Jean-Philippe Guilloux

• PhD
• University of Paris-Saclay

R,S )-ketamine (ketamine) has rapid and sustained antidepressant (AD) efficacy at sub-anesthetic doses in depressed patients. A metabolite of ketamine, including ( 2R,6R )-hydroxynorketamine (( 6 )-HNKs) has been reported to exert antidepressant actions in rodent model of anxiety/depression. To further understand the specific role of ketamine’s met...

La kétamine, un antagoniste non compétitif du récepteur N-méthyl-D-aspartate (R-NMDA) du glutamate, possède un effet antidépresseur rapide (dès 24 h post-dose) et prolongé (jusqu’à une semaine) dans la dépression résistante au traitement par des antidépresseurs « classiques » et dans les modèles rongeurs d’anxiété/dépression. Les arguments concerna...

Objectives Intensive insulin therapy provides optimal glycemic control in patients with diabetes. However, intensive insulin therapy causes so‐called iatrogenic hypoglycemia as a major adverse effect. The ventromedial hypothalamus (VMH) has been described as the primary brain area initiating the counter‐regulatory response (CRR). Nevertheless, the...

Major Depressive Disorder (MDD) is a serious public health problem, as it is the most common psychiatric disorder worldwide. Antidepressant drugs increase adult hippocampal neurogenesis, which is required to induce some behavioral effects of antidepressants. Adult-born granule cells in the dentate gyrus (DG) and the glutamate receptors subunits 2 (...

Major depressive disorder (MDD) is the psychiatric disorder with the highest prevalence in the world. Pharmacological antidepressant treatment (AD), such as selective serotonin reuptake inhibitors [SSRI, i.e., fluoxetine (Flx)] is the first line of treatment for MDD. Despite its efficacy, lack of AD response occurs in numerous patients characterizi...

Recent contradictory data has renewed discussion regarding the existence of adult hippocampal neurogenesis (AHN) in humans, i.e., the continued production of new neurons in the brain after birth. The present review revisits the debate of AHN in humans from a historical point of view in the face of contradictory evidence, analyzing the methods emplo...

Introduction Si l’efficacité des antidépresseurs a été démontrée, 47 % des patients ne répondent pas à une première ligne de traitement antidépresseur et 20-30 % des patients développent une dépression résistante. L’amélioration des stratégies thérapeutiques visant à traiter les patients résistants passe par une meilleure compréhension des mécanism...

Résumé Les inhibiteurs sélectifs de la recapture de la sérotonine sont le traitement de première intention du trouble dépressif majeur, malgré leur efficacité retardée. Si l’action pharmacologique des inhibiteurs sélectifs de la recapture de la sérotonine a pour cible principale le système sérotoninergique, ce dernier est connecté anatomiquement à...

Major Depressive Disorders (MDD) patients may exhibit cognitive deficits and it is currently unclear to which degree treatment with antidepressants may affect cognitive function. Preclinical and clinical observations showed that vortioxetine (VORT, an antidepressant with multimodal activity), presents beneficial effects on aspects of cognitive func...

Effects of VORT (1.8 g/kg; ∼10 mg/kg) treatment on body weight in C57BL/6J Rj mice.

Statistical results for the effects of VORT treatment on shock-induced c-Fos activation in the adult hippocampus in GFAP-TK TG mice (Figure 6).

Effects of VORT (1.8 g/kg; ∼10 mg/kg) treatment on doublecortin (DCX) immunostaining in the adult dentate gyrus of the hippocampus of C57BL/6J Rj mice. Unpaired one-tailed student’s t-tests between VEH and VORT group; Abbreviations: VEH, vehicle; VORT, Vortioxetine.

Statistical results for context discrimination paradigm (Figures 2A,B, 3A–D).

Statistical results for freezing behavior in context A of CD paradigm (Figures 4E,F).

Statistical results for discrimination index analysis (Figures 2C, 3E).

Statistical results for the effects of VORT treatment on shock-induced c-Fos activation in the adult hippocampus in C57BL/6J Rj mice (Figure 5).

The dentate gyrus (DG) has distinct roles along its dorso-ventral axis. In the mouse, we recently demonstrated that dorsal DG (dDG) stimulation enhances exploratory behavior (Kheirbek et al., 2013). Dopamine (DA) release in the Nucleus Accumbens (NAcc), which belongs to the reward system, could be a key target of dDG mediating this motivation-relat...

Emotionality score of the “most” affected mice of each groups used for proteomics analysis. Normalization of data using z-score method was performed for each behavioral parameter in EPM, NSF, and ST after the second session of behavior. Test z-values were then calculated by averaging individual z-scores, and averaged to obtain the emotionality scor...

Overall statistical results for behavioral studies.

Protein identification by X!Tandem Pipeline across all samples.Group ID: Group which the protein belongs. All the proteins in a group have at least one peptide in common; Sub-Group ID: Sub-Group which the protein belongs. All the proteins in a sub-group are identified with the same valid peptides. The number of subgroups in which this peptide is pr...

