State-dependent activity dynamics of hypothalamic stress effector neurons
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Curated by eLife
Evaluation Summary:
The observations from high quality in vivo and in vitro recordings of tagged CHR neurons are supported by a computational model that suggests feedback inhibition may regulate the activity patterns of CRH neurons in distinct states, and represent an important contribution. The authors also present an unexpected observation that uncovers interesting neural dynamics that will provide the impetus for new studies exploring firing characteristics in discrete physiological and emotional states. Previous work reaching an opposite conclusion and likely effects of urethane on in vivo recordings are not discussed.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)
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Abstract
The stress response necessitates an immediate boost in vital physiological functions from their homeostatic operation to an elevated emergency response. However, the neural mechanisms underlying this state-dependent change remain largely unknown. Using a combination of in vivo and ex vivo electrophysiology with computational modeling, we report that corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN), the effector neurons of hormonal stress response, rapidly transition between distinct activity states through recurrent inhibition. Specifically, in vivo optrode recording shows that under non-stress conditions, CRH PVN neurons often fire with rhythmic brief bursts (RB), which, somewhat counterintuitively, constrains firing rate due to long (~2 s) interburst intervals. Stressful stimuli rapidly switch RB to continuous single spiking (SS), permitting a large increase in firing rate. A spiking network model shows that recurrent inhibition can control this activity-state switch, and more broadly the gain of spiking responses to excitatory inputs. In biological CRH PVN neurons ex vivo, the injection of whole-cell currents derived from our computational model recreates the in vivo-like switch between RB and SS, providing direct evidence that physiologically relevant network inputs enable state-dependent computation in single neurons. Together, we present a novel mechanism for state-dependent activity dynamics in CRH PVN neurons.
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Evaluation Summary:
The observations from high quality in vivo and in vitro recordings of tagged CHR neurons are supported by a computational model that suggests feedback inhibition may regulate the activity patterns of CRH neurons in distinct states, and represent an important contribution. The authors also present an unexpected observation that uncovers interesting neural dynamics that will provide the impetus for new studies exploring firing characteristics in discrete physiological and emotional states. Previous work reaching an opposite conclusion and likely effects of urethane on in vivo recordings are not discussed.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed …
Evaluation Summary:
The observations from high quality in vivo and in vitro recordings of tagged CHR neurons are supported by a computational model that suggests feedback inhibition may regulate the activity patterns of CRH neurons in distinct states, and represent an important contribution. The authors also present an unexpected observation that uncovers interesting neural dynamics that will provide the impetus for new studies exploring firing characteristics in discrete physiological and emotional states. Previous work reaching an opposite conclusion and likely effects of urethane on in vivo recordings are not discussed.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
The paper by Ichiyama et al. characterizes how CRH-expressing neurons of the paraventricular nucleus of hypothalamus (PVN) alter their firing characteristics during an acutely stressful experience. The authors first use in vivo single-unit extracellular recordings from optogenetically identified CRH neurons in PVN, before and during noxious stimulation of the sciatic nerve. CRH neurons fire in bursts during basal conditions that included long interburst non-spiking periods. During the stressful stimulus, instead, these cells stopped bursting, became tonically active and had increased overall firing rates. An in silico network model simulated the PVn network and used realistic synaptic currents injected into CRH cells. This model illustrated how simple recurrent inhibition can act as a switch changing the …
Reviewer #1 (Public Review):
The paper by Ichiyama et al. characterizes how CRH-expressing neurons of the paraventricular nucleus of hypothalamus (PVN) alter their firing characteristics during an acutely stressful experience. The authors first use in vivo single-unit extracellular recordings from optogenetically identified CRH neurons in PVN, before and during noxious stimulation of the sciatic nerve. CRH neurons fire in bursts during basal conditions that included long interburst non-spiking periods. During the stressful stimulus, instead, these cells stopped bursting, became tonically active and had increased overall firing rates. An in silico network model simulated the PVn network and used realistic synaptic currents injected into CRH cells. This model illustrated how simple recurrent inhibition can act as a switch changing the cells from one firing pattern to the other.
The experiments are carried out with care and the data are of high quality. This manuscript represents the first time to my knowledge that electrophysiological recordings have been used in vivo to track the firing of individual CRH neurons before and during acute stress. The authors then created a network model to test the idea that synaptic currents may shift the firing patterns of these cells from a bursting to a tonic firing state, and present evidence that a drop in GABAergic inhibition coupled with an increase in spike-triggered adaptation mimicked the effects seen in vivo after stress. Taking this information back to neurons in brain slices, the authors use their model to drive similar changes in spike patterns by altering relevant synaptic and intrinsic currents.
There is some concern that previous work examining the role of other intrinsic currents in burst behavior as well as in vitro data from CRH neurons in slices after stress are not discussed or considered.
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Reviewer #2 (Public Review):
Ichiyama et al. revealed the neural mechanism of state-dependent change by recording from corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) and by in silico remodeling. The firing pattern in CRHPVN neurons is rhythmic brief burst (RB) and continuous single spike (SS). The authors revealed that recurrent inhibition is involved in the activity state switch between RB and SS. In silico remodeling will help to understand changing of the firing pattern in the peptidergic neurons in the hypothalamus and the neural regulatory mechanism of stress response by CRHPVN neurons.
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Reviewer #3 (Public Review):
This manuscript by Ichiyama et al examines the firing properties of identified CRH neurons in the paraventricular nucleus of the hypothalamus in anaesthetized mice. They make a rather surprising observation that CRH neurons show high frequency, albeit brief, rhythmic bursts in unstressed mice only. A brief stressor converts cell activity into a more sustained, single spike firing mode. The authors support their observations with a computational model that suggests feedback inhibition may regulate the activity patterns of CRH neurons in distinct states.
As the authors correctly note, this is the first electrophysiological study showing spike activity in CRH neurons. Although there have been other studies using Ca imaging, none have shown spike activity. Part of the challenge is obtaining high-quality …
Reviewer #3 (Public Review):
This manuscript by Ichiyama et al examines the firing properties of identified CRH neurons in the paraventricular nucleus of the hypothalamus in anaesthetized mice. They make a rather surprising observation that CRH neurons show high frequency, albeit brief, rhythmic bursts in unstressed mice only. A brief stressor converts cell activity into a more sustained, single spike firing mode. The authors support their observations with a computational model that suggests feedback inhibition may regulate the activity patterns of CRH neurons in distinct states.
As the authors correctly note, this is the first electrophysiological study showing spike activity in CRH neurons. Although there have been other studies using Ca imaging, none have shown spike activity. Part of the challenge is obtaining high-quality recordings from a deep structure like the PVN; the other is identifying individual cells with high confidence when they are surrounded by other, non-CRH cells.
This is an important contribution that furthers our understanding of CRH activity in vivo. It is also an unexpected observation that uncovers interesting neural dynamics that will provide the impetus for new studies exploring firing characteristics in discrete physiological and emotional states. The work will be influential. It is critical, therefore, that the authors are certain about the identity of the neurons.
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