Research

Paraventricular nucleus CRH neurons encode stress controllability and regulate defensive behavior selection

In humans and rodents, the perception of control during stressful events has lasting behavioral consequences. These consequences are apparent even in situations that are distinct from the stress context. Yet, how the brain links prior stressful experiences to subsequent behaviors remains poorly understood. Here we propose that CRH^PVN neurons encode stress controllability and contribute to shifts between active and passive innate defensive strategies.

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Hypothalamic CRH neurons orchestrate complex behaviours after stress

All organisms use innate behavioural and physiological programs to ensure survival. Yet, to have maximal adaptive benefit, these programs must be flexible to account for environmental changes. Here we show that CRH^PVN neurons in mice orchestrate a flexible repertoire of behaviours following acute stress, indicating that said neurons are part of a previously unexplored circuit matching behavioural patterns to environmental stress. Overactivity in this network in the absence of stress may result in context-inappropriate behavioural strategies.

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Stress gates an astrocytic energy reservoir to impair synaptic plasticity

Astrocytes support the energy demands of synaptic transmission and plasticity. Here we show that stress constrains the shuttling of glucose and lactate through astrocyte networks. Impaired substrate shuttling creates a barrier for neuronal access to an astrocytic energy reservoir, compromising long-term potentiation in the process. The stress-related gating of synaptic plasticity through astrocytic metabolic networks indicates a broader role for astrocyte bioenergetics in controlling experience-dependent information.

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Balancing tonic and phasic inhibition in hypothalamic corticotropin-releasing hormone neurons

CRH^PVN neurons are integratory hubs that regulate the endocrine response to stress. GABA inputs provide a basal inhibitory tone that constrains this system and glucocorticoids act as feedback controllers of CRH^PVN output. Here we show that efficient GABA clearance and autoinhibition control the balance between synaptic and extrasynaptic inhibition in CRH^PVN neurons, and that glucocorticoids shift the balance towards increased extrasynaptic inhibition.

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Noradrenaline is a stress-associated metaplastic signal at GABA synapses

Exposure to stress sensitizes synapses for future stressors. Here, we show that noradrenaline released in the CRH^PVN partially primes GABA synapses to undergo activity-dependent potentiation from inhibitory to excitatory following stress (i.e., metaplasticity). This change may contribute to neuroendocrine sensitization to future stressors.

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Glucocorticoid feedback uncovers retrograde opioid signaling at hypothalamic synapses

Glucocorticoids feed back to the brain, causing adaptations that prevent excessive hormonal responses to future challenges. Yet, how these changes occur remains unknown. Here, we show that glucocorticoid receptor activation of CRHPVN neurons following stress act as a metaplastic signal that allows opioid-dependant long-term depression of GABA synapses. These findings provide evidence for retrograde opioid signaling at neuroendocrine circuit synapses and may represent a potential mechanism for underlying glucocorticoid contributions to stress adaptation.

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Altered chloride homeostasis removes synaptic inhibitory constraint of the stress axis

In mammals, stress elicits a stereotyped endocrine response that requires an increase in CRH^PVN activation. The output of these cells is normally constrained by powerful GABA-mediated synaptic inhibition. We found that acute restraint stress in rats released the system from inhibitory synaptic drive by downregulating the transmembrane anion transporter KCC2. Therefore, our data indicate that CRH^PVN neurons integrate psychological cues to mount a stress-induced endocrine response by regulating anion gradients.

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Sex-specific vasopressin signaling buffers stress-dependent synaptic changes in female mice

Social networks can provide benefits both to the individual and the collective. In addition to transmitting information to others, social networks can provide an emotional buffer for distressed individuals. Yet, the underlying mechanism behind stress-buffering is poor. Here, we show that vasopressin, acting locally in CRH^PVN neurons, is a potential mediator of social buffering in female mice.

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Social transmission and buffering of synaptic changes after stress

Stress can trigger enduring changes in neural circuits and synapses. The behavioral and hormonal The behavioral and hormonal consequences of stress can be transmitted to others, but whether transmitted stress has similar effects on synapses is not known. We found that authentic stress and transmitted stress in mice primed CRH^PVN neurons, enabling the induction of metaplasticity at glutamate synapses. Our findings demonstrate that transmitted stress has the same lasting effects on glutamate synapses as authentic stress and reveal an unexpected role for CRH^PVN neurons in transmitting distress signals among individuals.

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Sexually dimorphic neuronal responses to social isolation

Many species use social networks to buffer the effects of stress. The mere absence of a social network, however, may also be stressful. We examined neuroendocrine, CRH^PVN neurons and found that social isolation alters the intrinsic properties of these cells in a sexually dimorphic fashion. Our observations demonstrate that social isolation, but not acute physical stress has sex-specific effects on CRH^PVN neurons.

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