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| 2. |
- Ardalan, Maryam, 1979, et al.
(författare)
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Rapid effects of S-ketamine on the morphology of hippocampal astrocytes and BDNF serum levels in a sex-dependent manner
- 2020
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Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X .- 1873-7862. ; 32, s. 94-103
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Tidskriftsartikel (refereegranskat)abstract
- The prevalence of major depressive disorder (MDD) is higher in women than men. Importantly, a differential behavioral response by sex to the antidepressant response to ketamine in rodents has been reported. Mechanistically, male depressed-like animals showed an increased spine density after ketamine treatment via restoration of synaptic protein levels while those proteins were not altered in female rats. In addition, preclinical studies indicate that the impairment of astrocytic plasticity is one of the contributing mechanisms in the pathophysiology of MDD. Accordingly, in this study, we determined the effect of sex on the rapid morphological alteration of hippocampal astrocytes and the serum level of BDNF one hour after S-ketamine injection. A single intraperitoneal dose of S-ketamine (15 mg/kg) or saline was injected to the male and female Flinders Sensitive Line (FSL) rats, a genetic animal model of depression and their brains were perfused one hour after treatment. The size of the GFAP positive astrocytes in the hippocampal subregions was measured. The volume of different hippocampal subregions was assessed using the Cavalieri estimator. Moreover, serum levels of BDNF were measured with enzyme-linked immunosorbent assay (ELISA) kits. The volume of hippocampal subregions significantly increased one hour after S-ketamine in both male and female FSL animals. However, a substantial alteration in the morphology of the hippocampal astrocytes was observed only in the female rats. Additionally, significantly increased serum BDNF levels in the female depressed rats were observed one hour after S-ketamine treatment. Our results indicate that the rapid effects of S-ketamine on the morphology of the hippocampal astrocytes and the serum level of BDNF are sex-dependent.
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| 3. |
- Barde, Swapnali, et al.
(författare)
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Substance P, NPY, CCK and their receptors in five brain regions in major depressive disorder with transcriptomic analysis of locus coeruleus neurons
- 2024
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Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X .- 1873-7862. ; 78, s. 54-63
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Tidskriftsartikel (refereegranskat)abstract
- Major depressive disorder (MDD) is a serious disease and a burden to patients, families and society. Rodent experiments and human studies suggest that several neuropeptide systems are involved in mood regulation. The aim of this study is two-fold: (i) to monitor, with qPCR, transcript levels of the substance P/tachykinin (TAC), NPY and CCK systems in bulk samples from control and suicide subjects, targeting five postmortem brain regions including locus coeruleus (LC); and (ii) to analyse expression of neuropeptide family transcripts in LC neurons of 'normal' postmortem brains by using laser capture microdissection with Smart-Seq2 RNA sequencing. qPCR revealed distinct regional expression patterns in male and female controls with higher levels for the TAC system in the dorsal raphe nucleus and LC, versus higher transcripts levels of the NPY and CCK systems in prefrontal cortex. In suicide patients, TAC, TAC receptors and a few NPY family transcript levels were increased mainly in prefrontal cortex and LC. The second study on 'normal' noradrenergic LC neurons revealed expression of transcripts for GAL, NPY, TAC1, CCK, and TACR1 and many other peptides (e.g. Cerebellin4 and CARTPT) and receptors (e.g. Adcyap1R1 and GPR173). These data and our previous results on suicide brains indicates that the tachykinin and galanin systems may be valid targets for developing antidepressant medicines. Moreover, the perturbation of neuropeptide systems in MDD patients, and the detection of further neuropeptide and receptor transcripts in LC, shed new light on signalling in noradrenergic LC neurons and on mechanisms possibly associated with mood disorders.
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| 5. |
- Bulik, Cynthia M., et al.
