Age-related LH surge dysfunction correlates with reduced responsiveness of hypothalamic anteroventral periventricular nucleus kisspeptin neurons to estradiol positive feedback in middle-aged rats

Reproductive success depends on a robust and appropriately timed preovulatory LH surge. The LH surge, in turn, requires ovarian steroid modulation of GnRH neuron activation by the neuropeptide kisspeptin and glutamate and γ-aminobutyric acid (GABA) neurotransmission in the medial preoptic area (mPOA). Middle-aged females exhibit reduced excitation of GnRH neurons and attenuated LH surges under estrogen-positive feedback conditions, in part, due to increased GABA and decreased glutamate neurotransmission in the mPOA. This study tested the hypothesis that altered kisspeptin regulation by ovarian steroids plays a role in age-related LH surge dysfunction. We demonstrate that middle-aged rats exhibiting delayed and attenuated LH surges have reduced levels of Kiss1 mRNA in the anterior hypothalamus under estrogen-positive feedback conditions. Kisspeptin application directly into the mPOA rescues total LH release and the LH surge amplitude in middle-aged rats and increases glutamate and decreases GABA release to levels seen in the mPOA of young females. Moreover, the N-methyl-d-aspartate receptor antagonist MK801 blocks kisspeptin reinstatement of the LH surge. These observations suggest that age-related LH surge dysfunction results, in part, from reduced kisspeptin drive under estrogen-positive feedback conditions and that kisspeptin regulates GnRH/LH release, in part, through modulation of mPOA glutamate and GABA release.

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Release of Norepinephrine in the Preoptic Area Activates Anteroventral Periventricular Nucleus Neurons and Stimulates the Surge of Luteinizing Hormone

Endocrinology ◽

10.1210/en.2012-1302 ◽

2013 ◽

Vol 154 (1) ◽

pp. 363-374 ◽

Cited By ~ 35

Author(s):

Raphael E. Szawka ◽

Maristela O. Poletini ◽

Cristiane M. Leite ◽

Marcelo P. Bernuci ◽

Bruna Kalil ◽

...

Keyword(s):

Positive Feedback ◽

Preoptic Area ◽

Lh Surge ◽

Ovx Rats ◽

Selective Lesion ◽

Periventricular Nucleus ◽

Reverse Microdialysis ◽

Fos Expression ◽

Lh Secretion

The role of norepinephrine (NE) in regulation of LH is still controversial. We investigated the role played by NE in the positive feedback of estradiol and progesterone. Ovarian-steroid control over NE release in the preoptic area (POA) was determined using microdialysis. Compared with ovariectomized (OVX) rats, estradiol-treated OVX (OVX+E) rats displayed lower release of NE in the morning but increased release coincident with the afternoon surge of LH. OVX rats treated with estradiol and progesterone (OVX+EP) exhibited markedly greater NE release than OVX+E rats, and amplification of the LH surge. The effect of NE on LH secretion was confirmed using reverse microdialysis. The LH surge and c-Fos expression in anteroventral periventricular nucleus neurons were significantly increased in OVX+E rats dialyzed with 100 nm NE in the POA. After Fluoro-Gold injection in the POA, c-Fos expression in Fluoro-Gold/tyrosine hydroxylase-immunoreactive neurons increased during the afternoon in the A2 of both OVX+E and OVX+EP rats, in the locus coeruleus (LC) of OVX+EP rats, but was unchanged in the A1. The selective lesion of LC terminals, by intracerebroventricular N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, reduced the surge of LH in OVX+EP but not in OVX+E rats. Thus, estradiol and progesterone activate A2 and LC neurons, respectively, and this is associated with the increased release of NE in the POA and the magnitude of the LH surge. NE stimulates LH secretion, at least in part, through activation of anteroventral periventricular neurons. These findings contribute to elucidation of the role played by NE during the positive feedback of ovarian steroids.