Change in emotionality z-score between behavioral sessions 1 and 2. (A) Normalization of data using z-score method was performed for each behavioral parameter in EPM, NSF, and ST after each behavioral session. Before fluoxetine treatment, emotionality score calculated after the first behavioral round did not differ significantly between groups cort...

Protein spectral counting by X!Tandem Pipeline. Group ID: Group which the protein belongs. All the proteins in a group have at least one peptide in common; Sub-Group ID: Sub-Group which the protein belongs. All the proteins in a sub-group are identified with the same valid peptides. The number of subgroups in which this peptide is present; Cort: Co...

Proteins significantly differentially expressed after one-way ANOVA. Protein ID: A single reference to the protein in this grouping experiment (unique within a sample in individual mode); Cort: Corticosterone; Flx_NR: Fluoxetine non-responder; Flx_R: Fluoxetine responder.

The incorporation of peripheral biomarkers in the treatment of major depressive disorders (MDD) could improve the efficiency of treatments and increase remission rate. Peripheral blood mononuclear cells (PBMCs) represent an attractive biological substrate allowing the identification of a drug response signature. Using a proteomic approach with high...

Glutamatergic dysfunctions are observed in the pathophysiology of depression. The glutamatergic synapse as well as the AMPA receptor’s (AMPAR) activation may represent new potential targets for therapeutic intervention in the context of major depressive disorders. S 47445 is a novel AMPARs positive allosteric modulator (AMPA-PAM) possessing procogn...

Effects of chronic S 47445 or fluoxetine treatment on additional emotionality measurements. Behavioural effects of S 47445 were studied after 28 days of administration at doses of 0.3, 1, 3, and 10 mg/kg, compared to those of vehicle and fluoxetine (18 mg/kg) in corticosterone treated animals. Additional measures of anxiety-related behavior were th...

Effects of chronic S 47445 administration on physiological and additional behavior outcomes in GFAP-TK+ and GFP-TK- mice. The effects of 28 days of treatment with S 47445 (10 mg/kg) on behavioral outcomes were compared to those of vehicle and fluoxetine in GFAP-TK+ and GFAP-TK- mice. In the open field, anxiety was expressed as the number of entries...

Chronic S 47445 administration stimulates cell proliferation, cell survival and dendritic arborization in the dentate gyrus of the hippocampus. The effects of 28 days of treatment with S 47445 on cell proliferation, cell survival and dendritic complexity were compared to those of vehicle and fluoxetine. Representative illustrations of Ki67 (A) or D...

Effects of chronic S 47445 administration on cell proliferation in the dentate gyrus of GFAP-TK+ and GFP-TK- mice. The effects of 28 days of treatment with S 47445 (10 mg/kg) on cell proliferation in the dentate gyrus of the hippocampus were compared to those of vehicle and fluoxetine in GFAP-TK+ and GFAP-TK- mice, using KI67 immunostaining. Cell p...

Understanding the pathophysiology of affective disorders and their treatment relies on the availability of experimental models that mimic aspects of the disease. Most of the studies on depressive disorders are conducted with male rodents, mostly because including females in protocols is more difficult. Indeed, there is a complex series of changes i...

Strategies designed to increase adult hippocampal neurogenesis (AHN) may have therapeutic potential for reversing memory impairments. H3 receptor antagonists/inverse agonists also may be useful for treating cognitive deficits. However, it remains unclear whether these ligands have effects on AHN. The present study aimed to investigate the effects o...

Rationale Evidence links alterations in α5-containing nicotinic receptors (α5*-nAChRs) to nicotine addiction. Notably, the rs16969968 polymorphism in the α5 gene (α5SNP) increases the risk for heavy smoking and impairs nicotine-rewarding properties in mice. Additional work is needed to understand how native and polymorphic α5*-nAChRs contribute to...

Background: Since the discovery of antidepressants, new treatments have emerged with fewer side effects but no greater efficacy. Glycogen synthase kinase 3 β (GSK-3β), a kinase known for its activity on glycogen synthesis, has in the last few years raised growing interest in biological psychiatry. Several efficient treatments in major depression h...

Major Depressive Disorder (MDD) is the most common psychiatric disease, affecting millions of people worldwide. In addition to the well-defined depressive symptoms, patients suffering from MDD consistently complain about cognitive disturbances, significantly exacerbating the burden of this illness. Among cognitive symptoms, impairments in attention...

Cognitive disturbances are often reported as serious invalidating symptoms in patients suffering from major depression disorders (MDD) and are not fully corrected by classical monoaminergic antidepressant drugs. If the role of 5-HT4 receptor agonists as cognitive enhancers is well established in naïve animals or in animal models of cognitive impair...

Selective Serotonin Reuptake Inhibitors (SSRIs) are extensively used for the treatment of major depressive disorder (MDD). SSRIs are defined as indirect receptor agonists since the activation of postsynaptic receptors is a consequence of an increase in extracellular concentrations of serotonin (5-HT) mediated by the blockade of serotonin transporte...

