Biology subjects

Fuzesi, T.

Publications and source records attributed to Fuzesi, T..

7 recordsLinked to original sources

bioRxiv2026

Exercise Leverages a Post-Stress Therapeutic Window in Hypothalamic CRH Neurons to Enable Recovery from Threat Sensitization

Exercise provides a range of benefits for physical and mental health. It relieves stress, yet paradoxically, it recruits the bodys stress response system. Here we show that activation of corticotropin-releasing hormone cells of the paraventricular nucleus of the hypothalamus (CRHPVN) and the endocrine arm of the stress axis is necessary, but not sufficient for the beneficial effects of exercise. Specifically, glucocorticoids act synergistically with brain-derived neurotrophic factor (BDNF) on CRHPVN cells during exercise to reverse behavioral and synaptic sensitization after stress. In the absence of exercise, optogenetic activation of the tropomyosin-related kinase B (TrkB) receptor after stress is sufficient to reverse behavioral sensitization and synaptic metaplasticity. Our findings reveal a novel, time-sensitive mechanism by which exercise alleviates the impact of acute stress.

neuroscience↗

bioRxiv2025

Hypothalamic CRH neurons gate rapid social appraisal of conspecifics

Successful navigation of the social environment requires rapid evaluation of conspecifics to distinguish safe from threatening encounters. While the corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRHPVN) are well known for orchestrating endocrine stress responses, their role in real-time social appraisal is unknown. Here, using fibre photometry and optogenetics during ethologically relevant social interactions, we show that CRHPVN neurons exhibit a rapid, transient increase in activity that precedes sniffing, an investigative behaviour through which mice gather social information. This transient signal scales with social context: it is heightened during interactions with unfamiliar and aggressive conspecifics and significantly reduced toward familiar partners. Inhibiting these neurons selectively diminished anogenital sniffing, demonstrating their necessity for optimal social evaluation. Strikingly, across repeated exposures to the same conspecific, behavioural investigation declined while CRHPVN activity remained robust, revealing a dissociation between neuronal and behavioural habituation. This persistence suggests that CRHPVN neurons encode stable neural representation of threat during social encounters. Together, our findings identify CRHPVN neurons as a fast, integrative node linking endocrine stress control to rapid social decision-making.

neuroscience↗

bioRxiv2025

Hypothalamic recurrent inhibition regulates functional states of stress effector neurons.

Stress triggers rapid and reversible shifts in vital physiological functions from homeostatic operation to emergency response. However, the neural mechanisms regulating such functional stress states remain poorly understood. Here we identify a novel recurrent inhibitory circuit governing functional states of key stress regulatory neurons: corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN). Microendoscopic calcium imaging in freely behaving mice revealed synchronized low-activity state at baselines and a reversible high-activity state during mild stress. Ensemble analysis indicated increased dimensionality of network dynamics during high-activity state. Computational modeling of calcium ensemble data, together with independent modeling of single-unit CRHPVN neurons spiking dynamics, converged to show that recurrent inhibition is a key circuit motif for stress-induced functional state transitions. Guided by model predictions, chemogenetic manipulations of PVN-projecting GABAergic neurons (PVN[->]GABA) revealed their roles in constraining CRHPVN neurons to low-activity state at baselines via a prolonged feedback inhibition. Unexpectedly, slow CRHergic excitation was dispensable for driving this prolonged feedback, whereas glutamatergic transmission predominated at CRH[->]PVN[->]GABA excitatory synapses. Incorporating these findings, we refined our computational model to include fast excitation and slow inhibition, yielding new predictions for circuit operation. Together, our results establish recurrent inhibition as a fundamental circuit motif controlling CRHPVN neurons functional states and highlight the value of iterative experiment-model integration in advancing understanding of neural circuits functions.

