Stress-related synaptic plasticity in the hypothalamus.

Stress necessitates an immediate engagement of multiple neural and endocrine systems. However, exposure to a single stressor causes adaptive changes that modify responses to subsequent stressors. Recent studies examining synapses onto neuroendocrine cells in the paraventricular nucleus of the hypothalamus demonstrate that stressful experiences leave indelible marks that alter the ability of these synapses to undergo plasticity. These adaptations include a unique form of metaplasticity at glutamatergic synapses, bidirectional changes in endocannabinoid signalling and bidirectional changes in strength at GABAergic synapses that rely on distinct temporal windows following stress. This rich repertoire of plasticity is likely to represent an important building block for dynamic, experience-dependent modulation of neuroendocrine stress adaptation.

Experience salience gates endocannabinoid signaling at hypothalamic synapses.

Alterations in synaptic endocannabinoid signaling are a widespread neurobiological consequence of many in vivo experiences, including stress. Here, we report that stressor salience is critical for bidirectionally modifying presynaptic CB-1 receptor (CB1R) function at hypothalamic GABA synapses controlling the neuroendocrine stress axis in male rats. While repetitive, predictable stressor exposure impairs presynaptic CB1R function, these changes are rapidly reversed upon exposure to a high salience experience such as novel stress or by manipulations that enhance neural activity levels in vivo or in vitro. Together these data demonstrate that experience salience, through alterations in afferent synaptic activity, induces rapid changes in endocannabinoid signaling.

Projection-Specific Dynamic Regulation of Inhibition in Amygdala Micro-Circuits.

Cannabinoid receptor type 1 (CB1R)-expressing CCK interneurons are key regulators of cortical circuits. Here we report that retrograde endocannabinoid signaling and CB1R-mediated regulation of inhibitory synaptic transmission onto basal amygdala principal neurons strongly depend on principal neuron projection target. Projection-specific asymmetries in the regulation of local inhibitory micro-circuits may contribute to the selective activation of distinct amygdala output pathways during behavioral changes.

Hypothalamic CRH neurons orchestrate complex behaviours after stress.

All organisms possess innate behavioural and physiological programmes that ensure survival. In order to have maximum adaptive benefit, these programmes must be sufficiently flexible to account for changes in the environment. Here we show that hypothalamic CRH neurons orchestrate an environmentally flexible repertoire of behaviours that emerge after acute stress in mice. Optical silencing of CRH neurons disrupts the organization of individual behaviours after acute stress. These behavioural patterns shift according to the environment after stress, but this environmental sensitivity is blunted by activation of PVN CRH neurons. These findings provide evidence that PVN CRH cells are part of a previously unexplored circuit that matches precise behavioural patterns to environmental context following stress. Overactivity in this network in the absence of stress may contribute to environmental ambivalence, resulting in context-inappropriate behavioural strategies.

Changing the tune: plasticity and adaptation of retrograde signals.

Retrograde signaling is a fundamental means by which neurons communicate. The acceptance of this statement has required a revision of how we view transmission and storage of information at the synapse. Although there is a substantial body of literature on the diverse molecules that serve as retrograde signals, less is known about how retrograde signal capacity can be modified. Is retrograde signaling plastic? How does this plasticity manifest? Are there behavioral correlates that may bias a neuron towards 'changing its tune', retrogradely speaking, of course? Here, we review recent findings that retrograde signaling is a highly labile process that adds additional layers of complexity that must be untangled to understand information processing in the nervous system.

Characterization of corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus of Crh-IRES-Cre mutant mice.

Corticotropin-releasing hormone (CRH)-containing neurons in the paraventricular nucleus of the hypothalamus (PVN) initiate and control neuroendocrine responses to psychogenic and physical stress. Investigations into the physiology of CRH neurons, however, have been hampered by the lack of tools for adequately targeting or visualizing this cell population. Here we characterize CRH neurons in the PVN of mice that express tdTomato fluorophore, generated by crosses of recently developed Crh-IRES-Cre driver and Ai14 Cre-reporter mouse strains. tdTomato containing PVN neurons in Crh-IRES-Cre;Ai14 mice are readily visualized without secondary-detection methods. These neurons are predominantly neuroendocrine and abundantly express CRH protein, but not other PVN phenotypic neuropeptides. After an acute stress, a large majority of tdTomato cells express neuronal activation marker c-Fos. Finally, tdTomato PVN neurons exhibit homogenous intrinsic biophysical and synaptic properties, and can be optogenetically manipulated by viral Cre-driven expression of channelrhodopsin. These observations highlight basic cell-type characteristics of CRH neurons in a mutant mouse, providing validation for its future use in probing neurophysiology of endocrine stress responses.

Glucocorticoid feedback uncovers retrograde opioid signaling at hypothalamic synapses.

Stressful experience initiates a neuroendocrine response culminating in the release of glucocorticoid hormones into the blood. Glucocorticoids feed back to the brain, causing adaptations that prevent excessive hormone responses to subsequent challenges. How these changes occur remains unknown. We found that glucocorticoid receptor activation in rodent hypothalamic neuroendocrine neurons following in vivo stress is a metaplastic signal that allows GABA synapses to undergo activity-dependent long-term depression (LTDGABA). LTDGABA was unmasked through glucocorticoid receptor-dependent inhibition of Regulator of G protein Signaling 4 (RGS4), which amplified signaling through postsynaptic metabotropic glutamate receptors. This drove somatodendritic opioid release, resulting in a persistent retrograde suppression of synaptic transmission through presynaptic µ receptors. Together, our data provide new evidence for retrograde opioid signaling at synapses in neuroendocrine circuits and represent a potential mechanism underlying glucocorticoid contributions to stress adaptation.

Noradrenaline is a stress-associated metaplastic signal at GABA synapses.

Exposure to a stressor sensitizes behavioral and hormonal responses to future stressors. Stress-associated release of noradrenaline enhances the capacity of central synapses to show plasticity (metaplasticity). We found noradrenaline-dependent metaplasticity at GABA synapses in the paraventricular nucleus of the hypothalamus in rat and mouse that controls the hypothalamic-pituitary-adrenal axis. In vivo stress exposure was required for these synapses to undergo activity-dependent long-term potentiation (LTPGABA). The activation of ß-adrenergic receptors during stress functionally upregulated metabotropic glutamate receptor 1 (mGluR1), allowing for mGluR1-dependent LTPGABA during afferent bursts. LTPGABA was expressed postsynaptically and manifested as the emergence of new functional synapses. Our findings provide, to the best of our knowledge, the first demonstration that noradrenaline release during an in vivo challenge alters information storage capacity at GABA synapses. Because these GABA synapses become excitatory following acute stress, this metaplasticity may contribute to neuroendocrine sensitization to stress.