Excitability and Burst Generation of AVPV Kisspeptin Neurons Are Regulated by the Estrous Cycle Via Multiple Conductances Modulated by Estradiol Action

Wang, Luhong; DeFazio, R. Anthony; Moenter, Suzanne M.

doi:10.1523/eneuro.0094-16.2016

Cited by 51 publications

(68 citation statements)

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“…As GnRH neurons typically do not express detectable ERa (8), 41 estradiol feedback is likely transmitted to GnRH neurons by ERa -expressing afferents. 5 previous observations (25) (Fig 1 C, D, E, Chi-square, DIB, p=0.02; rebound, p=0.02; Fisher's 81 exact post hoc test, DIB, OVX vs OVX+E, p=0.008, rebound OVX vs OVX+E p=0.03, for other 82 paired comparisons, p>0.2) ). In KERKO mice, these two types of bursts were rare (<25% of 83 cells) in all steroid conditions tested and were not regulated by estradiol ( Fig 1C, D, E, Chi-84 square, DIB, p=0.4, rebound, p=0.3).…”

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Genetic dissection of the different roles of hypothalamic kisspeptin neurons in regulating female reproduction

Wang

Vanacker

Burger

et al. 2018

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1 The brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Estradiol 2 induces negative feedback on pulsatile GnRH/luteinizing hormone (LH) release and positive 3 feedback generating preovulatory GnRH/LH surges. Negative and positive feedback are 4 postulated to be mediated by kisspeptin neurons in arcuate and anteroventral periventricular 5 (AVPV) nuclei, respectively. Kisspeptin-specific ERa knockout mice exhibit disrupted LH pulses 6 and surges. This knockout approach is neither location-specific nor temporally-controlled. We 7 utilized CRISPR-Cas9 to disrupt ERa in adulthood. Mice with ERa disruption in AVPV 8 kisspeptin neurons have typical reproductive cycles but blunted LH surges, associated with 9 decreased excitability of these neurons. Mice with ERa knocked down in arcuate kisspeptin 10 neurons showed disrupted cyclicity, associated with increased glutamatergic transmission to 11 these neurons. These observations suggest activational effects of estradiol regulate surge 12 generation and maintain cyclicity through AVPV and arcuate kisspeptin neurons, respectively, 13 independent from its role in the development of hypothalamic kisspeptin neurons or puberty 14 onset. 15 16 3 Significant Statement 17 The brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Ovarian 18 estradiol regulates GnRH pulses (negative feedback) and the GnRH surge release that 19 ultimately triggers ovulation (positive feedback). Kisspeptin neurons in the arcuate and 20 anteroventral periventricular nuclei are postulated to convey negative and positive feedback to 21 GnRH neurons, respectively. Kisspeptin-specific ERa knockout mice exhibited disrupted 22 negative and positive feedback. However, it is not clear what roles each kisspeptin population 23 plays, and not possible to separate their roles during development vs adulthood in this model. 24 Here we utilized CRISPR-Cas9 to disrupt ERa in each population in adulthood. We found 25 activational effects of estradiol regulate surge generation and maintain cyclicity through AVPV 26 and arcuate kisspeptin neurons, respectively, independent from estradiol action during 27 development. 28 42 Kisspeptin neurons in the arcuate and anteroventral periventricular (AVPV) regions are 43 estradiol-sensitive GnRH afferents that are postulated to mediate estradiol negative and positive 44 feedback, respectively (9, 10). Kisspeptin potently stimulates GnRH neurons and Kiss1 mRNA 45 is differentially regulated in these nuclei by estradiol (10-16). ERa in kisspeptin cells is critical 46 for estradiol negative and positive feedback, as kisspeptin-specific ERa knockout (KERKO) 47 mice exhibit higher frequency LH pulses and fail to exhibit estradiol-induced LH surges(17-20). 4Although informative, the KERKO model has several caveats that limit interpretation. First, ERa 49 is deleted as soon as Kiss1 is expressed, before birth in arcuate kisspeptin neurons (also called 50 KNDy neurons for coexpression of kisspeptin, neurokinin B and dynorphin) and ...

