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  1. Article ; Online: Preface to the special issue.

    Lehman, Michael N

    Journal of neuroendocrinology

    2022  Volume 34, Issue 5, Page(s) e13150

    Language English
    Publishing date 2022-05-20
    Publishing country United States
    Document type Editorial
    ZDB-ID 1007517-3
    ISSN 1365-2826 ; 0953-8194
    ISSN (online) 1365-2826
    ISSN 0953-8194
    DOI 10.1111/jne.13150
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  2. Article ; Online: Interviews: A collection of stories and perspectives about the past and future of GnRH research.

    Lehman, Michael N

    Journal of neuroendocrinology

    2022  Volume 34, Issue 5, Page(s) e13140

    MeSH term(s) Gonadotropin-Releasing Hormone
    Chemical Substances Gonadotropin-Releasing Hormone (33515-09-2)
    Language English
    Publishing date 2022-05-28
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 1007517-3
    ISSN 1365-2826 ; 0953-8194
    ISSN (online) 1365-2826
    ISSN 0953-8194
    DOI 10.1111/jne.13140
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  3. Article ; Online: Origins of the 'KNDy hypothesis' of GnRH pulse generation.

    Lehman, Michael N

    Nature reviews. Endocrinology

    2022  Volume 18, Issue 9, Page(s) 521

    MeSH term(s) Arcuate Nucleus of Hypothalamus/metabolism ; Gonadotropin-Releasing Hormone/metabolism ; Humans ; Kisspeptins/metabolism ; Neurokinin B
    Chemical Substances Kisspeptins ; Gonadotropin-Releasing Hormone (33515-09-2) ; Neurokinin B (86933-75-7)
    Language English
    Publishing date 2022-05-24
    Publishing country England
    Document type Journal Article
    ZDB-ID 2489381-X
    ISSN 1759-5037 ; 1759-5029
    ISSN (online) 1759-5037
    ISSN 1759-5029
    DOI 10.1038/s41574-022-00703-5
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  4. Article ; Online: KNDy Neurons of the Hypothalamus and Their Role in GnRH Pulse Generation: an Update.

    Moore, Aleisha M / Novak, Alyssa G / Lehman, Michael N

    Endocrinology

    2023  Volume 165, Issue 2

    Abstract: There is considerable evidence that synchronized activity within a reciprocally connected population of cells in the arcuate nucleus (ARC) coexpressing kisspeptin, neurokinin B (NKB), and dynorphin (KNDy cells) is crucial for the generation of ... ...

    Abstract There is considerable evidence that synchronized activity within a reciprocally connected population of cells in the arcuate nucleus (ARC) coexpressing kisspeptin, neurokinin B (NKB), and dynorphin (KNDy cells) is crucial for the generation of gonadotrophin-releasing hormone (GnRH) pulses in mammals. The initial "KNDy hypothesis" proposed that pulsatile GnRH secretion is elicited by episodic kisspeptin release from KNDy cells following synchronized activation and termination of the population by NKB and dynorphin, respectively. Since then, the role of KNDy cells as a critical component of the pulse generator has been further supported by studies at the single-cell level, demonstrating that the population is both necessary and sufficient for pulsatility. In addition, there have been considerable modifications and expansion of the original hypothesis, including work demonstrating the critical role of glutamate in synchronization of the KNDy cell network, functional interactions with other ARC subpopulations, and the existence of species differences in the role of dynorphin in pulse generation. Here we review these recent changes and discuss how the translation of these findings has led to the development of new therapies for disorders related to pulse generation. We also outline critical gaps in knowledge that are currently limiting the application of KNDy research in the clinic, particularly regarding the role of dynorphin in pulse generation in primates.
    MeSH term(s) Animals ; Gonadotropin-Releasing Hormone ; Dynorphins ; Kisspeptins ; Hypothalamus ; Arcuate Nucleus of Hypothalamus ; Neurokinin B ; Neurons ; Mammals
    Chemical Substances Gonadotropin-Releasing Hormone (33515-09-2) ; Dynorphins (74913-18-1) ; Kisspeptins ; Neurokinin B (86933-75-7)
    Language English
    Publishing date 2023-12-04
    Publishing country United States
    Document type Review ; Journal Article
    ZDB-ID 427856-2
    ISSN 1945-7170 ; 0013-7227
    ISSN (online) 1945-7170
    ISSN 0013-7227
    DOI 10.1210/endocr/bqad194
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  5. Article ; Online: A new society for the "New World".

