5 days. Dex caused an increase in both GS activity and GS mRNA in fast-twitch and slow-twitch skeletal muscles from adult and aged rats. In contrast, Dex increased GS activity in heart of adult rats, without any concomitant change in GS mRNA levels. Furthermore, Dex did not affect GS activity in aged heart. Thus the responsiveness of GS to an excess of glucocorticoids is preserved in skeletal muscle but not in heart from aged animals.

Multiple forms of estrogen receptor-α in cerebral blood vessels: regulation by estrogen

2003 ◽  
Vol 284 (1) ◽  
pp. E184-E192 ◽  
Author(s):  
Chris Stirone ◽  
Sue P. Duckles ◽  
Diana N. Krause
Keyword(s):  
Estrogen Receptor ◽  
Blood Vessels ◽  
Estrogen Receptor Α ◽  
26S Proteasome ◽  
Target Tissue ◽  
Female Rat ◽  
Cerebral Vasculature ◽  
Cerebral Blood Vessels ◽  
Multiple Forms

The cerebral vasculature is an important target tissue for estrogen, as evidenced by significant effects of estrogen on vascular reactivity and protein levels of endothelial nitric oxide synthase and prostacyclin synthase. However, the presence, localization, and regulation of estrogen receptors in the cerebral vasculature have not been investigated. In this study, we identified the presence of estrogen receptor-α (ER-α) in female rat cerebral blood vessels and localized this receptor to both smooth muscle and endothelial cells by use of immunohistochemistry and confocal microscopy. With immunoblot analysis, multiple forms of ER-α were detected at 110, 93, 82, 50, and 45 kDa in addition to a relatively weak band corresponding to the 66-kDa putative unmodified receptor. The 82-kDa band was identified as Ser118-phosphorylated ER-α, whereas the 50-kDa band lacks the normal NH2 terminus, suggestive of an ER-α splice variant. Lower molecular mass bands persisted after in vivo inhibition of 26S proteasome activity with lactacystin, whereas the 110- and 93-kDa bands increased. All forms of ER-α in cerebral vessels were decreased after ovariectomy but significantly increased after chronic estrogen exposure in vivo.

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