High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons

Qiu, Jian; Nestor, Casey C; Zhang, Chunguang; Padilla, Stéphanie L.; Palmiter, Richard D.; Kelly, Martin J.; Rønnekleiv, Oline K.

doi:10.7554/elife.16246

Cited by 175 publications

(282 citation statements)

References 66 publications

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“…Previous work demonstrated that both hM3Dq-and ChR2-mediated stimulation can evoke immediate early Fos expression in AgRP neurons (28,44). However, we have shown that specific frequencies of laser stimulation can modulate the differential release of peptide vs. fast transmitter from ChR2-expressing neurons (6). The more quantitative approach of activating AgRP neurons with ChR2 is not practical for the long periods of time needed to study fertility.…”

Section: Discussionmentioning

confidence: 63%

“…Thus, neurophysiological mechanisms detect deficits in energy reserves and inhibit the neuroendocrine axis to prevent pregnancy (2,31 (6), and this circuit is likely responsible for attenuating fertility during metabolic deficiency. There may be additional sources of inhibition onto Kiss1 neurons during starvation, but the observation that ablation of AgRP neurons can restore fertility in leptin-deficient mice (15) argues that AgRP neurons are an important source of inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…For optogenetic stimulation, a lightinduced response was evoked using a light-emitting diode (LED) 470 nm blue light source controlled by a variable 2A driver (ThorLabs) with the light path delivered directly through an Olympus 40× water-immersion lens. We varied the stimulation parameters (frequency and pulse width) to evoke both fast amino acid and slow neuropeptide release as previously published (6). AgRP ablation study.…”

Section: Electrophysiologymentioning

confidence: 99%

“…Gonadal hormone-sensitive neurons [located in the anteroventral periventricular hypothalamus (AVPV), Kiss1 AVPV , and arcuate hypothalamus (ARH), Kiss1 ARH ] drive the pulsatile activity of gonadotropin-releasing hormone (GnRH) neurons and subsequent neuroendocrine release of gonadotropins from the pituitary (4)(5)(6). Within this circuit, Kiss1…”

mentioning

confidence: 99%

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AgRP to Kiss1 neuron signaling links nutritional state and fertility

Padilla

Qiu

Nestor

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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182

175

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Mammalian reproductive function depends upon a neuroendocrine circuit that evokes the pulsatile release of gonadotropin hormones (luteinizing hormone and follicle-stimulating hormone) from the pituitary. This reproductive circuit is sensitive to metabolic perturbations. When challenged with starvation, insufficient energy reserves attenuate gonadotropin release, leading to infertility. The reproductive neuroendocrine circuit is well established, composed of two populations of kisspeptin-expressing neurons (located in the anteroventral periventricular hypothalamus, Kiss1AVPV, and arcuate hypothalamus, Kiss1ARH), which drive the pulsatile activity of gonadotropin-releasing hormone (GnRH) neurons. The reproductive axis is primarily regulated by gonadal steroid and circadian cues, but the starvation-sensitive input that inhibits this circuit during negative energy balance remains controversial. Agouti-related peptide (AgRP)-expressing neurons are activated during starvation and have been implicated in leptin-associated infertility. To test whether these neurons relay information to the reproductive circuit, we used AgRP-neuron ablation and optogenetics to explore connectivity in acute slice preparations. Stimulation of AgRP fibers revealed direct, inhibitory synaptic connections with Kiss1ARH and Kiss1AVPV neurons. In agreement with this finding, Kiss1ARH neurons received less presynaptic inhibition in the absence of AgRP neurons (neonatal toxin-induced ablation). To determine whether enhancing the activity of AgRP neurons is sufficient to attenuate fertility in vivo, we artificially activated them over a sustained period and monitored fertility. Chemogenetic activation with clozapine N-oxide resulted in delayed estrous cycles and decreased fertility. These findings are consistent with the idea that, during metabolic deficiency, AgRP signaling contributes to infertility by inhibiting Kiss1 neurons.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Electrophysiologymentioning

confidence: 99%

mentioning

confidence: 99%

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AgRP to Kiss1 neuron signaling links nutritional state and fertility

Padilla

Qiu

Nestor

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

182

175

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“…Of the two kisspeptin neuron populations that innervate GnRH neurons, particular attention has focused upon the arcuate nucleus kisspeptin (ARN KISS ) neurons in terms of pulse generation (14,15). Investigators have shown that ARN KISS neurons coexpress a variety of different neurotransmitters, including glutamate, neurokinin B, and dynorphin (15,16), for which these cells also express functional receptors (17,18). Alongside anatomical evidence, it has been suggested that the ARN KISS neurons may exhibit synchronized behavior that could intermittently activate GnRH neurons and, thus, act as a pulse generator (15,16,19).…”

mentioning

confidence: 99%

Definition of the hypothalamic GnRH pulse generator in mice

Clarkson

Han

Piet

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

297

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The pulsatile release of luteinizing hormone (LH) is critical for mammalian fertility. However, despite several decades of investigation, the identity of the neuronal network generating pulsatile reproductive hormone secretion remains unproven. We use here a variety of optogenetic approaches in freely behaving mice to evaluate the role of the arcuate nucleus kisspeptin (ARN KISS ) neurons in LH pulse generation. Using GCaMP6 fiber photometry, we find that the ARN KISS neuron population exhibits brief (∼1 min) synchronized episodes of calcium activity occurring as frequently as every 9 min in gonadectomized mice. These ARN KISS population events were found to be near-perfectly correlated with pulsatile LH secretion. The selective optogenetic activation of ARN KISS neurons for 1 min generated pulses of LH in freely behaving mice, whereas inhibition with archaerhodopsin for 30 min suppressed LH pulsatility. Experiments aimed at resetting the activity of the ARN KISS neuron population with halorhodopsin were found to reset ongoing LH pulsatility. These observations indicate the ARN KISS neurons as the long-elusive hypothalamic pulse generator driving fertility.fertility | GnRH | kisspeptin | pulse | arcuate nucleus

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