Biology subjects

Obrietan, K.

Publications and source records attributed to Obrietan, K..

4 recordsLinked to original sources

bioRxiv2026

Loss of PEA-15 Alters ERK/MAPK Signaling and Circadian Function in the Suprachiasmatic Nucleus

Circadian rhythms are a fundamental biological process that coordinates physiological functions, behavior, and metabolism with an approximately 24-hour periodicity. At the center of the mammalian circadian timing system is the suprachiasmatic nucleus (SCN) of the hypothalamus, which generates robust, clock-gated neuronal output that establishes the temporal organization of cellular and physiological processes throughout the body. Our previous work demonstrated that the scaffold protein PEA-15 (phosphoprotein enriched in astrocytes 15) is highly expressed in the SCN and dynamically interacts with ERK, a key effector kinase of the MAPK pathway, to regulate its subcellular localization. Given the important role of ERK/MAPK signaling in circadian timing and photic entrainment, we extended this work using PEA-15 knockout (PEA-15-/-) mice to determine how loss of PEA-15 affects circadian timing, entrainment, and ERK signaling within the SCN. At the cellular level, both clock-gated and light-evoked ERK activation were significantly reduced in PEA-15-/- mice compared with wild-type controls. Under constant darkness, PEA-15-/- mice exhibited a significantly shorter free-running period and reduced locomotor activity relative to wild-type animals. Assessment of circadian entrainment using jet-lag resetting and Aschoff type I light-pulse paradigms revealed a blunted phase-delay response to light and an accelerated rate of entrainment to a phase-advancing light stimulus. Thus, loss of PEA-15 alters multiple properties of the SCN clock, including its intrinsic period and its responsiveness to photic input, with effects that depend on the direction of phase resetting. Collectively, these findings identify PEA-15 as an important regulator of SCN circadian function and implicate ERK/MAPK signaling as one mechanism through which PEA-15 modulates clock timing and photic entrainment.

neuroscience↗

bioRxiv2025

Cellular- and systems-level profiling of amyloid-beta effects on circadian timing

Disruption of the circadian timing system has been reported in the preclinical phase of Alzheimers disease (AD) and is a well-characterized component of mid- and late-stage AD. Given the distributed nature of the circadian timing system, with a central pacemaker in the suprachiasmatic nucleus (SCN) and peripheral clocks throughout the brain, understanding how AD affects this system has been challenging. To investigate how AD may disrupt circadian physiology, we focused on the amyloid-beta peptide, a key contributor to familial early-onset AD. Using the 5xFAD mouse model and ex vivo single-cell profiling, we examined how amyloid-beta influences clock timing in both SCN neurons and hippocampal neuronal populations. Circadian profiling of 5xFAD mice (4-and 8-months-old) showed only modest changes in key clock timing properties, including a shortening of the SCN rhythm. Interestingly, the mice showed enhanced rates of re-entrainment to changes in the light cycle, suggesting that elevated amyloid-beta levels increase the sensitivity of the SCN clock to light. Further, using both in vitro SCN slice explant and dispersed SCN culture models, the exogenous administration of oligomerized amyloid-beta had no significant effect on inherent clock timing capacity. In contrast, the timing properties of cultured hippocampal neurons showed a dose-dependent sensitivity to amyloid-beta. This included an elevated mesor and an increased rhythm amplitude. These findings reveal a divergence in amyloid-beta sensitivity between the central SCN clock and peripheral oscillators. This raises the possibility that circadian disruptions in AD may stem from both the destabilization and decoupling of peripheral oscillators from the central timing properties of the SCN.

neuroscience↗

bioRxiv2025

Circadian timing and entrainment properties of the SCN pacemaker in the PS19 mouse model of Tau pathology

Tauopathies are a group of neurodegenerative disorders caused by the misfolded microtubule-associated protein tau (MAPT), leading to its abnormal accumulation and hyperphosphorylation, and resulting in neuronal dysfunction and death. Tauopathy patients also experience disruptions to circadian rhythms of behavior and sleep. The connection between tau pathology and circadian dysfunction is not well understood, especially regarding the role of the suprachiasmatic nucleus (SCN), the brains central circadian pacemaker. Here, we conducted histological and functional analyses of the SCN in the PS19 (Prnp-huMAPT*P301S) mouse model of tauopathy. The SCN of PS19 mice had accumulation of phosphorylated tau as early as 2 months of age, and tau pathology was detected in both major neuronal subpopulations of the SCN: VIPergic (core) and AVPergic (shell) neurons. To assess SCN timing and entrainment properties, daily locomotor activity was monitored in PS19 and wild-type (WT) mice from 3 to 11 months-of-age. Activity profiles, rates of re-entrainment to changes in the light/dark cycle, and intrinsic circadian timing properties were unchanged in PS19 mice compared to age-matched WT mice. Finally, profiling circadian gene expression in tau fibril-seeded SCN explants from PS19 and WT mice did not reveal differences in network-level oscillator properties. Together, these findings suggest that tau pathology within the SCN is not sufficient to trigger marked disruptions of core circadian timing mechanisms in this tauopathy model. Further, these results raise the possibility that circadian disruptions in tauopathies arise from dysfunction in SCN-gated output pathways or downstream clock-gated circuits rather than the SCN oscillator itself.

neuroscience↗

bioRxiv2020

Pharmacological prevention of neonatal opioid withdrawal in a pregnant guinea pig model.

Newborns exposed to prenatal opioids often experience intense postnatal withdrawal after cessation of the opioid, called neonatal opioid withdrawal syndrome (NOWS), with limited pre- and postnatal therapeutic options available. In a prior study in pregnant mice we demonstrated that the peripherally selective neutral opioid antagonist, 6{beta}-naltrexol (6BN), is a promising drug candidate for preventive prenatal treatment of NOWS. Here, we have developed methadone (MTD) treated pregnant guinea pigs as a physiologically more suitable model, enabling detection of robust spontaneous neonatal withdrawal. Prenatal MTD significantly aggravates two classic maternal separation stress behaviors in newborn guinea pigs: calling (vocalizing) and searching (locomotion) - natural attachment behaviors thought to be controlled by the endogenous opioid system. In addition, prenatal MTD significantly increases the levels of plasma cortisol in newborns, showing that cessation of MTD at birth engages the hypothalamic-pituitary-adrenal (HPA) axis. We find that co-administration of 6BN with MTD prevents these withdrawal symptoms in newborn pups with extreme potency (ID50 [~]0.02 mg/kg), at doses unlikely to induce maternal or fetal withdrawal or to interfere with opioid antinociception based on many prior studies. Furthermore, we demonstrate a similarly high potency of 6BN in preventing opioid withdrawal in adult guinea pigs (ID50 = 0.01 mg/kg). This suggests a novel receptor mechanism to account for the selectively high potency of 6BN to suppress opioid dependence as compared to its low potency as a classical opioid antagonist. In conclusion, 6BN is an attractive compound for development of a preventive therapy for NOWS.

pharmacology and toxicology↗