Unlabelled: Numerous clinical reports underscore the frequency of olfactory impairments in patients suffering from major depressive disorders (MDDs), yet the underlying physiopathological mechanisms remain poorly understood. We hypothesized that one key link between olfactory deficits and MDD lies in hypercortisolemia, a cardinal symptom of MDD. C...

Understanding the pathophysiology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. The use of exogenously administered corticosterone (CORT model) can mimic the effects of a chronic stress and has been validated as an animal model to study disease states displ...

Genome-wide expression and genotyping technologies have uncovered the genetic bases of complex diseases at unprecedented rates. However, despite its heavy burden and high prevalence, the molecular characterization of ma- jor depressive disorder (MDD) has lagged behind. Transcrip- tome studies report multiple brain disturbances but are lim- ited by...

Aging is commonly associated with increased incidence of depression and anxiety disorders and declines in cognitive functions. Furthermore, stress is commonly associated with development of depression and anxiety. Here we investigated the role of age and chronic corticosterone administration on depression/anxiety-related behavior in mice in neuroge...

Major depressive disorder (MDD) in general, and anxious depression in particular, are characterized by poor rates of remission with first-line treatments, contributing to the chronic illness burden suffered by many patients. Prospective research is needed to identify biomarkers predicting non-remission prior to treatment initiation. We collected bl...

Vortioxetine (Brintellix®, 1-[2-(2,4-dimethylphenyl-sulfanyl)-phenyl]-piperazine) is a multimodal antidepressant targeting the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT3, 5-HT7 receptors and the serotonin (5-HT) transporter (5-HTT). Vortioxetine administration induces antidepressant- and anxiolytic-like effects, and can enhance cognitive performance in rodents....

Sleep/wake disorders are frequently associated with anxiety and depression and to elevated levels of cortisol. Even though these alterations are increasingly sought in animal models, no study has investigated the specific effects of chronic corticosterone (CORT) administration on sleep. We characterized sleep/wake disorders in a neuroendocrine mous...

Sleep/wake disorders are frequently associated with anxiety and depression and to elevated levels of cortisol. Even though these alterations are increasingly sought in animal models, no study has investigated the specific effects of chronic corticosterone administration on sleep. We characterized sleep/wake disorders in a neuroendocrine mouse model...

Cognitive disturbances are often reported as serious incapacitating symptoms by patients suffering from major depressive disorders (MDDs). Such deficits have been observed in various animal models based on environmental stress. Here, we performed a complete characterization of cognitive functions in a neuroendocrine mouse model of depression based...

Vortioxetine (Lu AA21004) is an investigational novel antidepressant with multimodal activity that functions as a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the 5-HT transporter in vitro. Here we explore its anxiolytic and antidepressant potential in adult mice. Vortioxetin...

Brain molecular aging, the pervasive and consistent transcriptome changes associated with normal brain aging, appears to overlap with disease pathways and may be anticipated in neurodegenerative and neuropsychiatric diseases, including major depressive disorder (MDD). Here, we characterize the global interaction of MDD-related gene changes with age...

Objective: The subgenual anterior cingulate cortex is implicated in the pathology and treatment response of major depressive disorder. Low levels of brain-derived neurotrophic factor (BDNF) and reduced markers for GABA function, including in the amygdala, are reported in major depression, but their contribution to subgenual anterior cingulate cort...

The serotonergic system has been widely implicated in stress related psychiatric disorders such as depression and anxiety. Generation of receptor knockout mice has offered a new approach to study processes underlying anxiety. For instance, knockout mice for both 5-HT(1A) and 5-HT(1B) receptors (5-HT(1A/1B)(-/-)) display an anxious phenotype, associ...

Women are twice as likely as men to develop major depressive disorder (MDD) and are more prone to recurring episodes. Hence, we tested the hypothesis that the illness may associate with robust molecular changes in female subjects, and investigated large-scale gene expression in the post-mortem brain of MDD subjects paired with matched controls (n=2...

Nicotine is the main addictive component of tobacco and modifies brain function via its action on neuronal acetylcholine nicotinic receptors (nAChRs). The mesolimbic dopamine (DA) system, where neurons of the ventral tegmental area (VTA) project to the nucleus accumbens (ACb), is considered a core site for the processing of nicotine's reinforcing p...

Agomelatine (S20098) is a novel antidepressant drug with melatonergic agonist and 5-HT2C receptor antagonist properties, displaying antidepressant/anxiolytic-like properties in animal models and in humans. In a depression/anxiety-like mouse model in which the response of the HPA axis is blunted, we investigated whether agomelatine could reverse beh...

Defining anxiety- and depressive-like states in mice (emotionality) is best characterized by the use of complementary tests, leading sometimes to puzzling discrepancies and lack of correlation between similar paradigms. To address this issue, we hypothesized that integrating measures along the same behavioral dimensions in different tests would red...

Recently, we have developed a novel paradigm appropriate and useful for screening early-stage and novel treatments for depression and anxiety based on the chronic delivery of corticosterone via the drinking water. Here, we investigated in mice the behavioral effects of agomelatine an antidepressant melatonergic (MT1/MT2) receptor agonist and 5-HT 2...