    Lehman, Michael N

    Journal of neuroendocrinology

    2017  Volume 29, Issue 5

    Language English
    Publishing date 2017-06-14
    Publishing country United States
    Document type Editorial
    ZDB-ID 1007517-3
    ISSN 1365-2826 ; 0953-8194
    ISSN (online) 1365-2826
    ISSN 0953-8194
    DOI 10.1111/jne.12478
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  6. Article ; Online: In vivo imaging of the GnRH pulse generator reveals a temporal order of neuronal activation and synchronization during each pulse.

    Moore, Aleisha M / Coolen, Lique M / Lehman, Michael N

    Proceedings of the National Academy of Sciences of the United States of America

    2022  Volume 119, Issue 6

    Abstract: A hypothalamic pulse generator located in the arcuate nucleus controls episodic release of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) and is essential for reproduction. Recent evidence suggests this generator is composed of ... ...

    Abstract A hypothalamic pulse generator located in the arcuate nucleus controls episodic release of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) and is essential for reproduction. Recent evidence suggests this generator is composed of arcuate "KNDy" cells, the abbreviation based on coexpression of kisspeptin, neurokinin B, and dynorphin. However, direct visual evidence of KNDy neuron activity at a single-cell level during a pulse is lacking. Here, we use in vivo calcium imaging in freely moving female mice to show that individual KNDy neurons are synchronously activated in an episodic manner, and these synchronized episodes always precede LH pulses. Furthermore, synchronization among KNDy cells occurs in a temporal order, with some subsets of KNDy cells serving as "leaders" and others as "followers" during each synchronized episode. These results reveal an unsuspected temporal organization of activation and synchronization within the GnRH pulse generator, suggesting that different subsets of KNDy neurons are activated at pulse onset than afterward during maintenance and eventual termination of each pulse. Further studies to distinguish KNDy "leader" from "follower" cells is likely to have important clinical significance, since regulation of pulsatile GnRH secretion is essential for normal reproduction and disrupted in pathological conditions such as polycystic ovary syndrome and hypothalamic amenorrhea.
    MeSH term(s) Animals ; Arcuate Nucleus of Hypothalamus/metabolism ; Dynorphins/metabolism ; Female ; Gonadotropin-Releasing Hormone/metabolism ; Kisspeptins/metabolism ; Luteinizing Hormone/metabolism ; Mice ; Mice, Inbred C57BL ; Neurokinin B/metabolism ; Neurons/metabolism ; Reproduction/physiology
    Chemical Substances Kisspeptins ; Gonadotropin-Releasing Hormone (33515-09-2) ; Dynorphins (74913-18-1) ; Neurokinin B (86933-75-7) ; Luteinizing Hormone (9002-67-9)
    Language English
    Publishing date 2022-02-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2117767119
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    Zs.A 1148: Show issues Location:
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  7. Article ; Online: KNDy neurons as the GnRH pulse generator: Recent studies in ruminants.

    Nestor, Casey C / Merkley, Christina M / Lehman, Michael N / Hileman, Stanley M / Goodman, Robert L

    Peptides

    2023  Volume 164, Page(s) 171005

    Abstract: This review considers three aspects of recent work on the role of KNDy neurons in GnRH pulse generation in ruminants. First, work on basic mechanisms of pulse generation includes several tests of this hypothesis, all of which support it, and evidence ... ...