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Late-onset caloric restriction alters skeletal muscle metabolism by modulating pyruvate metabolism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00508.2014 ◽

2015 ◽

Vol 308 (11) ◽

pp. E942-E949 ◽

Cited By ~ 11

Author(s):

Chiao-nan (Joyce) Chen ◽

Shang-Ying Lin ◽

Yi-Hung Liao ◽

Zhen-jie Li ◽

Alice May-Kuen Wong

Keyword(s):

Energy Metabolism ◽

Muscle Mass ◽

Mitochondrial Biogenesis ◽

Muscle Metabolism ◽

Muscle Loss ◽

Aged Rats ◽

Middle Aged ◽

Pyruvate Metabolism ◽

Age Related ◽

Age Dependent

Caloric restriction (CR) attenuates age-related muscle loss. However, the underlying mechanism responsible for this attenuation is not fully understood. This study evaluated the role of energy metabolism in the CR-induced attenuation of muscle loss. The aims of this study were twofold: 1) to evaluate the effect of CR on energy metabolism and determine its relationship with muscle mass, and 2) to determine whether the effects of CR are age dependent. Young and middle-aged rats were randomized into either 40% CR or ad libitum (AL) diet groups for 14 wk. Major energy-producing pathways in muscles, i.e., glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), were examined. We found that the effects of CR were age dependent. CR improved muscle metabolism and normalized muscle mass in middle-aged animals but not young animals. CR decreased glycolysis and increased the cellular dependency for OXPHOS vs. glycolysis in muscles of middle-aged rats, which was associated with the improvement of normalized muscle mass. The metabolic reprogramming induced by CR was related to modulation of pyruvate metabolism and increased mitochondrial biogenesis. Compared with animals fed AL, middle-aged animals with CR had lower lactate dehydrogenase A content and greater mitochondrial pyruvate carrier content. Markers of mitochondrial biogenesis, including AMPK activation levels and SIRT1 and COX-IV content, also showed increased levels. In conclusion, 14 wk of CR improved muscle metabolism and preserved muscle mass in middle-aged animals but not in young developing animals. CR-attenuated age-related muscle loss is associated with reprogramming of the metabolic pathway from glycolysis to OXPHOS.

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Absent Progesterone Signaling in Kisspeptin Neurons Disrupts the LH Surge and Impairs Fertility in Female Mice

Endocrinology ◽

10.1210/en.2015-1300 ◽

2015 ◽

Vol 156 (9) ◽

pp. 3091-3097 ◽

Cited By ~ 54

Author(s):

Shannon B. Z. Stephens ◽

Kristen P. Tolson ◽

Melvin L. Rouse ◽

Matthew C. Poling ◽

Minako K. Hashimoto-Partyka ◽

...

Keyword(s):

Positive Feedback ◽

Progesterone Receptors ◽

Sex Steroid ◽

Corpora Lutea ◽

Neuronal Activation ◽

Estrogen Regulation ◽

Lh Surge ◽

Normal Fertility ◽

Periventricular Nucleus

Kisspeptin, encoded by Kiss1, stimulates GnRH neurons to govern reproduction. In rodents, estrogen-sensitive kisspeptin neurons in the anterior ventral periventricular nucleus and neighboring periventricular nucleus are thought to mediate sex steroid-induced positive feedback induction of the preovulatory LH surge. These kisspeptin neurons coexpress estrogen and progesterone receptors and display enhanced neuronal activation during the LH surge. However, although estrogen regulation of kisspeptin neurons has been well studied, the role of progesterone signaling in regulating kisspeptin neurons is unknown. Here we tested whether progesterone action specifically in kisspeptin cells is essential for proper LH surge and fertility. We used Cre-lox technology to generate transgenic mice lacking progesterone receptors exclusively in kisspeptin cells (termed KissPRKOs). Male KissPRKOs displayed normal fertility and gonadotropin levels. In stark contrast, female KissPRKOs displayed earlier puberty onset and significant impairments in fertility, evidenced by fewer births and substantially reduced litter size. KissPRKOs also had fewer ovarian corpora lutea, suggesting impaired ovulation. To ascertain whether this reflects a defect in the ability to generate sex steroid-induced LH surges, females were exposed to an estradiol-positive feedback paradigm. Unlike control females, which displayed robust LH surges, KissPRKO females did not generate notable LH surges and expressed significantly blunted cfos induction in anterior ventral periventricular nucleus kisspeptin neurons, indicating that progesterone receptor signaling in kisspeptin neurons is required for normal kisspeptin neuronal activation and LH surges during positive feedback. Our novel findings demonstrate that progesterone signaling specifically in kisspeptin cells is essential for the positive feedback induction of normal LH surges, ovulation, and normal fertility in females.

