Key points Corticotroph cells of the anterior pituitary are electrically excitable and are an integral component of the hypothalamic‐pituitary‐adrenal axis which governs the neuroendocrine response to stress.Corticotrophs display predominantly single spike activity under basal conditions that transition to complex bursting behaviours upon stimulation by the hypothalamic secretagogues corticotrophin‐releasing hormone (CRH) and arginine vasopressin (AVP); however, the underlying mechanisms controlling bursting are unknown.In this study, we show that CRH and AVP induce different patterns of corticotroph electrical activity, and we use an electrophysiological approach combined with mathematical modelling to show the ionic mechanisms for these differential effects.The data reveal that secretagogue‐induced bursting is dependent on large conductance Ca2+‐activated K+ (BK) channels and is driven primarily by CRH whereas AVP promotes an increase in single‐spike frequency through BK‐independent pathways involving activation of non‐selective cation conductances.As corticotroph excitability is differentially regulated by CRH and AVP this may allow corticotrophs to respond appropriately to different stressors. AbstractAnterior pituitary corticotroph cells are a central component of the hypothalamic‐pituitary‐adrenal (HPA) axis essential for the neuroendocrine response to stress. Corticotrophs are excitable cells that receive input from two hypothalamic secretagogues, corticotrophin‐releasing hormone (CRH) and arginine vasopressin (AVP) to control the release of adrenocorticotrophic hormone (ACTH). Although corticotrophs are spontaneously active and increase in excitability in response to CRH and AVP the patterns of electrical excitability and underlying ionic conductances are poorly understood. In this study, we have used electrophysiological, pharmacological and genetic approaches coupled with mathematical modelling to investigate whether CRH and AVP promote distinct patterns of electrical excitability and to interrogate the role of large conductance calcium‐ and voltage‐activated potassium (BK) channels in spontaneous and secretagogue‐induced activity. We reveal that BK channels do not play a significant role in the generation of spontaneous activity but are critical for the transition to bursting in response to CRH. In contrast, AVP promotes an increase in single spike frequency, a mechanism independent of BK channels but dependent on background non‐selective conductances. Co‐stimulation with CRH and AVP results in complex patterns of excitability including increases in both single spike frequency and bursting. The ability of corticotroph excitability to be differentially regulated by hypothalamic secretagogues provides a mechanism for differential control of corticotroph excitability in response to different stressors.

Key points r Corticotroph cells of the anterior pituitary are electrically excitable and are an integral component of the hypothalamic-pituitary-adrenal axis which governs the neuroendocrine response to stress. r Corticotrophs display predominantly single spike activity under basal conditions that transition to complex bursting behaviours upon stimulation by the hypothalamic secretagogues corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP); however, the underlying mechanisms controlling bursting are unknown. r In this study, we show that CRH and AVP induce different patterns of corticotroph electrical activity, and we use an electrophysiological approach combined with mathematical modelling to show the ionic mechanisms for these differential effects. r The data reveal that secretagogue-induced bursting is dependent on large conductance Ca 2+-activated K + (BK) channels and is driven primarily by CRH whereas AVP promotes an increase in single-spike frequency through BK-independent pathways involving activation of non-selective cation conductances. r As corticotroph excitability is differentially regulated by CRH and AVP this may allow cortico-trophs to respond appropriately to different stressors. Abstract Anterior pituitary corticotroph cells are a central component of the hypothalamic-pituitary-adrenal (HPA) axis essential for the neuroendocrine response to stress. Corticotrophs are excitable cells that receive input from two hypothalamic secretagogues, corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) to control the release of adrenocorticotrophic hormone (ACTH). Although corticotrophs are spontaneously active and increase in excitability in response to CRH and AVP the patterns of electrical excitability and underlying ionic conductances are poorly understood. In this study, we have used electrophysiological, pharmacological and genetic approaches coupled with mathematical modelling to investigate whether CRH and AVP promote distinct patterns of electrical excitability and to interrogate the role of large conductance calcium-and voltage-activated potassium (BK) channels in spontaneous and secretagogue-induced activity. We reveal that BK channels do not play a significant role in the generation of spontaneous activity but are critical for the transition to bursting in response to CRH. In contrast, AVP promotes an increase in single spike frequency, a mechanism independent of BK channels but dependent on background non-selective conductances. Co-stimulation with CRH and AVP results in complex patterns of excitability including increases in both single spike frequency and bursting. The ability of corticotroph excitability to be differentially regulated by hypothalamic secretagogues provides a mechanism for differential control of corticotroph excitability in response to different stressors.

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The Hodgkin-Huxley (HH) model is the basis for numerous neural models. There are two negative feedback processes in the HH model that regulate rhythmic spiking. The first is an outward current with an activation variable n that has an opposite influence to the excitatory inward current and therefore provides subtractive negative feedback. The other is the inactivation of an inward current with an inactivation variable h that reduces the amount of positive feedback and therefore provides divisive feedback. Rhythmic spiking can be obtained with either negative feedback process, so we ask what is gained by having two feedback processes. We also ask how the different negative feedback processes contribute to spiking. We show that having two negative feedback processes makes the HH model more robust to changes in applied currents and conductance densities than models that possess only one negative feedback variable. We also show that the contributions made by the subtractive and divisive feedback variables are not static, but depend on time scales and conductance values. In particular, they contribute differently to the dynamics in Type I versus Type II neurons.