    Abstract This review considers three aspects of recent work on the role of KNDy neurons in GnRH pulse generation in ruminants. First, work on basic mechanisms of pulse generation includes several tests of this hypothesis, all of which support it, and evidence that Kiss1r-containing neurons form a positive feedback circuit with the KNDy neural network that strengthen the activity of this network. The second section on pathways mediating external inputs focuses on the influence of nutrition and photoperiod, and describes the evidence supporting roles for proopiomelanocortin (POMC) and agouti-related peptide (AgRP) afferents to KNDy cells in each of these. Finally, we review studies exploring the potential applications of manipulating signaling by kisspeptin, and the other KNDy peptides, to control reproductive function in domestic animals and conclude that, although these approaches show some promise, they do not have major advantages over current practices at this time.
    MeSH term(s) Animals ; Gonadotropin-Releasing Hormone ; Arcuate Nucleus of Hypothalamus/metabolism ; Dynorphins/metabolism ; Neurokinin B/metabolism ; Neurons/metabolism ; Ruminants/metabolism ; Kisspeptins/metabolism
    Chemical Substances Gonadotropin-Releasing Hormone (33515-09-2) ; Dynorphins (74913-18-1) ; Neurokinin B (86933-75-7) ; Kisspeptins
    Language English
    Publishing date 2023-03-27
    Publishing country United States
    Document type Review ; Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 769028-9
    ISSN 1873-5169 ; 0196-9781
    ISSN (online) 1873-5169
    ISSN 0196-9781
    DOI 10.1016/j.peptides.2023.171005
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    Zs.A 1649: Show issues Location:
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  8. Article ; Online: Neuroendocrine control of gonadotropin-releasing hormone: Pulsatile and surge modes of secretion.

    Goodman, Robert L / Herbison, Allan E / Lehman, Michael N / Navarro, Victor M

    Journal of neuroendocrinology

    2022  Volume 34, Issue 5, Page(s) e13094

    Abstract: The concept that different systems control episodic and surge secretion of gonadotropin-releasing hormone (GnRH) was well established by the time that GnRH was identified and formed the framework for studies of the physiological roles of GnRH, and later ... ...

    Abstract The concept that different systems control episodic and surge secretion of gonadotropin-releasing hormone (GnRH) was well established by the time that GnRH was identified and formed the framework for studies of the physiological roles of GnRH, and later kisspeptin. Here, we focus on recent studies identifying the neural mechanisms underlying these two modes of secretion, with an emphasis on their core components. There is now compelling data that kisspeptin neurons in the arcuate nucleus that also contain neurokinin B (NKB) and dynorphin (i.e., KNDy cells) and their projections to GnRH dendrons constitute the GnRH pulse generator in mice and rats. There is also strong evidence for a similar role for KNDy neurons in sheep and goats, and weaker data in monkeys and humans. However, whether KNDy neurons act on GnRH dendrons and/or GnRH soma and dendrites that are found in the mediobasal hypothalamus (MBH) of these species remains unclear. The core components of the GnRH/luteinising hormone surge consist of an endocrine signal that initiates the process and a neural trigger that drives GnRH secretion during the surge. In all spontaneous ovulators, the core endocrine signal is a rise in estradiol secretion from the maturing follicle(s), with the site of estrogen positive feedback being the rostral periventricular kisspeptin neurons in rodents and neurons in the MBH of sheep and primates. There is considerable species variations in the neural trigger, with three major classes. First, in reflex ovulators, this trigger is initiated by coitus and carried to the hypothalamus by neural or vascular pathways. Second, in rodents, there is a time of day signal that originates in the suprachiasmatic nucleus and activates rostral periventricular kisspeptin neurons and GnRH soma and dendrites. Finally, in sheep nitric oxide-producing neurons in the ventromedial nucleus, KNDy neurons and rostral kisspeptin neurons all appear to participate in driving GnRH release during the surge.
    MeSH term(s) Animals ; Arcuate Nucleus of Hypothalamus/metabolism ; Dendrimers/metabolism ; Dynorphins/metabolism ; Gonadotropin-Releasing Hormone/metabolism ; Kisspeptins/metabolism ; Mice ; Neurokinin B/metabolism ; Rats ; Sheep
    Chemical Substances Dendrimers ; Kisspeptins ; Gonadotropin-Releasing Hormone (33515-09-2) ; Dynorphins (74913-18-1) ; Neurokinin B (86933-75-7)
    Language English
    Publishing date 2022-02-02
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1007517-3
    ISSN 1365-2826 ; 0953-8194
    ISSN (online) 1365-2826
    ISSN 0953-8194
    DOI 10.1111/jne.13094
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  9. Article: Food Entrainment, Arousal, and Motivation in the Neonatal Rabbit Pup.

    Caba, Mario / Lehman, Michael N / Caba-Flores, Mario Daniel

    Frontiers in neuroscience

    2021  Volume 15, Page(s) 636764

    Abstract: In the newborn rabbit, the light entrainable circadian system is immature and once a day nursing provides the primary timing cue for entrainment. In advance of the mother's arrival, pups display food anticipatory activity (FAA), and metabolic and ... ...