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“…For voltage-clamp recordings of IT, ACSF containing antagonists of ionotropic GABAA and 446 glutamate receptors was supplemented with TTX (2µM) and the Cs-based pipette solution was 447 used. Two voltage protocols were used to isolate IT as reported (25). First, total calcium current 448 activation was examined.…”

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Genetic dissection of the different roles of hypothalamic kisspeptin neurons in regulating female reproduction

Wang

Vanacker

Burger

et al. 2018

Preprint

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“…These data suggest a complexity whereby estradiol can control both positive and negative feedback action. Arcuate nucleus kisspeptin, neurokinin B, and dynorphin co-expressing neurons initiate pulsatile hormone patterns in the absence of estradiol and are inhibited at low levels of estradiol to account for negative feedback, yet AVPV localized kisspeptin neurons are activated by rising titers of estradiol and initiate the pre-ovulatory surge of LH (Wang, DeFazio, & Moenter, 2016). …”

Section: The Hypothalamic–pituitary–gonadal Axismentioning

confidence: 99%

Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity

Oyola

Handa

2017

Stress

494

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Gonadal hormones play a key role in the establishment, activation, and regulation of the hypothalamic–pituitary–adrenal (HPA) axis. By influencing the response and sensitivity to releasing factors, neurotransmitters, and hormones, gonadal steroids help orchestrate the gain of the HPA axis to fine-tune the levels of stress hormones in the general circulation. From early life to adulthood, gonadal steroids can differentially affect the HPA axis, resulting in sex differences in the responsivity of this axis. The HPA axis influences many physiological functions making an organism’s response to changes in the environment appropriate for its reproductive status. Although the acute HPA response to stressors is a beneficial response, constant activation of this circuitry by chronic or traumatic stressful episodes may lead to a dysregulation of the HPA axis and cause pathology. Compared to males, female mice and rats show a more robust HPA axis response, as a result of circulating estradiol levels which elevate stress hormone levels during non-threatening situations, and during and after stressors. Fluctuating levels of gonadal steroids in females across the estrous cycle are a major factor contributing to sex differences in the robustness of HPA activity in females compared to males. Moreover, gonadal steroids may also contribute to epigenetic and organizational influences on the HPA axis even before puberty. Correspondingly, crosstalk between the hypothalamic–pituitary–gonadal (HPG) and HPA axes could lead to abnormalities of stress responses. In humans, a dysregulated stress response is one of the most common symptoms seen across many neuropsychiatric disorders, and as a result, such interactions may exacerbate peripheral pathologies. In this review, we discuss the HPA and HPG axes and review how gonadal steroids interact with the HPA axis to regulate the stress circuitry during all stages in life.

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“…In normal mice, estradiol's negative feedback increases glutamatergic transmission to ARC kisspeptin neurons and decrease it to AVPV neurons, while estradiol positive feedback had the antipode effect [9]. Estradiol elevation exits the AVPV kisspeptin neurons by increasing the number of depolarization-induced bursts and rebound bursts [10]. Knocked alpha estradiol receptor in the ARC kisspeptin neurons tends to associate with cycle disruption, where, knocked ERα in AVPV kisspeptin neurons tends to associate with the normal cycle, but blunted the LH surge [8].…”

Section: Introductionmentioning

confidence: 99%

The Correlation between Hormonal Disturbance in PCOS Women and Serum Level of Kisspeptin

Ibrahim

Omer

Fattah

2020

International Journal of Endocrinology

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Background. Kisspeptin is a neuropeptide that upregulates gonadotropin-releasing hormone (GnRH) secretion. It is an essential element for the luteinizing hormone (LH) surge and ovulation. Women with polycystic ovary syndrome (PCOS) expose alteration in both GnRH and LH secretion levels. Objective. This paper aims to evaluate serum kisspeptin levels in healthy and polycystic ovarian syndrome women. Furthermore, it investigates the effect of obesity and age on circulating kisspeptin levels in both normal and PCOS women. Moreover, it points out the correlation between kisspeptin and other hormonal parameters. Methods and Patients. One hundred women (60 are with PCOS and 40 are normal) were enrolled in the study. Five milliliter samples of blood from all the patients and control women were obtained twice during the menstrual cycle. All the study samples were classified depending on the age factor for several subgroups. Results. Kisspeptin levels were higher in PCOS patients than those in the normal group. Kisspeptin correlated with serum free testosterone level (r=0.26). In healthy women, preovulatory kisspeptin levels were higher than follicular kisspeptin levels (P<0.05), while this difference was insignificant in PCOS patients. The variation in serum kisspeptin levels between overweight/obese and normal-weight women was insignificant. In normal women, serum kisspeptin levels were higher in women >35 years than those <24 years at (P=0.03). Conclusion. The serum kisspeptin level is higher in PCOS women. Its levels fluctuate during the menstrual cycle, but these fluctuations are disturbed in PCOS women. The effect of BMI on serum kisspeptin levels is insignificant, and kisspeptin serum levels increase with age.

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Excitability and Burst Generation of AVPV Kisspeptin Neurons Are Regulated by the Estrous Cycle Via Multiple Conductances Modulated by Estradiol Action

Cited by 51 publications

References 74 publications

Genetic dissection of the different roles of hypothalamic kisspeptin neurons in regulating female reproduction

Genetic dissection of the different roles of hypothalamic kisspeptin neurons in regulating female reproduction

Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity

The Correlation between Hormonal Disturbance in PCOS Women and Serum Level of Kisspeptin

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