349 research outputs found
Chronic mild stress-induced alterations of local protein synthesis: a role for cognitive impairment
No full textDepression, a major cause of disability worldwide, is characterized by a complex and heterogeneous symptomatology. With this respect, cognitive deterioration represents a major problem that has a strong impact on patient's function. Thus, within the context of a depressive phenotype, it is important to characterize the mechanisms that sustain cognitive dysfunctions and may represent an important target for pharmacological intervention. Here, using the chronic mild stress (CMS) paradigm of depression, we found that, independently from the anhedonic phenotype, CMS rats showed a deficit in the novel object recognition (NOR) test, which is associated with an inability to phosphorylate GluN2B subunit on Ser1303 and to activate the mTOR pathway. In agreement with the role of these systems in the control of local protein synthesis, we observed an increase phosphorylated of the eukaryotic Elongation Factor 2 (eEF2) in the crude synaptosomal fraction after the NOR test specifically in control animals. Since it has been demonstrated that peEF2 leads to the translation of specific mRNAs, we investigated if the gene-specific translational control depends on the presence of uORFs. Interestingly, we found a significant increase of oligophrenin-1 (2 uORFs) and of Bmal1 (7 uORFs) protein levels specifically in the control animals exposed to the NOR test. Our results demonstrated that the cognitive decline associated with stress exposure might be due to alterations in local protein translation of specific mRNAs, suggesting that a pharmacological intervention able to correct these defects might be useful in the improvement of deteriorated functions in patients with major depression and stress-related disorders
Inter-Nord
No full textOn 5 February 2024, Professor Jean Malaurie passed away at his home in Dieppe at the age of 101. Having refused to join the compulsory work service (STO – Service du travail obligatoire) of the Nazi occupant in 1943, he went into hiding, joining the Résistance movement, an act of recalcitrance which characterized him profoundly and which was to entitle him to military honours during his funeral. The ceremony took place at the Saint-Louis-des-Invalides Cathedral in Paris on 14 February 2024, followed by the military honours and eulogy pronounced by the French Minister of Higher Education and Research, Professor Sylvie Retailleau.
It is with emotion that the editorial board of Inter-Nord wishes him farewell, paying a last tribute to the President of honour of our journal which he had founded with historian Fernand Braudel at the CNRS in the 1960s. We are publishing in French and English the homily of Father Geoffroy de la Tousche, the final remarks by Jean Malaurie’s son Guillaume and the minister’s speech, as well as a homage published in Le Canard enchaîné and a letter of condolences by Mrs Audrey Azoulay, Director-General of UNESCO.
Inter-Nord 23 continues in the interdisciplinary and intersectorial vein which has been its imprint introduced by Jean Malaurie right from the start, trying to propose bilingual versions of texts as far as possible. The current issue contains a special section with three scientific research articles on Iceland, two of which were first presented at the annual Humanities conference of the University of Iceland in 2023. These texts are accompanied by graphic works of the Icelandic artist Thóra Sigurðardóttir. Many thanks to Thóra for letting us publish some of her intriguing artwork discussed in a stunning piece by the Icelandic poetess Sigurbjörg Thrastardóttir.