    Abstract In the newborn rabbit, the light entrainable circadian system is immature and once a day nursing provides the primary timing cue for entrainment. In advance of the mother's arrival, pups display food anticipatory activity (FAA), and metabolic and physiological parameters are synchronized to this daily event. Central structures in the brain are also entrained as indicated by expression of Fos and Per1 proteins, GFAP, a glial marker, and cytochrome oxidase activity. Under fasting conditions, several of these rhythmic parameters persist in the periphery and brain, including rhythms in the olfactory bulb (OB). Here we provide an overview of these physiological and neurobiological changes and focus on three issues, just beginning to be examined in the rabbit. First, we review evidence supporting roles for the organum vasculosum of lamina terminalis (OVLT) and median preoptic nucleus (MnPO) in homeostasis of fluid ingestion and the neural basis of arousal, the latter which also includes the role of the orexigenic system. Second, since FAA in association with the daily visit of the mother is an example of conditioned learning, we review evidence for changes in the corticolimbic system and identified nuclei in the amygdala and extended amygdala as part of the neural substrate responsible for FAA. Third, we review recent evidence supporting the role of oxytocinergic cells of the paraventricular hypothalamic nucleus (PVN) as a link to the autonomic system that underlies physiological events, which occur in preparation for the upcoming next daily meal. We conclude that the rabbit model has contributed to an overall understanding of food entrainment.
    Language English
    Publishing date 2021-03-17
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2411902-7
    ISSN 1662-453X ; 1662-4548
    ISSN (online) 1662-453X
    ISSN 1662-4548
    DOI 10.3389/fnins.2021.636764
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  10. Article ; Online: Evidence that synaptic plasticity of glutamatergic inputs onto KNDy neurones during the ovine follicular phase is dependent on increasing levels of oestradiol.

    Porter, Danielle T / Goodman, Robert L / Hileman, Stanley M / Lehman, Michael N

    Journal of neuroendocrinology

    2021  Volume 33, Issue 3, Page(s) e12945

    Abstract: Neurones in the arcuate nucleus co-expressing kisspeptin, neurokinin B (NKB) and dynorphin (KNDy) play a critical role in the control of gonadotrophin-releasing hormone (GnRH) and luteinising hormone (LH) secretion. In sheep, KNDy neurones mediate both ... ...

    Abstract Neurones in the arcuate nucleus co-expressing kisspeptin, neurokinin B (NKB) and dynorphin (KNDy) play a critical role in the control of gonadotrophin-releasing hormone (GnRH) and luteinising hormone (LH) secretion. In sheep, KNDy neurones mediate both steroid-negative- and -positive-feedback during pulsatile and preovulatory surge secretions of GnRH/LH, respectively. In addition, KNDy neurones receive glutamatergic inputs expressing vGlut2, a glutamate transporter that serves as a marker for those terminals, from both KNDy neurones and other populations of glutamatergic neurones. Previous work reported higher numbers of vGlut2-positive axonal inputs onto KNDy neurones during the LH surge than in luteal phase ewes. In the present study, we further examined the effects of the ovarian steroids progesterone (P) and oestradiol (E
    MeSH term(s) Animals ; Dynorphins/physiology ; Estradiol/metabolism ; Estradiol/physiology ; Female ; Follicular Phase/physiology ; Glutamates/physiology ; Gonadotropin-Releasing Hormone/blood ; Kisspeptins/physiology ; Luteal Phase/drug effects ; Luteinizing Hormone/blood ; Neurokinin B/physiology ; Neuronal Plasticity/physiology ; Ovariectomy ; Sheep ; Synapses/physiology ; Vesicular Glutamate Transport Protein 2/metabolism
    Chemical Substances Glutamates ; Kisspeptins ; Vesicular Glutamate Transport Protein 2 ; Gonadotropin-Releasing Hormone (33515-09-2) ; Estradiol (4TI98Z838E) ; Dynorphins (74913-18-1) ; Neurokinin B (86933-75-7) ; Luteinizing Hormone (9002-67-9)
    Language English
    Publishing date 2021-03-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1007517-3
    ISSN 1365-2826 ; 0953-8194
    ISSN (online) 1365-2826
    ISSN 0953-8194
    DOI 10.1111/jne.12945
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