neuroscience↗

bioRxiv2025

Psilocybin induces sex- and context-specific recruitment of the stress axis

Psychedelics have reemerged as potential treatments for mental health disorders, yet their impact on stress-related brain regions remains poorly understood. Here, we provide the first real-time, in vivo evidence of psilocybin-induced neuronal activation, specifically in hypothalamic corticotropin-releasing hormone neurons. Notably, psilocybin elicited more pronounced responses in female mice and produced context-related alterations in threat assessment. Our findings provide valuable insight into the impact of psychedelics on a key stress center in the brain.

neuroscience↗

bioRxiv2023

Unilateral hippocampal stroke in freely behaving mice reveals sex differences in contralesional spreading depolarization and associated behavior

Ischemic stroke, brain tissue infarction following obstructed cerebral blood flow, leads to long-term neurological deficits and death. While neocortex is a commonly affected region with established preclinical models, less is known about deeper brain strokes, despite having unique neurological outcomes. We induced focal ischemic stroke while simultaneously monitors neuronal activity in awake behaving Thy1-GCaMP6f mice by delivering and collecting light through bilateral fiberoptic implants. Unilateral hippocampal stroke resulted in atypical mouse behavior coincident with ipsilesional terminal spreading depolarization (sustained increase in GCaMP6f fluorescence). Ischemia induced seizures that propagated to the contralesional hippocampus triggering a transient spreading depolarization (SD), predominantly in females. Hippocampal stroke impaired contextual fear conditioning acquired pre-stroke. Yet, 7 days post-stroke, contextual fear conditioning was only improved in mice with evidence of contralesional SD. Here, recovery of hippocampal function was lost by blunting peri-stroke SD with NMDAR antagonism, indicating that contralesional SD improves recovery following hippocampal stroke.

neuroscience↗

bioRxiv2022

Disruption of Tonic Endocannabinoid Signaling Triggers the Generation of a Stress Response

Endocannabinoid (eCB) signalling gates many aspects of the stress response, including the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is controlled by corticotropin releasing hormone (CRH) producing neurons in the paraventricular nucleus of the hypothalamus (PVN). Disruption of eCB signalling increases drive to the HPA axis, but the mechanisms subserving this process are poorly understood. Using an array of cellular, endocrine and behavioral readouts associated with activation of CRH neurons in the PVN, we evaluated the contributions of tonic eCB signaling to the generation of a stress response. The CB1 receptor antagonist/inverse agonist AM251, neutral antagonist NESS243, and NAPE PLD inhibitor LEI401 all uniformly increased c-fos in the PVN, unmasked stress-linked behaviors, such as grooming, and increased circulating CORT, recapitulating the effects of stress. Similar effects were also seen after direct administration of AM251 into the PVN, while optogenetic inhibition of PVN CRH neurons ameliorated stress-like behavioral changes produced by disruption of eCB signaling. These data indicate that under resting conditions, constitutive eCB signaling restricts activation of the HPA axis through local regulation of CRH neurons in the PVN.

neuroscience↗

bioRxiv2020

Adaptive synaptic plasticity maintains CRH neuron output during chronic glucocorticoid exposure

An increase in circulating glucocorticoids (CORT) is an essential part of the response to stress. Sustained elevations of CORT, however, have dramatic consequences on behavior, endocrine systems and peripheral organs. Critically, they dampen the endocrine response to acute challenges and decrease intrinsic excitability of corticotropin-releasing hormone neurons in the paraventricular nucleus (CRHPVN), suggesting key circuits may be less responsive to stress. Here, we make the surprising discovery that CRHPVN neurons harness a form of adaptive synaptic scaling to escape the persistent negative feedback pressure from CORT and maintain stable output in vivo. Specifically, there is an increase in glutamatergic drive to these cells that is mediated by a postsynaptic, multiplicative increase in synaptic strength. These findings suggest that dysfunctions associated with chronic stress may not be due to the primary actions of CORT, but instead reflect the emergence of synaptic adaptations as networks seek to re-establish intrinsic activity setpoints.

neuroscience↗