Biology subjects

Grundschober, C.

Publications and source records attributed to Grundschober, C..

3 recordsLinked to original sources

bioRxiv2025

Modelling the effect of V1a receptor antagonism and its potential therapeutic effect in circadian disorders

BackgroundThe suprachiasmatic nucleus (SCN) is the central circadian clock in mammals, regulating many daily physiological and behavioral rhythms. Dysregulation of the SCN is associated with various circadian disorders, highlighting the potential therapeutic benefits of targeting its neurons and output pathways. Vasopressin signaling is one of the main regulators of the synchronicity and the functional output of the SCN. MethodsWe investigated the effect of a single dose (30mg/kg) of the vasopressin V1a receptor (V1aR) antagonist, balovaptan, on resynchronization of locomotor activity rhythms in mice after a 6-hour phase advance of the light-dark cycle. To mechanistically model the effect of V1aR antagonism, we developed a mathematical framework simulating the SCN, its control of circadian biomarkers (melatonin, core body temperature), and the impact of V1aR antagonism. ResultsA single administration of the V1a antagonist balovaptan significantly accelerated resynchronization of locomotor activity rhythms to new light-dark cycles. To mechanistically understand this effect, we devised a mathematical model of the SCN that successfully captures this accelerated synchronization of circadian rhythms under V1aR antagonism. Additionally, the model replicates well-established SCN behaviors in both humans and rodents, including the phase response curve triggered by a light pulse at various circadian phases, and the desynchronization of the SCN observed in forced desynchronization experiments. Mechanistically, our model suggests that weakening vasopressin signaling via V1aR antagonism strengthens the SCNs resistance to internal desynchronization. Additionally, our model suggests a strong link between the endogenous period (tau) and the phase of circadian biomarkers, with longer tau values resulting in delayed biomarker rhythms. Importantly, the model predicts that V1aR antagonism induces a phase advance proportional to tau. The model predicts that individuals with longer endogenous periods, who consequently exhibit greater phase delays in their circadian rhythms, could experience more substantial phase advances in response to V1aR antagonism. DiscussionWe show that targeting V1aR is enough to cause a faster resynchronization to a new light-dark cycle in the jet lag paradigm and establish a computational framework for investigating its therapeutic potential in circadian rhythm disorders. This framework, adaptable to incorporate pharmacodynamic data, can be used to design clinical trials evaluating V1aR antagonism for treating circadian disorders.

neuroscience↗

bioRxiv2025

Neuromedin U Receptor 2 orchestrates sleep continuity and circadian entrainment

Neuromedin S signaling has recently been identified as a modulator of both sleep and circadian rhythms in the central nervous systems of mammals. Nevertheless, the involvement of its preferred receptor, NMUR2, in sleep and circadian regulation remains elusive. Here, employing its only selective antagonist R-PSOP, we demonstrate that NMUR2 function in the mouse brain is essential for physiological sleep architecture under baseline conditions, as well as for responses to homeostatic and circadian challenges. Using a combination of pharmacological, neuronal tagging, brain clearing and chemogenetic tools, we identified and functionally validated a group of PVH neurons as one of the targets mediating the effect of R-PSOP on sleep. These findings establish NMUR2 as a potential therapeutic target for the integral treatment of sleep and circadian neurological disorders. HIGHLIGHTSSelective NMUR2 antagonism via R-PSOP disrupts vigilance state continuity in a dose- and circadian phase-dependent manner R-PSOP administration delays circadian phase entrainment and hinders sleep homeostasis recovery PVH neurons are activated by R-PSOP and boost wake-to-NREM sleep transitions in the active period

neuroscience↗

bioRxiv2022

Selective oxytocin receptor activation prevents prefrontal circuit dysfunction and social behavioral alterations in response to chronic prefrontal cortex activation in rats

Social behavioral changes are a hallmark of several neurodevelopmental and neuropsychiatric conditions, nevertheless the underlying neural substrates of such dysfunction remain poorly understood. Building evidence points to the prefrontal cortex (PFC) as one of the key brain regions that orchestrates social behavior. We used this concept with the aim to develop a translational rat model of social-circuit dysfunction, the chronic PFC activation model (CPA). Chemogenetic designer receptor hM3Dq was used to induce chronic activation of the PFC over 10 days, and the behavioral and electrophysiological signatures of prolonged PFC hyperactivity were evaluated. To test the sensitivity of this model to pharmacological interventions on longer timescales, and validate its translational potential, the rats were treated with our novel highly selective oxytocin receptor (OXTR) agonist RO6958375, which has a significantly improved pharmacokinetic profile over oxytocin. CPA rats showed reduced sociability in the three-chamber sociability test, and a concomitant decrease in neuronal excitability and synaptic transmission within the PFC as measured by electrophysiological recordings in acute slice preparation. Sub-chronic treatment with a low dose of the novel OXTR agonist following CPA interferes with the emergence of PFC circuit dysfunction, abnormal social behavior and specific transcriptomic changes. These results demonstrate that sustained PFC hyperactivity modifies circuit characteristics and social behaviors in ways that can be modulated by selective OXTR activation and that this model may be used to understand the circuit recruitment of prosocial therapies in drug discovery.

neuroscience↗