Biology subjects

Colledge, W. H.

Publications and source records attributed to Colledge, W. H..

4 recordsLinked to original sources

bioRxiv2026

Kiss1 neurons in the medial amygdala of mice are sexually dimorphic and unique from hypothalamic anteroventral periventricular Kiss1 neurons in their action potential firing properties

Abstract The importance of hypothalamic kisspeptin (Kiss1) neurons in controlling the reproductive axis is well established, while a population of extra-hypothalamic Kiss1 neurons is found in the medial amygdala (MeA) of both males and females in rodents and is less well understood. The MeA is connected with the olfactory bulbs, the hypothalamus and cortical areas. MeA Kiss1 neurons have been implicated in sexual behaviour and modulation of the reproductive axis; however, little is known about their action potential firing properties, which would influence kisspeptin release in target brain regions, nor whether their physiological properties are sex- or estrous cycle-dependent. In this study, whole-cell patch-clamp recordings were made from Kiss1 neurons in brain slices containing the MeA of adult female (estrous and diestrous) and male mice. MeA Kiss1 (Kiss1MeA) neurons were sexually dimorphic, with greater numbers in male compared to female mice and a slower change in excitability in estrous females compared with males. However, combining a range of electrophysiological parameters using principal component analysis did not reveal a distinct sex- or estrous cycle-linked phenotype, suggesting that the properties of Kiss1MeA neurons- and therefore kisspeptin release- are broadly similar. Interestingly, Kiss1MeA neurons had unique electrophysiological properties compared with anteroventral periventricular (AVPV) hypothalamic Kiss1 (Kiss1AVPV) neurons in female mice; with their reduced excitability, achieving action potential firing frequencies greater than 10Hz required a larger current input, indicating that Kiss1MeA neurons require stronger synaptic input to achieve firing frequencies that drive kisspeptin release. These findings provide new information about the physiological properties of Kiss1MeA neurons, showing subtle sex differences and profound regional differences between the MeA and AVPV.

neuroscience↗

bioRxiv2024

Neuronal plasticity at puberty in hypothalamic neurons controlling fertility in female mice

Puberty is a critical transition period to achieve fertility and reproductive capacity in all mammalian species. At puberty, the hypothalamic-pituitary-gonadal (HPG) is activated by neuroendocrine changes in the brain. Central to this are Kiss1 neurons that produce kisspeptin, a neuropeptide which is a potent stimulator of gonadotropin releasing hormone (GnRH) secretion. Kiss1 neurons in the arcuate region of the hypothalamus (Kiss1ARC) increase pulsatile secretion of GnRH at puberty. Other developmental maturational changes in the brain are often accompanied by neuronal plasticity changes but this has not been studied in Kiss1 neurons. Electrophysiological characterisation of Kiss1ARC neurons from female mice shows that these neurons undergo profound intrinsic plasticity at puberty with a critical window between 3 and 4 weeks. Immature Kiss1ARC neurons cannot sustain depolarisation-evoked firing for even 500 ms and instead fire a brief burst of high frequency spikes before falling silent. This would make them unsuitable for the sustained activity that is needed to activate GnRH neurons and trigger LH secretion in the HPG axis. After puberty, sustained firing can be maintained, which endows post-puberty Kiss1ARC neurons with a mature physiological phenotype that is amenable to neuropeptide modulation for generation of burst firing and pulsatile release of kisspeptin. There is a corresponding decrease in the threshold for action potential initiation, a more hyperpolarised post-spike trough and a larger medium after-hyperpolarisation (mAHP). Gene expression analysis showed a significant decrease in Scn2a (Nav1.2 channel), Kcnq2 (Kv7.2 channel) and Lrrc55 (BK channel auxiliary {gamma}3-subunit) expression and an increase in Hcn1 (hyperpolarization activated cyclic nucleotide-gated potassium channel) expression which may contribute to the observed electrophysiological changes. Ovariectomy and {beta}-estradiol replacement defined a window of estrogen-dependent plasticity of action potential firing at puberty, such that post-puberty Kiss1ARC neurons achieve a mature physiological phenotype for activation of the HPG axis.

neuroscience↗

bioRxiv2021

GnRH pulse generator frequency is modulated by kisspeptin and GABA-glutamate interactions in the posterodorsal medial amygdala in female mice

Kisspeptin neurons in the arcuate nucleus of the hypothalamus generate GnRH pulses, and act as critical initiators of functional gonadotrophin secretion, and reproductive competency. However, kisspeptin in other brain regions, most notably the posterodorsal subnucleus of the medial amygdala (MePD), plays a significant modulatory role over the hypothalamic kisspeptin population; our recent studies using optogenetics have shown that low frequency light stimulation of MePD kisspeptin results in increased LH pulse frequency. Nonetheless, the neurochemical pathways that underpin this regulatory function remain unknown. To study this, we have utilised an optofluid technology, precisely combining optogenetic stimulation with pharmacological receptor antagonism, to investigate the neurotransmission involved in this circuitry. We have shown that functional neurotransmission of both GABAA and glutamate is a requirement for effective modulation of the GnRH pulse generator by amygdala kisspeptin neurons.

neuroscience↗

bioRxiv2018

Optogenetic stimulation of kisspeptin neurones within the posterodorsal medial amygdala increases LH pulse frequency in female mice

Kisspeptin within the arcuate nucleus of the hypothalamus is a critical neuropeptide in the regulation of reproduction. Together with neurokinin B and dynorphin A, arcuate kisspeptin provides the oscillatory activity that drives the pulsatile secretion of GnRH, and therefore LH pulses, and is believed to be a central component of the GnRH pulse generator. It is well established that the amygdala also exerts an influence over gonadotrophic hormone secretion and reproductive physiology. The discovery of kisspeptin and its receptor within the posterodorsal medial amygdala (MePD), and our recent finding showing that intra-MePD administration of kisspeptin or a kisspeptin receptor antagonist results in increased LH secretion and decreased LH pulse frequency, respectively, suggests an important role for amygdala kisspeptin signalling in the regulation of the GnRH pulse generator. To further investigate the function of amygdala kisspeptin, the present study used an optogenetic approach to selectively stimulate MePD kisspeptin neurones and examine the effect on pulsatile LH secretion. MePD kisspeptin neurones in conscious Kiss1-CRE mice were virally infected to express a channelrhodopsin protein and selectively stimulated by light via a chronically implanted fibre optic cannula. Continuous stimulation using 5 Hz resulted in an increased LH pulse frequency, which was not observed at the lower stimulation frequencies of 0.5 and 2 Hz. In wild-type animals, continuous stimulation at 5 Hz did not affect LH pulse frequency. These results demonstrate that selective activation of MePD Kiss1 neurons can modulate hypothalamic GnRH pulse generator frequency.

neuroscience↗