In the creative writing section, we are also publishing two pieces by the Quebecois author Monique Durand about the Faroe Islands and interviews with Alaskan author Nancy Lord and the journalist Olivera Tornau. Other contributions include a viewpoint signed by four UArctic Chairs, an original French research project and some reviews of Malaurie’s and other works
Effect of lurasidone treatment on chronic mild stress-induced behavioural deficits in male rats: The potential role for glucocorticoid receptor signalling
No full textBackground: Stress represents one of the main precipitating factors for psychiatric diseases, characterised by an altered function of glucocorticoid receptors (GR), known to play a role in mood and cognitive function. We investigated the ability of the antipsychotic lurasidone to modulate the involvement of genomic and non-genomic GR signalling in the behavioural alterations due to chronic stress exposure Methods: Male Wistar rats were exposed to seven weeks of chronic mild stress (CMS) and treated with lurasidone (3 mg/kg/day) starting from the second week of stress for more five weeks. Gene expression and protein analyses were conducted in dorsal hippocampus. Results: Seven weeks of CMS induced anhedonia and cognitive impairment, which were normalised by lurasidone. At molecular level, CMS rats showed an increase of GR protein levels by 60% (p<0.001 vs. CTRL/VEH) in the membrane compartment, which was paralleled by an up-regulation of phosphoSINAPSYN Ia/b by 88% (p<0.01 vs. CTRL/VEH) and of the mitochondrial marker Cox3 by 21% (p<0.05 vs. CTRL/VEH). Moreover, while exposure to the novel object recognition test increased the nuclear translocation of GRs by 96% (p<0.01 vs. CTRL/VEH/Naïve) and their transcriptional activity in non-stressed rats, such mechanisms were impaired in CMS rats. Interestingly, the genomic and non-genomic alterations of GR, induced by CMS, were normalised by lurasidone. Conclusion: Our results further support the role of glucocorticoid signalling in the dysfunction associated with stress exposure. We provide novel insights on the mechanism of lurasidone, suggesting its effectiveness on different domains associated with psychiatric disorders
Resilience and vulnerability to stress-induced anhedonia differently affects the molecular acute responsiveness in the rat brain
No full textMajor depressive disorder (MDD) is a psychiatric disease characterized by low mood and anhedonia Although its etiology is associated with the interaction between vulnerability genes and environmental risk factors such as stress, it is important to note that not all stressed subjects develop the disease indeed some of them show resilience.
The aim of this study was to evaluate if and how the vulnerability or resilience to the anhedonic phenotype induced in the rat by the chronic mild stress paradigm (CMS) could influence the molecular response to an acute challenge. In particular, we focused our attention on the redox system, which is altered in psychiatric diseases and is often acutely activated.
Adult male Wistar rats were subjected to 3 weeks of CMS, divided in vulnerable and resilient groups based on their sucrose intake and then exposed again to 3 weeks of CMS. After that, half of these rats were subjected to an acute challenge by 1-hour restraint (ARS) at the end of which all animals were euthanized and the brain areas dissected for the subsequent gene expression analyses through qRT-PCR.
We found a significant increase of the mRNA levels of several antioxidant genes (i.e. MT1a and SRXN1) after ARS, an effect observed only in CMS-vulnerable animals, Conversely, other genes such as CAT or GPX are less affected.
Our results suggest that despite the “static” molecular impairment of the redox machinery induced by CMS, the behavioral consequences of the chronic procedure clearly influence the subsequent dynamic ability of the animals to respond to a second stimulus. In particular, we observed an increase in the antioxidant component in vulnerable rats and a decrease in resilient ones, a profile that might mirror a stronger need of the former to balance an oxidative state, that conversely is not necessary for the latter
Stress-induced anhedonia is associated with the activation of the inflammatory system in the rat brain : restorative effect of pharmacological intervention
No full textMajor depression is a complex disease that originates from the interaction between a genetic background of susceptibility and environmental factors such as stress. At molecular level, it is characterized by dysfunctions of multiple systems including neurotransmitters, hormones, signalling pathways, neurotrophic and neuroplastic molecules and - more recently - inflammatory mediators. Accordingly, in the present study we used the chronic mild stress (CMS) paradigm in the rat to elucidate to what extent brain inflammation may contribute to the development and/or the maintenance of an anhedonic phenotype and how pharmacological intervention may interfere with such behavioral and molecular stress-induced alterations. To this aim, adult male rats were exposed to CMS for 2 weeks and the cerebral expression of several mediators of the inflammatory system was evaluated in the hippocampus and prefrontal cortex of both stressed and control animals in parallel with the sucrose intake. Next, the animals showed decreased sucrose consumption were exposed to five further weeks of CMS and treated with the antidepressants imipramine or agomelatine, or the antipsychotic lurasidone. Our results demonstrate that only the stressed animals that were characterized by a deficit in sucrose intake showed increased expression of the pro-inflammatory cytokines IL-1β, IL-6 and up-regulation of markers and mediators of microglia activation such as CD11b, CX3CL1 and its receptor CX3CR1 in comparison with stress-resilient animals. Some of these molecular alterations persisted also after longer stress exposure and were modulated, similarly to the behavioral effects of CMS, by chronic pharmacological treatment. These data suggest that neuroinflammation may have a key role in the pathological consequences of stress exposure, thus contributing to the subject's vulnerability for depression
Inter-Nord
No full textInter-Nord 24 is largely dedicated to Alaska. On the front and back covers feature three Yup’ik masks brought back to Pennsylvania by Moravian missionaries in the early 20th century. They are now held in the collections of the Moravian Historical Society in Nazareth, PA, USA, to which we are grateful for granting permission to publish these images. The front cover also includes a photograph from a series taken by Bruce Jackson during his field trip with Jean Malaurie to Nome and its region in 1997. Many thanks to Bruce for letting us reprint several of his images.