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Effects of β-adrenergic receptor agonists on drinking and arterial blood pressure in young and old rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00737.2010 ◽

2011 ◽

Vol 300 (4) ◽

pp. R1001-R1008 ◽

Cited By ~ 6

Author(s):

Robert L. Thunhorst ◽

Connie L. Grobe ◽

Terry G. Beltz ◽

Alan Kim Johnson

Keyword(s):

Blood Pressure ◽

Arterial Blood Pressure ◽

Adrenergic Receptors ◽

Adrenergic Receptor ◽

Aged Rats ◽

Middle Aged ◽

Young Rats ◽

Arterial Blood ◽

Age Related ◽

Old Rats

These experiments examined water-drinking and arterial blood pressure responses to β-adrenergic receptor activation in young (4 mo), “middle-aged” adult (12 mo), and old (29 mo) male rats of the Brown-Norway strain. We used isoproterenol to simultaneously activate β1- and β2-adrenergic receptors, salbutamol to selectively activate β2-adrenergic receptors, and the combination of isoproterenol and the β2-adrenergic receptor antagonist ICI 118,551 to stimulate only β1-adrenergic receptors. Animals received one of the drug treatments, and water drinking was measured for 90 min. About 1 wk later, animals received the same drug treatment for measurement of arterial blood pressure responses for 90 min. In some rats, levels of renin and aldosterone secretion in response to isoproterenol or salbutamol were measured in additional tests. Old and middle-aged rats drank significantly less after isoproterenol than did young rats and also had greater reductions in arterial blood pressure. Old and middle-aged rats drank significantly less after salbutamol than did young rats, although reductions in arterial blood pressure were equivalent across the ages. The β2-adrenergic antagonist ICI 118,551 abolished drinking after isoproterenol and prevented most of the observed hypotension. Renin secretion after isoproterenol and salbutamol was greater in young rats than in middle-aged rats, and wholly absent in old rats. Aldosterone secretion was reduced in old rats compared with young and middle-aged rats after treatment with isoproterenol, but not after treatment with salbutamol. In conclusion, there are age-related differences in β-adrenergic receptor-mediated drinking that can be explained only in part by age-related differences in renin secretion after β-adrenergic receptor stimulation.

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Enhanced Calcium Buffering in F344 Rat Cholinergic Basal Forebrain Neurons Is Associated With Age-Related Cognitive Impairment

Journal of Neurophysiology ◽

10.1152/jn.00301.2009 ◽

2009 ◽

Vol 102 (4) ◽

pp. 2194-2207 ◽

Cited By ~ 18

Author(s):

David Murchison ◽

Angelika N. McDermott ◽

Candi L. LaSarge ◽

Kathryn A. Peebles ◽

Jennifer L. Bizon ◽

...

Keyword(s):

Basal Forebrain ◽

Cholinergic Neurons ◽

Cognitive Status ◽

Cognitively Impaired ◽

Aged Rats ◽

Middle Aged ◽

Cholinergic Basal Forebrain ◽

Age Related ◽

Forebrain Neurons ◽

Firing Properties

Alterations in neuronal Ca2+ homeostasis are important determinants of age-related cognitive impairment. We examined the Ca2+ influx, buffering, and electrophysiology of basal forebrain neurons in adult, middle-aged, and aged male F344 behaviorally assessed rats. Middle-aged and aged rats were characterized as cognitively impaired or unimpaired by water maze performance relative to young cohorts. Patch-clamp experiments were conducted on neurons acutely dissociated from medial septum/nucleus of the diagonal band with post hoc identification of phenotypic marker mRNA using single-cell RT-PCR. We measured whole cell calcium and barium currents and dissected these currents using pharmacological agents. We combined Ca2+ current recording with Ca2+-sensitive ratiometric microfluorimetry to measure Ca2+ buffering. Additionally, we sought changes in neuronal firing properties using current-clamp recording. There were no age- or cognition-related changes in the amplitudes or fractional compositions of the whole cell Ca2+ channel currents. However, Ca2+ buffering was significantly enhanced in cholinergic neurons from aged cognitively impaired rats. Moreover, increased Ca2+ buffering was present in middle-aged rats that were not cognitively impaired. Firing properties were largely unchanged with age or cognitive status, except for an increase in the slow afterhyperpolarization in aged cholinergic neurons, independent of cognitive status. Furthermore, acutely dissociated basal forebrain neurons in which choline acetyltransferase mRNA was detected had the electrophysiological profiles of identified cholinergic neurons. We conclude that enhanced Ca2+ buffering by cholinergic basal forebrain neurons may be important during aging.

