We use a multi-pronged approach — ex vivo patch clamp recordings, in vivo single cell imaging, optogenetics, behavioural manipulations, and computational tools — to probe brain function from single synapses to hundreds of neurons in awake, freely behaving animals.
Our goal is to understand how physiological and psychological challenges lead to long-term changes within the brain. We primarily focus on neurons within the hypothalamus (CRHPVN) which coordinate the mammalian response to stress.
We are particularly interested in how stress imprints neural circuits to alter subsequent stress responses.
Below are three distinct themes within our research: control, adaptation, and social behaviour.

Control
CRHPVN neurons in the hypothalamus are the canonical controllers of the endocrine response to stress. Based on findings from our lab and others, we propose an additional role for these cells in gating state transitions for initiating stress-related behaviours.
These ideas are reviewed here.
Key Papers

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 CRHPVN neurons encode stress controllability and contribute to shifts between active and passive innate defensive strategies.
Access the article here.

Visual-looming shadow task with in-vivo calcium activity monitoring to assess defensive behaviours in mice
There has been a movement in recent years towards the adoption of more naturalistic experimental regimes for the study of behavior and its underlying neural architecture. Here we provide a protocol that allows experimenters working with mice to mimic a looming and advancing predatory threat from the sky.
Access the article here.

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 CRHPVN 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.
Access the article here.

Adaptation
Stress necessitates the immediate engagement of multiple neural and endocrine systems while also sensitizing behavioral and hormonal responses to future stressors. We have described several synaptic and cellular mechanisms that are modified by a single stressor, demonstrating that stress leaves lasting alterations on synaptic plasticity potential.
A review of this rich repertoire of plasticity that likely represents an important building block for dynamic, experience-dependent modulation of neuroendocrine stress adaptation can be found here.
Key Papers

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.
Access the article here.

Balancing tonic and phasic inhibition in hypothalamic corticotropin-releasing hormone neurons
CRHPVN 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 CRHPVN output. Here we show that efficient GABA clearance and autoinhibition control the balance between synaptic and extrasynaptic inhibition in CRHPVN neurons, and that glucocorticoids shift the balance towards increased extrasynaptic inhibition.
Access the article here.

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 CRHPVN 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.
Access the full here.

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.
Access the article here.

Altered chloride homeostasis removes synaptic inhibitory constraint of the stress axis
In mammals, stress elicits a stereotyped endocrine response that requires an increase in CRHPVN 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 CRHPVN neurons integrate psychological cues to mount a stress-induced endocrine response by regulating anion gradients.
Access the article here.

Social Behaviour
Social interactions promote the communication of explicit and implicit information between individuals. Implicit or subconscious sharing of cues can be useful in conveying affective states. Knowing the affective state of others can guide future interactions, while an inability to decipher another’s affective state is a core feature of conditions like autism spectrum disorder.
A review of this topic can be found here.
Key Papers

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 CRHPVN neurons, is a potential mediator of social buffering in female mice.
Access the article here.

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 CRHPVN 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 CRHPVN neurons in transmitting distress signals among individuals.
Access the article here.

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, CRHPVN 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 CRHPVN neurons.
Access the article here.


© 2022 Stressynomics
Research funding:
Canadian Institutes for Health Research
Natural Sciences and Engineering Research Council
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