The issue’s contributions dedicated to Alaska include three peer-reviewed scientific articles, two student research papers from the University of Vienna based on field work, introduced by Peter Schweitzer and Olga Povoroznyuk, and two interviews: one with Iñupiaq contemporary artist Aisa Warden conducted by Daniel Chartier and the other with Mrs Lyn Trodahl Chynoweth, daughter of a Moravian missionary who grew up at Nunapitsinghak, site of the Moravian Children’s Home on the Kwethluk, a tributary to the Kuskokwim river, conducted by Benjamin Ferguson, as well as polar readings offered by Muriel Brot.
Inter-Nord 24 also pays homage to British poet and anthropologist Tom Lowenstein who passed away in March 2025 in his 84th year. Tom was notably the author of the acclaimed volume Ancient Land: Sacred Whale (1993, republished 1999). We are grateful to his literary executors to have authorised us to republish two longer excerpts, accompanied by translations into French for which we would like to sincerely thank Professor Hélène Aji of the École normale supérieure in Paris. Hélène had translated these poems on the occasion of the international conference “Problèmes arctiques : environnement, sociétés et patrimoine/ Arctic problems: environment, societies and heritage” organised by Jean Malaurie and myself at the National Museum of Natural History in Paris in March 2007 during the Fourth International Polar Year. Tom was one of the invited speakers, contributing a paper about his then forthcoming history of Point Hope, Alaska, Ultimate Americans (University of Alaska Press, 2008) published in Inter-Nord 21 (2011, pp. 149-152). Tom has published a fascinating volume about his field work, The Structure of Days Out (2021) which has not received the attention it deserves so far. Farewell to the poet!
Inter-Nord 24 also features three other peer-reviewed scientific articles in the section entitled “Varia”, illustrating the fact that we are open to scientific papers on any topic in relation to the Arctic. It also contains a viewpoint. Many thanks to all contributors
Chronic Stress Exposure Reduces Parvalbumin Expression in the Rat Hippocampus through an Imbalance of Redox Mechanisms : Restorative Effect of the Antipsychotic Lurasidone
No full textBackground
Psychiatric disorders are associated with altered function of inhibitory neurotransmission within the limbic system, which may be due to the vulnerability of selective neuronal subtypes to challenging environmental conditions, such as stress. In this context, parvalbumin-positive GABAergic interneurons, which are critically involved in processing complex cognitive tasks, are particularly vulnerable to stress exposure, an effect that may be the consequence of dysregulated redox mechanisms.
Methods
Adult Male Wistar rats were subjected to the chronic mild stress procedure for 7 weeks. After 2 weeks, both control and stress groups were further divided into matched subgroups to receive chronic administration of vehicle or lurasidone (3 mg/kg/d) for the subsequent 5 weeks. Using real-time RT-PCR and western blot, we investigated the expression of GABAergic interneuron markers and the levels of key mediators of the oxidative balance in the dorsal and ventral hippocampus.
Results
Chronic mild stress induced a specific decrease of parvalbumin expression in the dorsal hippocampus, an effect normalized by lurasidone treatment. Interestingly, the regulation of parvalbumin levels was correlated to the modulation of the antioxidant master regulator NRF2 and its chaperon protein KEAP1, which were also modulated by pharmacological intervention.
