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Kisspeptin Neurons in the Arcuate Nucleus of the Hypothalamus Orchestrate Circadian Rhythms and Metabolism.

ABSTRACT: Successful reproduction in female mammals is precisely timed and must be able to withstand the metabolic demand of pregnancy and lactation. We show that kisspeptin-expressing neurons in the arcuate hypothalamus (Kiss1ARH) of female mice control the daily timing of food intake, along with the circadian regulation of locomotor activity, sleep, and core body temperature. Toxin-induced silencing of Kiss1ARH neurons shifts wakefulness and food consumption to the light phase and induces weight gain. Toxin-silenced mice are less physically active and have attenuated temperature rhythms. Because the rhythm of the master clock in the suprachiasmatic nucleus (SCN) appears to be intact, we hypothesize that Kiss1ARH neurons signal to neurons downstream of the master clock to modulate the output of the SCN. We conclude that, in addition to their well-established role in regulating fertility, Kiss1ARH neurons are a critical component of the hypothalamic circadian oscillator network that times overt rhythms of physiology and behavior.

SUBMITTER: Padilla SL

PROVIDER: S-EPMC7147454 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Kisspeptin Neurons in the Arcuate Nucleus of the Hypothalamus Orchestrate Circadian Rhythms and Metabolism.

Padilla Stephanie L SL Perez Jazmine G JG Ben-Hamo Miriam M Johnson Christopher W CW Sanchez Raymond E A REA Bussi Ivana L IL Palmiter Richard D RD de la Iglesia Horacio O HO

Current biology : CB 20190207 4

Successful reproduction in female mammals is precisely timed and must be able to withstand the metabolic demand of pregnancy and lactation. We show that kisspeptin-expressing neurons in the arcuate hypothalamus (Kiss1<sup>ARH</sup>) of female mice control the daily timing of food intake, along with the circadian regulation of locomotor activity, sleep, and core body temperature. Toxin-induced silencing of Kiss1<sup>ARH</sup> neurons shifts wakefulness and food consumption to the light phase and ...[more]

PMID: 30744968

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Project description:KEY POINTS:Neurons in the hypothalamus of the brain which secrete the peptide kisspeptin are important regulators of reproduction, and normal reproductive development. Electrical activity, in the form of action potentials, or spikes, leads to secretion of peptides and neurotransmitters, influencing the activity of downstream neurons; in kisspeptin neurons, this activity is highly irregular, but the mechanism of this is not known. In this study, we show that irregularity depends on the presence of a particular type of potassium ion channel in the membrane, which opens transiently in response to electrical excitation. The results contribute to understanding how kisspeptin neurons generate and time their membrane potential spikes, and how reliable this process is. Improved understanding of the activity of kisspeptin neurons, and how it shapes their secretion of peptides, is expected to lead to better treatment for reproductive dysfunction and disorders of reproductive development. ABSTRACT:Kisspeptin neurons in the hypothalamus are critically involved in reproductive function, via their effect on GnRH neuron activity and consequent gonadotropin release. Kisspeptin neurons show an intrinsic irregularity of firing, but the mechanism of this remains unclear. To address this, we carried out targeted whole-cell patch-clamp recordings of kisspeptin neurons in the arcuate nucleus (Kiss1Arc ), in brain slices isolated from adult male Kiss-Cre:tdTomato mice. Cells fired irregularly in response to constant current stimuli, with a wide range of spike time variability, and prominent subthreshold voltage fluctuations. In voltage clamp, both a persistent sodium (NaP) current and a fast transient (A-type) potassium current were apparent, activating at potentials just below the threshold for spiking. These currents have also previously been described in irregular-spiking cortical interneurons, in which the A-type current, mediated by Kv4 channels, interacts with NaP current to generate complex dynamics of the membrane potential, and irregular firing. In Kiss1Arc neurons, A-type current was blocked by phrixotoxin, a specific blocker of Kv4.2/4.3 channels, and consistent expression of Kv4.2 transcripts was detected by single-cell RT-PCR. In addition, firing irregularity was correlated to the density of A-type current in the membrane. Using conductance injection, we demonstrated that adding Kv4-like potassium conductance (gKv4 ) to a cell produces a striking increase in firing irregularity, and excitability is reduced, while subtracting gKv4 has the opposite effects. Thus, we propose that Kv4 interacting dynamically with NaP is a key determinant of the irregular firing behaviour of Kiss1Arc neurons, shaping their physiological function in gonadotropin release.

Dataset Information

Kisspeptin Neurons in the Arcuate Nucleus of the Hypothalamus Orchestrate Circadian Rhythms and Metabolism.

Publications

Kisspeptin Neurons in the Arcuate Nucleus of the Hypothalamus Orchestrate Circadian Rhythms and Metabolism.

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