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Principal Investigator: Richard Piet
Organization: KENT STATE UNIVERSITY
Fiscal Year: 2024
Award: $338,580
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
The circadian clock is a fundamental regulator of many aspects of physiology and behavior, including
reproduction. Reproductive success depends on appropriate daily timing of neuroendocrine events that control
ovulation. Kisspeptin (Kiss1) neurons in the preoptic area (POA) of the hypothalamus play a critical role in this
by driving the activity of downstream gonadotropin-releasing hormone (GnRH) neurons to generate the surge in
GnRH and LH secretion that triggers ovulation. The surge in rodents is timed by the central circadian clock in
the suprachiasmatic nucleus (SCN) to initiate just before the onset of diurnal activity, ensuring that ovulation,
which occurs a few hours later, coincides with sexual behavior. Projections from the SCN provide timing signals
to the GnRH neuronal network, including to POA Kiss1 neurons. Indeed, reports indicate that arginine
vasopressin (AVP)-expressing SCN neurons may play a key role in daily timing of the surge by activating POA
Kiss1 neurons. Our prior published studies provide evidence that SCN projections release AVP to stimulate POA
Kiss1 neuron electrical activity, and that this circuit is most effective in driving Kiss1 neuron activity on the day
the surge occurs. Recently, we have obtained exciting preliminary data that indicate that a distinct SCN
population releases GABA and inhibits Kiss1 neuron activity. These new observations, along with our published
work, reveal that SCN neurons may bidirectionally control the electrical activity of Kiss1 neurons, through the
release of GABA and AVP. This has led us to hypothesize that a shift in the balance of SCN-derived AVP-
mediated excitation and GABA-mediated inhibition contributes to gating the activation of POA Kiss1 neurons for
the surge.
We will employ a combination of anatomical and functional approaches to address this central
hypothesis. Our first aim will be to establish that SCN neurons directly project to and release GABA on POA
Kiss1 neurons using brain slice electrophysiology and optogenetics. Further, we will determine the functional
impact of GABA release on Kiss1 neuron electrical activity across the estrous cycle. In the second aim, we will
use tract-tracing and immunohistochemical approaches to establish that SCN neuron projections target those
POA Kiss1 cells that are involved in the surge and determine the identity of the cells that contribute these
projections as well as their activation patterns prior to the surge. In our third aim, we will first assess the electrical
activity of SCN neuronal populations in the hours that precede the preovulatory surge. Using this information,
we will then determine how Kiss1 neurons integrate SCN timing signals, mediated through GABA and AVP
release, on the day of the surge. Together, this research will provide new information about the circadian control
of reproduction, and specifically the daily timing of the neuroendocrine events that trigger ovulation. A better
understanding of the neural mechanisms responsible for circadian regulation of these circuits under physiological
conditions may open new avenues for potential future treatments of ovulatory dysfunction.
Terms: <4-Aminobutanoic Acid><4-Aminobutyric Acid><4-amino-butanoic acid><8-Arg-vasopressin-receptor><Action Potentials><Address><Aminalon><Aminalone><Anatomic Sites><Anatomic structures><Anatomy><Area><Arginine Vasopressin><Argipressin><Automobile Driving><Axon><Behavior><Brain><Brain Nervous System><Cell Body><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cells><Circadian Rhythms><Cues><Data><Diurnal Rhythm><ERalpha><ERα><ESR1><ESR1 gene><Electrophysiology><Electrophysiology (science)><Encephalon><Ensure><Equilibrium><Estradiol Receptor alpha><Estradiol Receptor α><Estrogen Receptor 1><Estrogen Receptor alpha><Estrogen Receptor α><Estrogens><Estrous Cycle><Event><Exhibits><FSH-Releasing Hormone><Fecundability><Fecundity><Female><Fertility><Foundations><Future><GABA><GNRH><GNRH1><GNRH1 gene><Goals><Gonadoliberin><Gonadorelinum><Gonadotropin Hormone Releasing Hormone><Gonadotropin Releasing Hormone 1><Gonadotropin-Releasing Hormone><Gonadotropins><Hormone secretion><Hour><Human><Hypothalamic structure><Hypothalamus><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Interstitial Cell Stimulating Hormone><Interstitial Cell-Stimulating Hormone><Intracellular Communication and Signaling><KISS1><KISS1 Metastasis Suppressor><KISS1 gene><KiSS-1><Knowledge><LH-FSH Releasing Hormone><LH-Releasing Hormone><LHFSH Releasing Hormone><LNRH><Leuteinizing Hormone><Luliberin><Luteinizing Hormone><Luteinizing Hormone-Releasing Factor><Luteinizing Hormone-Releasing Hormone><Lutropin><MGC39258><Mediating><Metastin><Modern Man><NR3A1><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Neural Cell><Neurocyte><Neuroendocrine><Neuroendocrine System><Neuronal Transmission><Neurons><Neuropeptides><Neurophysiology / Electrophysiology><Neurosecretory Systems><Nucleus><Nyctohemeral Rhythm><Oophorectomy><Output><Ovariectomy><Ovulation><Pattern><Physiologic><Physiological><Physiology><Pituitary Lutenizing Hormone><Play><Population><Preoptic Areas><Preparation><Proestrus><Publishing><Pulsti><Receptor Signaling><Recombinant Gonadorelin><Recombinant Luteinizing Hormone><Regulation><Reporting><Reproduction><Research><Rodent><Rodentia><Rodents Mammals><Role><Sex Behavior><Sexual Activity><Sexual Behavior><Signal Transduction><Signal Transduction Systems><Signaling><Slice><Synapses><Synaptic><Testing><Therapeutic Estrogen><Therapeutic GRH><Therapeutic LH><Third Cerebral Ventricle><Third Ventricle><Third ventricle structure><Time><Twenty-Four Hour Rhythm><Vasopressin-Neurophysin II-Copeptin><Ventricular><Woman><Work><arginine vasopressin receptor><argipressin receptor><axon signaling><axon-glial signaling><axonal signaling><balance><balance function><biological signal transduction><circadian><circadian clock><circadian pacemaker><circadian process><circadian regulation><daily biorhythm><diurnal variation><driving><electrophysiological><female gonadectomy><follicle stimulating hormone-releasing factor><gamma-Aminobutyric Acid><glia signaling><glial signaling><gonadotropin releasing factor><hormonal secretion><hypothalamic><kisspeptin><nerve signaling><neural circuit><neural circuitry><neural mechanism><neural signaling><neurocircuitry><neuromechanism><neuronal><neuronal circuit><neuronal circuitry><neuronal signaling><neurotransmission><optogenetics><ovarian dysfunction><ovulatory dysfunction><preoptic region><preparations><presynaptic><reproductive success><response><sex activity><sexual activities><social role><suprachiasmatic nucleus><synapse><synaptic circuit><synaptic circuitry><third brain ventricle><γ-Aminobutyric Acid>