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Hypotension- and osmotically induced thirst in old Brown Norway rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00118.2009 ◽

2009 ◽

Vol 297 (1) ◽

pp. R149-R157 ◽

Cited By ~ 11

Author(s):

Robert L. Thunhorst ◽

Terry G. Beltz ◽

Alan Kim Johnson

Keyword(s):

Arterial Pressure ◽

Brown Norway ◽

Aged Rats ◽

Middle Aged ◽

Young Rats ◽

Age Related ◽

Cellular Dehydration ◽

Old Rats ◽

Middle Aged Adult ◽

Norway Rats

Compared to young cohorts, old rats drink less water in response to several thirst-inducing stimuli. In these experiments, we characterized water drinking in response to hypotension and cellular dehydration in young (4 mo), middle-aged adult (12 mo) and old (29–30 mo) male Brown Norway rats. We injected the vasodilator, minoxidil as an intravenous bolus in a range of doses (0–20 mg/kg), so that drinking responses could be compared at equivalent reductions of arterial pressure. Old rats had greatly diminished reflex tachycardia and became significantly more hypotensive after minoxidil compared with young and middle-aged rats. When compared at equivalent reductions of arterial pressure, old rats drank one-third as much as middle-aged rats, and one-fifth as much as young rats. In addition, there were age-related deficits in drinking in response to a range of administered loads of sodium (0.15–2 M NaCl, 2 ml/100 g body wt). Urinary excretion of water and sodium in response to the loads was equivalent across ages. Both middle-aged and old rats were less able than young rats to repair their water deficits after sodium loading, attributable almost entirely to their reduced drinking responses compared with young rats. Lastly, age-related declines in drinking appeared to be more severe in response to hypotension than in response to cellular dehydration.

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Age-related changes in carotid vascular responses to adenosine and nitric oxide in the rat: in vitro and in vivo studies

Journal of Applied Physiology ◽

10.1152/japplphysiol.01245.2009 ◽

2010 ◽

Vol 109 (2) ◽

pp. 305-313 ◽

Cited By ~ 1

Author(s):

Nisreen Mansour Omar ◽

Janice M. Marshall

Keyword(s):

Carotid Artery ◽

Cerebral Autoregulation ◽

No Synthase ◽

Aged Rats ◽

Middle Aged ◽

Juvenile Rats ◽

Age Related ◽

Carotid Circulation

We investigated how the ability of adenosine to release nitric oxide (NO) from carotid artery in vitro, and dilator responses evoked in carotid circulation in vivo by systemic infusion of adenosine, change with age in rats of 4–5, 10–12, and 42–44 wk (juvenile, mature, and middle aged). A secondary aim was to follow age-related changes in carotid/cerebral autoregulation. In opened carotid artery, graded doses of adenosine evoked graded increases in NO output measured with a NO sensor that were greater in mature and middle-aged than juvenile rats. Infusion of adenosine to reduce mean arterial pressure (ABP) to ∼60 mmHg increased carotid vascular conductance (CVC) in all groups, but the increase was larger in mature rats; carotid blood flow (CBF) was unchanged in juvenile, increased in mature, but fell in 4/8 middle-aged rats. The NO synthase inhibitor nitro l-arginine methyl ester (l-NAME; 10 mg/kg iv) increased baseline ABP in all groups but caused larger percentage reductions in baseline CVC and CBF in mature and middle-aged than juvenile rats. Thereafter, the adenosine-evoked increase in CVC was unchanged in juvenile and middle-aged rats, yet CBF remained constant in juvenile but increased in middle-aged rats. In mature rats, the evoked increases in CVC and CBF were attenuated and further attenuated by l-NAME at 30 mg/kg. We propose that the ability of adenosine to release NO and cause vasodilation in the carotid artery and its circulation is greater in mature, than juvenile or middle-aged rats, but NO has greater tonic dilator influence in carotid circulation of mature and middle-aged than juvenile rats. By middle age, the lower limit of cerebral autoregulation has increased such that the tonic dilator influence of NO on ABP and CVC limits autoregulation of CBF to depressor responses. However, partial NO synthase inhibition overcomes this impairment, raising baseline ABP and allowing adenosine-evoked increases in CVC to increase CBF.

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