Biology subjects

Iremonger, K. J.

Publications and source records attributed to Iremonger, K. J..

3 recordsLinked to original sources

bioRxiv2024

Ultradian rhythms of CRHPVN neuron activity, behaviour and stress hormone secretion

The stress axis is always active, even in the absence of any threat. This manifests as hourly pulses of corticosteroid stress hormone secretion over the day. Corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRHPVN) control both the neuroendocrine stress axis as well as stress-associated behaviours. However, it is currently unclear how the resting activity of these neurons is coordinated with both spontaneous behaviour and ultradian pulses of corticosteroid secretion. To investigate this, we performed fiber photometry recordings of CRHPVN neuron activity in Crh-Ires-Cre mice and a newly generated line of Crh-Ires-Cre rats. In both mice and rats, CRHPVN neurons displayed an ultradian rhythm of activity with reoccurring upstates of activity approximately once per hour over the 24-hour day. Upstates in activity were coordinated with increases in animal activity/arousal. Chemogenetic activation of CRHPVN neurons was also sufficient to induce behavioural arousal. In rats, increases in CRH neural activity preceded some pulses of corticosteroid secretion but not others. Thus, while CRHPVN neurons display an ultradian rhythm of activity over the 24-hour day that is coordinated with behavioural arousal, the relationship between CRHPVN activity and pulses of corticosteroid secretion is not one-to-one. Significance StatementUltradian rhythms are present in many biological systems, however, the underlying neural mechanisms responsible for generating these rhythms is unclear. Corticotropin-releasing hormone (CRH) neurons control corticosteroid levels in the body as well as arousal and behaviour. Here we show that CRH neurons exhibit a pronounced ultradian rhythm in neural activity over the 24-hour day. CRH neural activity was highly correlated with, and predictive of, behavioral arousal. However, CRH neural activity was not as well correlated with pulses of corticosteroid secretion. Together, these data revel the patterns of CRH neuron activity over the 24-hour day and their relationship with behaviour and stress hormone secretion.

neuroscience↗

bioRxiv2024

Direct modulation of CRH nerve terminal function by noradrenaline and corticosterone.

Nerve terminals are the final point of regulation before neurosecretion. As such, neuromodulators acting on nerve terminals can exert significant influence on neural signalling. Hypothalamic corticotropin-releasing hormone (CRH) neurons send axonal projections to the median eminence where CRH is secreted to stimulate the hypothalamic-pituitary-adrenal (HPA) axis. Noradrenaline and corticosterone are two of the most important neuromodulators of HPA axis function; noradrenaline excites CRH neurons and corticosterone inhibits CRH neurons by negative feedback. Here, we used GCaMP6f Ca2+ imaging and measurement of nerve terminal CRH secretion using sniffer cells to determine whether these neuromodulators act directly on CRH nerve terminals. Contrary to expectations, noradrenaline inhibited action potential-dependent Ca2+ elevations in CRH nerve terminals and suppressed evoked CRH secretion. This inhibitory effect was blocked by 2-adrenoreceptor antagonism. Corticosterone also suppressed evoked CRH peptide secretion from nerve terminals, independent of action potential-dependent Ca2+ levels. This inhibition was prevented by the glucocorticoid receptor antagonist, RU486, and indicates that CRH nerve terminals may be a site of fast glucocorticoid negative feedback. Together these findings establish median eminence nerve terminals as a key site for regulation of the HPA axis. SignificanceCorticotropin-releasing hormone (CRH) neurons control the stress axis. Noradrenaline and corticosterone are two signalling molecules that control CRH neuron cell body excitability. However, their effect on CRH nerve terminal function is unknown. To examine this, we performed live Ca2+ imaging and measured CRH secretion. We found that noradrenaline suppressed nerve terminal Ca2+ levels and inhibited nerve terminal CRH secretion. Corticosterone had no effect on nerve terminal Ca2+, but inhibited nerve terminal CRH secretion. This suggests that CRH nerve terminals may be a site of fast corticosteroid negative feedback. Together, these data demonstrate that CRH nerve terminals are a critical point of regulation in the control of the stress axis.

neuroscience↗

bioRxiv2023

Estradiol regulates voltage-gated potassium currents in corticotropin-releasing hormone neurons

Corticotropin-releasing hormone (CRH) neurons are the primary neural population controlling the hypothalamic-pituitary-adrenal (HPA) axis and the secretion of adrenal stress hormones. Previous work has demonstrated that stress hormone secretion can be regulated by circulating levels of estradiol. However, the effect of estradiol on CRH neuron excitability is less clear. Here we show that chronic estradiol replacement following ovariectomy increases two types of potassium channel currents in CRH neurons; fast inactivating voltage-gated A-type K+ channel (IA) currents and non-inactivating M-type K+ currents (IM). Despite the increase in K+ currents following estradiol replacement, there was no overall change in CRH neuron spiking excitability assessed with either frequency-current curves or current ramps. Together, these data reveal a complex picture whereby ovariectomy and estradiol replacement differentially modulate distinct aspects of CRH neuron and HPA axis function. Summary statementChronic estradiol replacement in ovariectomised mice influences voltage-gated potassium channel function.

neuroscience↗