Biology subjects

Albrecht, U.

Publications and source records attributed to Albrecht, U..

6 recordsLinked to original sources

bioRxiv2026

Region specific Per1 induction dissociates circadian and mood responses to light

Light is a major environmental cue that synchronizes circadian rhythms and modulates affective behaviors. In mammals, photic information reaches multiple brain regions, including the suprachiasmatic nuclei (SCN), the master circadian pacemaker, and the lateral habenula (LHb), a structure implicated in mood-related behaviors such as despair. Both regions harbor the light-inducible clock gene Per1, which contributes to circadian phase shifting and behavioral regulation. Although light can simultaneously shift circadian phase and improve mood-related behaviors in mice and humans, it remains unclear whether these processes share a common mechanism. To address this question, we selectively deleted Per1 in SCN or LHb neurons of Per1-floxed mice using region-specific viral Cre recombinase delivery. Loss of Per1 in the SCN reduced light-induced phase advances at circadian time (CT) 22, whereas deletion in the LHb had no effect on phase shifting. In contrast, light-induced improvement of despair-like behavior was abolished by Per1 deletion in the LHb but preserved in SCN-targeted knockouts. Furthermore, according to RT-PCR, Per1-induction relied on different promoter usage. These findings demonstrate that the mood-related effects of light are independent from its circadian phase-shifting properties, revealing distinct Per1-dependent mechanisms through which light regulates behavior. This dissociation suggests that light-based therapies could be optimized by targeting mood-regulating pathways without necessarily altering circadian activity cycles. Author summaryThe present study identifies Per1 as a molecular node through which light exerts two distinct therapeutic actions: circadian phase resetting via the SCN and mood improvement via the LHb. This dissociation has major translational implications. It suggests that the antidepressant effects of light therapy--widely used in seasonal affective disorder (SAD) and increasingly in major depressive disorder (MDD)--do not require circadian phase shifting and instead rely on a Per1-dependent LHb pathway. Understanding this separation opens the door to more targeted, faster, and potentially more effective light-based interventions.

neuroscience↗

bioRxiv2024

Cyclin-dependent kinase 5 (Cdk5) activity is modulated by light and gates rapid phase shifts of the circadian clock

The circadian clock enables organisms to synchronize biochemical and physiological processes over a 24-hour period. Natural changes in lighting conditions, as well as artificial disruptions like jet lag or shift work, can advance or delay the clock phase to align physiology with the environment. Within the suprachiasmatic nucleus (SCN) of the hypothalamus, circadian timekeeping and resetting rely on both membrane depolarization and intracellular second-messenger signaling. Voltage-gated calcium channels (VGCCs) facilitate calcium influx in both processes, activating intracellular signaling pathways that trigger Period (Per) gene expression. However, the precise mechanism by which these processes are concertedly gated remains unknown. Our study demonstrates that cyclin-dependent kinase 5 (Cdk5) activity is modulated by light and regulates phase shifts of the circadian clock. We observed that knocking down Cdk5 in the SCN of mice affects phase delays but not phase advances. This is linked to uncontrolled calcium influx into SCN neurons and an unregulated protein kinase A (PKA) - calcium/calmodulin-dependent kinase (CaMK) - cAMP response element-binding protein (CREB) signaling pathway. Consequently, genes such as Per1 are not induced by light in the SCN of Cdk5 knock-down mice. Our experiments identified Cdk5 as a crucial light-modulated kinase that influences rapid clock phase adaptation. This finding elucidates how light responsiveness and clock phase coordination adapt activity onset to seasonal changes, jet lag, and shift work.

neuroscience↗

bioRxiv2021

CDK5 influences the organization of the Circadian Machinery in peripheral clocks.