Conclusions
Our findings suggest that the susceptibility of parvalbumin neurons to stress may represent a key mechanism contributing to functional and structural impairments in specific brain regions relevant for psychiatric disorders. Moreover, we provide new insights on the mechanism of action of lurasidone, demonstrating that its chronic treatment normalizes chronic mild stress-induced parvalbumin alterations, possibly by potentiating antioxidant mechanisms, which may ameliorate specific functions that are deteriorated in psychiatric patients
Chronic N-Acetyl-Cysteine Treatment Enhances the Expression of the Immediate Early Gene Nr4a1 in Response to an Acute Challenge in Male Rats: Comparison with the Antidepressant Venlafaxine
No full textDespite several antidepressant treatments being available in clinics, they are not effective in all patients. In recent years, N-acetylcysteine (NAC) has been explored as adjunctive therapy for many psychiatric disorders, including depression, for its antioxidant properties. Given the promising efficacy of this compound for the treatment of such pathologies, it is fundamental to investigate, at the preclinical level, the ability of the drug to act in the modulation of neuroplastic mechanisms in basal conditions and during challenging events in order to highlight the potential features of the drug useful for clinical efficacy. To this aim, adult male Wistar rats were treated with the antidepressant venlafaxine (VLX) (10 mg/kg) or NAC (300 mg/kg) for 21 days and then subjected to 1 h of acute restraint stress (ARS). We found that NAC enhanced the expression of several immediate early genes, markers of neuronal plasticity in the ventral and dorsal hippocampus, prefrontal cortex and amygdala, and in particular it mediated the acute-stress-induced upregulation of Nr4a1 expression more than VLX. These data suggested the ability of NAC to induce coping strategies to face external challenges, highlighting its potential for the improvement of neuroplastic mechanisms for the promotion of resilience, in particular via the modulation of Nr4a1
Classics. Fibular hemimelia or deficiency (defectus fibulae)
No full textThe author presents an original technique of reconstruction of the ankle joint (including reconstruction of the lateral malleolus) in the congenital absence of the fibula.Autor prezentuje oryginalną technikę rekonstrukcji stawu skokowo-goleniowego (w tym odtworzenie kostki bocznej) we wrodzonym braku kości strzałkowej
Investigating the involvement of different hippocampal cell populations in the molecular changes associated with vulnerability and resilience to stress-induced anhedonia: focus on redox balance mediators
No full textMajor depressive disorder (MDD) is a severe psychiatric disorder characterized by low mood, anhedonia and other debilitating behavioural, cognitive and emotional symptoms. Over the past decades, preclinical and clinical studies have shown that a maladaptive stress response is strongly associated with the onset of MDD, with a consequent deregulation of several molecular systems. It is noteworthy that the effects of stress are highly variable, with most exposed individuals being resilient and able to cope positively with the adverse situation, and a smaller percentage being susceptible and developing psychopathology. The molecular mechanisms underlying resilience and susceptibility are still elusive and their characterization is crucial to identify new targets for a more effective therapeutic strategy. In this context, using the well-known Chronic Mild Stress (CMS) animal model of depression, our group has previously reported that stress-induced vulnerability to anhedonia is associated with increased levels of pro-inflammatory and oxidative stress mediators in the brain. Since both glial and neuronal cells are known to be either actively involved in these processes or severely affected by their dysregulation, the aim of the present study was to investigate the potential involvement of different cell populations in the vulnerability or resilience to the anhedonic-like phenotype induced by 2 weeks of CMS. Specifically, by using the sucrose consumption test (SCT) we differentiated between vulnerable and resilient animals, while immunofluorescence staining was used to assess the co-localisation of astrocytic (GFAP) and microglial (IBA-1) markers with HO-1, an antioxidant mediator, in ventral (VH) and dorsal (DH) hippocampal slices.
Our results showed that the CMS paradigm affected both glial cell density and HO-1 expression, with most of the changes occurring within the hippocampal dentate gyrus (DG). Specifically, we observed increased astrocyte numbers in the DH and VH of both stress-vulnerable and resilient groups, suggesting that astrocytic reactivity reflects a general stress response. Conversely, we found increased microglial numbers only in the VH of vulnerable rats, whereas resilient rats showed either unchanged (VH) or decreased (DH) IBA1-positive cell numbers, suggesting that microglial activation appears to be related to stress vulnerability and pointing to the VH as a potential hub for this process. Furthermore, we observed that the HO-1 signal was only partially attributable to glial cells, as neuron-like cells appeared to be mainly responsible for its expression. In conclusion, although further studies are required, our data provide novel information on the cell populations involved in development of stress-induced vulnerability or resilience to anhedonia
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