(författare)
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SUBJECTIVE EXPERIENCES OF ANOREXIA NERVOSA IN PATIENTS WITH HIGH VS LOW ANOREXIA NERVOSA POLYGENIC RISK
- 2023
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Ingår i: European Neuropsychopharmacology. - : Elsevier. - 0924-977X .- 1873-7862. ; 75:Suppl. 1, s. S14-S14
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Recent genome-wide association studies (GWAS) suggest that genetic factors play a key role in its development and expression and that anorexia nervosa (AN) might have both psychiatric and metabolic underpinnings. One hypothesis is that those with high genetic vulnerability to AN may experience negative energy balance (NEB) (i.e., expending more energy than you consume) in a positive manner, rendering self-starvation and excessive exercise exceptionally reinforcing. This “paradoxical” response to NEB may also complicate recovery. In the Polygenic risk of Anorexia nervosa and its Clinical Expression (PACE) study, we explored differences in clinical and phenomenological/experiential phenotypes (i.e., how patients reported their experience of illness) in 10 individuals with AN who were in the top decile of AN polygenic risk (PRS) and 10 individuals with AN who were in the lowest decile in the Swedish subsample of the Anorexia Nervosa Genetics Initiative (ANGI) study. We interviewed the participants in a double-blind study design using a structured interview guide focusing on the experience of AN, including experiences of NEB (e.g., hunger, satiety, dietary restriction), the development of symptoms, as well as the reactions of others including family members and treatment providers to patients’ experiences of NEB. All interviews have been coded and the blind will be broken in May 2023 at which point group comparisons will be analyzed. This is the first study, to our knowledge, to explore experiential impact of genetic risk. Findings may aid in understanding risk, clinical course, and individual experience of AN and contribute suggestions for tailoring interventions with input from genetic risk profiles.
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| 7. |
- Chen, Fenghua, et al.
(författare)
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The rat hippocampal gliovascular system following one week vortioxetine and fluoxetine
- 2021
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Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X .- 1873-7862. ; 42, s. 45-56
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Tidskriftsartikel (refereegranskat)abstract
- We have previously reported that vortioxetine, unlike the selective serotonin reuptake inhibitor fluoxetine, produces a rapid increase of dendritic spine number and Brain Derived Neurotrophic Factor (BDNF)-associated formation of synapses with mitochondrial support in the rat hippocampal CA1 and dentate gyrus. As a continuation of this line of research, and given the putative role of brain glial cells in mediating antidepressant responses the present study investigated early effects of vortioxetine on hippocampal microvasculature and Vascular Endothelial Growth Factor (VEGF) and astrocytes and microglia cells. Rats were treated for 1 week with vortioxetine (1.6 g/kg food chow) or fluoxetine (160 mg/L drinking water) at pharmacologically relevant doses. Stereological principles were used to estimate the number of ALDH1L1 positive astrocytes and Iba1 positive microglia cells, and the length of microvessels in subregions of hippocampus. VEGF protein levels were visualized with immunohistochemistry. Our results showed that vortioxetine significantly increased the number of ramified (resting) microglia and astrocytes accompanied by VEGF level elevation, whereas fluoxetine had no effect after 7 days treatment on these measures. Our findings suggest that astrocytes and microglia may have a role in mediating the pharmacological effects of vortioxetine in rats and that these effects are mediated through mechanisms that go beyond inhibition of the serotonin transporter and may target specific 5-HT receptors. It remains to be investigated whether these findings are relevant for the therapeutic effects of vortioxetine.
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| 9. |
- Faria, Vanda, et al.