Circadian rhythms are self-sustained physiological changes that drive rhythmicity within the 24-hours cycles. Posttranslational modifications (PMTs), such as protein phosphorylation, acetylation, sumoylation, and ubiquitination, are biochemical processes that modify protein structure and functions, ensuring circadian rhythm precision. For example, phosphorylation is considered the most important hallmark of rhythmicity from cyanobacteria to mammals. Cyclin-dependent kinase 5 (CDK5) has been shown to regulate the mammalian SCNs circadian clock via phosphorylation of PER2. Here, we show that CDK5 influences the clock machinery assembling, using immortalized mouse embryonic fibroblast as an in vitro model for studying the peripheral clock. In fact, the circadian period at the cellular level is lengthened. Furthermore, the clock-controlled genes expression amplitude is dampened in Cdk5 ko cell lines, while the phase is delayed about 4 hours. Taken together, we show in vitro that CDK5 is critically involved in regulating the peripheral clocks, influencing their temporal and spatial dynamics.

molecular biology↗

bioRxiv2020

Deletion of the Clock Gene Period2 (Per2) in Glial Cells Alters Mood-Related Behavior in Mice

The circadian clock regulates many biochemical and physiological pathways, and lack of clock genes, such as Period (Per) 2, do not only affect circadian activity rhythms, but can also modulate food-anticipatory and mood-related behaviors. However, it is not known how cell-type specific expression of Per2 contributes to these behaviors. In this study, we find that Per2 in glial cells is important for balancing mood-related behaviors. Genetic and adeno-associated virus-mediated deletion of Per2 in glial cells of mice leads to a depression-resistant phenotype, as manifested in reduced despair and anxiety. This is paralleled by an increase of the GABA transporter 3 (Gat3) mRNA and a reduction of glutamate levels in the nucleus accumbens (NAc). Exclusive deletion of Per2 in glia of the NAc reduced despair, but had no influence on anxiety. Our data provide strong evidence for an important role of glial Per2 in regulating mood-related behavior.

neuroscience↗

bioRxiv2020

Light affects behavioral despair involving the clock gene Period 1

Light at night has strong effects on physiology and behavior of mammals. It affects mood in humans, which is exploited as light therapy, and has been shown to reset the circadian clock in the suprachiasmatic nuclei (SCN). This resetting is paramount to align physiological and biochemical timing to the environmental light-dark cycle. Here we provide evidence that light affects mood-related behaviors also in mice by activating the clock gene Period1 (Per1) in the lateral habenula (LHb), a brain region known to modulate mood-related behaviors. A light pulse given at ZT22 to wild type mice caused profound changes of gene expression in the mesolimbic dopaminergic system including the nucleus accumbens (NAc). Sensory perception of smell and G-protein coupled receptor signaling was affected the most in this brain region. Interestingly, most of these genes were not affected in Per1 knock-out animals, indicating that induction of Per1 by light serves as a filter for light-mediated gene induction in the brain. Taken together we show that light affects mood-related behavior in mice at least in part via induction of Per1 in the LHb with consequences on signaling mechanisms in the mesolimbic dopaminergic system.

genetics↗

bioRxiv2019

Cyclin Dependent Kinase 5 (CDK5) Regulates the Circadian Clock

Circadian oscillations emerge from transcriptional and post-translational feedback loops. An important step in generating rhythmicity is the translocation of clock components into the nucleus, which is regulated in many cases by kinases. In mammals, the kinase promoting the nuclear import of the key clock component Period 2 (PER2) is unknown. Here we show that the cyclin-dependent kinase 5 (CDK5) regulates the mammalian circadian clock involving phosphorylation of PER2. Knock-down of Cdk5 in the suprachiasmatic nuclei (SCN), the main coordinator site of the mammalian circadian system, shortened the free-running period in mice. CDK5 phosphorylated PER2 at serine residue 394 (S394) in a diurnal fashion. This phosphorylation facilitated interaction with Cryptochrome 1 (CRY1) and nuclear entry of the PER2-CRY1 complex. Taken together, we found that CDK5 drives nuclear entry of PER2, which is critical for establishing an adequate circadian period of the molecular circadian cycle. Therefore, CDK5 is critically involved in the regulation of the circadian clock and may represent a link to various diseases affected by the circadian clock.

neuroscience↗