Biology subjects

Philipsen, A.

Publications and source records attributed to Philipsen, A..

4 recordsLinked to original sources

bioRxiv2024

Spermidine alleviates depression via control of the stress response

Depression is a stress-associated disorder, and it represents a major global health issue. Its pathophysiology is complex and remains insufficiently understood, with current medications often showing limited efficacy and undesirable side effects. Here, we identify imbalanced polyamine levels and dysregulated autophagy as key components of the acute stress response in humans, and as hallmarks of chronic stress and depressive disorders. Moreover, conventional antidepressant pharmacotherapy increases endogenous plasma concentrations of the polyamine spermidine exclusively in patients who respond to the treatment, suggesting a link between spermidine and successful outcomes. In a clinical trial, involving drug-naive depressed individuals, three weeks of spermidine supplementation increased autophagy and alleviated symptoms of depression. Behavioral and mechanistic findings of spermidine supplementation were validated in various mouse stress and depression models. In summary, spermidine supplementation mitigates polyamine dysregulation and stimulates autophagy under pathological stress conditions, offering a novel and well-tolerated treatment approach for stress-related depressive disorders.

neuroscience↗

bioRxiv2021

Estradiol and oxytocin modulate sex differences in hippocampal reactivity and episodic memory

Considerable evidence supports sex differences in episodic memory, which may translate to heightened vulnerability to stress- and trauma-related disorders in women. The hormones estradiol and oxytocin both affect episodic memory, but possible underlying hormonal interactions have not been systemically tested in humans. To this end, healthy women (n = 111) and men (n = 115) received estradiol gel (2 mg) or placebo before the administration of intranasal oxytocin (24 IU) or placebo in a randomized, placebo-controlled, parallel-group functional magnetic resonance imaging (fMRI) study. In the fMRI session, participants viewed positive, neutral, and negative scenes. A surprise recognition task was conducted three days later. Under placebo, women showed a significantly better recognition memory and increased hippocampal responses to subsequently remembered items independent of the emotional valence compared to men. The separate treatments with either hormone significantly diminished this mnemonic sex difference and reversed the hippocampal activation pattern. However, the combined treatments led to a memory performance comparable to that of the placebo group. Collectively, the results suggest that both hormones play a crucial role in modulating sex differences in episodic memory. Furthermore, possible antagonistic interactions between estradiol and oxytocin could explain previously observed opposing hormonal effects in women and men.

neuroscience↗

bioRxiv2021

Lonely in the dark: trauma memory and sex-specific dysregulation of amygdala reactivity to fear signals

Loneliness exacerbates psychological distress and increases the risk of psychopathology after trauma exposure. The prevalence of trauma-associated disorders varies substantially between sexes, and accumulating evidence indicates sex-specific effects of loneliness. However, it is still unclear whether a lack of social connectedness affects trauma-induced intrusions and the neural processing of fear signals. Moreover, it is uncertain, whether loneliness plays a different role in women and men. We used a prestratification strategy and recruited n=47 (n=20 women) healthy individuals with high loneliness and n=35 controls (n=18 women). Participants were exposed to an experimental trauma and evoked intrusive thoughts in daily life were monitored for three consecutive days. Functional magnetic resonance imaging was used to assess neural habituation to fearful faces and fear learning (conditioning and extinction) prior to trauma exposure. The total number of intrusions and amygdala reactivity in neural fear processing served as the primary study outcomes. Our results revealed a significant interaction between loneliness and sex such that loneliness was associated with more intrusions in men, but not in women. A similar pattern emerged at the neural level, with both reduced amygdala habituation to repeated fearful faces and amygdala hyperreactivity during the conditioning of fear signals in lonely men, but not in women. Our findings indicate that loneliness may confer vulnerability to intrusive memories after trauma exposure in healthy men and that this phenotype relates to altered limbic processing of fear signals. Collectively, interventions targeting social connectedness may mitigate the sequelae of traumatic experiences.

neuroscience↗

bioRxiv2020

Stress-primed secretory autophagy drives extracellular BDNF maturation

The stress response is an essential mechanism that strives to maintain homeostasis, and its disruption is implicated in several psychiatric disorders. As a cellular response to stressors, autophagy is activated to regulate homeostasis through protein degradation and recycling. Secretory autophagy is a recently described pathway where autophagosomes fuse with the plasma membrane rather than lysosomes. In this study, we demonstrate that glucocorticoid-mediated stress enhances secretory autophagy, via the stress-responsive co-chaperone FK506-binding protein 51. We identified the matrix metalloproteinase 9 (MMP9) as one of the stress-induced secreted proteins. Using cellular assays and in vivo microdialysis, we further found that stress-enhanced MMP9 secretion increases the cleavage of pro-brain derived neurotrophic factor (proBDNF) to its mature form. BDNF is essential for adult synaptic plasticity and its pathway is associated with major depression and posttraumatic stress disorder. These findings unravel a novel mechanistic link between stress, stress adaptation and the development of psychiatric disorders, with possible therapeutic implications.

molecular biology↗