(författare)
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Verbal suggestions of nicotine content modulate ventral tegmental neural activity during the presentation of a nicotine-free odor in cigarette smokers
- 2020
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Ingår i: European Neuropsychopharmacology. - : ELSEVIER. - 0924-977X .- 1873-7862. ; 31, s. 100-108
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Tidskriftsartikel (refereegranskat)abstract
- Expectancies of nicotine content have been shown to impact smokers' subjective responses and smoking behaviors. However, little is known about the neural substrates modulated by verbally induced expectancies in smokers. In this study we used functional magnetic resonance imaging (fMRI) to investigate how verbally induced expectations, regarding the presence or absence of nicotine, modulated smokers' neural response to a nicotine-free odor. While laying in the scanner, all participants (N = 24) were given a nicotine-free odor, but whereas one group was correctly informed about the absence of nicotine (control group n = 12), the other group was led to believe that the presented odor contained nicotine (expectancy group n = 12). Smokers in the expectancy group had significantly increased blood-oxygen-level-dependent (BOLD) responses during the presentation of the nicotine-free odor in the left ventral tegmental area (VTA), and in the right insula, as compared to smokers in the control group (Regions of interest analysis with pFWE-corrected p <= 0.05). At a more liberal uncorrected statistical level (p-unc <= 0.001), increased bilateral reactivity in the dorsolateral prefrontal cortex (dlPFC) was also observed in the expectancy group as compared with the control group. Our findings suggest that nicotine-expectancies induced through verbal instructions can modulate nicotine relevant brain regions, without nicotine administration, and provide further neural support for the key role that cognitive expectancies play in the cause and treatment of nicotine dependence.
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| 10. |
- Grimes, Poppy, et al.
(författare)
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UNVEILING GENETIC ARCHITECTURES FOR STRATIFYING TRAJECTORIES OF ADOLESCENT DEPRESSION
- 2023
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Ingår i: European Neuropsychopharmacology. - : Elsevier. - 0924-977X .- 1873-7862. ; 75:Suppl. 1, s. S127-S127
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Adolescent-onset depression is characterised by high levels of inter-individual variability and genetic heritability. Investigating the genetic factors that underlie trajectories of depression is crucial to enhancing mechanistic understanding of the onset, persistence and severity of adolescent depression. However, predicting trajectories from complex and heterogeneous genetic architectures in psychopathology poses challenges due to the high genetic correlation among traits. It remains unclear whether multi-trait models provide a superior prediction of depression trajectories compared to univariate models focused solely on depression. Addressing this question is important for effective stratification and targeted treatments.Methods: To validate depression trajectories during adolescence, we conducted growth mixture modelling in two longitudinal cohorts (ABCD and ALSPAC; total N=20,509). We then computed polygenic risk scores for seven traits: major depressive disorder (MDD), anxiety, neuroticism, schizophrenia, bipolar disorder, attention-deficit-hyperactivity disorder (ADHD), and autism for participants with European ancestry. We also generated MDD scores for individuals of African, East Asian, and Hispanic ancestries in ABCD. Using genomic structural equation modelling, we compared three multi-trait factor models (common, correlated, hierarchical) to assess the relationships among the seven traits. To generate multi-trait risk scores from these models in our target cohorts, we conducted multivariate genome-wide association analysis to determine the effects of single nucleotide polymorphisms on genetic latent p-factors. Finally, we examined the association between all polygenic risk scores for univariate traits and multi-trait models with depression trajectories.Results: Four distinct trajectories were replicated across two cohorts with partial age-range overlap encompassing adolescents from two generations. Trajectories included stable low, adolescent acute, increasing and decreasing. The hierarchical factor model was the best fit for multi-trait genetic information and was most predictive of adolescent acute trajectories (odds ratio [OR], 1.46; 95% CI, 1.27-1.68), with increasing and decreasing showing comparable risk (OR, 1.32; 95% CI, 1.16-1.50). Multi-trait models showed a similar genetic risk for depression trajectory as MDD-only risk across trajectories. Anxiety was associated with the adolescent acute trajectories (OR, 1.27; 95% CI, 1.10-1.45). Psychotic conditions were associated with later-onset depression patterns and ADHD with earlier-onset, aligning with the developmental timelines of these respective conditions.Discussion: The investigated genetic traits collectively contribute to diverse longitudinal patterns of depression, varying in severity, onset, and duration. A hierarchical factor model of multivariate genetic psychopathology demonstrated a comparable prediction of genetic risk to univariate depression scores for stratifying longitudinal depression in adolescence. It is important to acknowledge the genetic influence of multiple conditions on depression outcomes, particularly at different stages of vulnerability. Taking into account detailed and integrated genetic information will be valuable in effectively stratifying trajectories across adolescence and mental health conditions.
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