Publications - All publications

Exploring the intersection of metabolic and neuropsychiatric health

Grassi-Oliveira, R. — Sun, 01 Dec 2024 01:23:10 +0100

Modulation of the endocannabinoid system by (S)-ketamine in an animal model of depression

Silva, N. R., Arjmand, S., Domingos, L. B., et al. — Tue, 10 Dec 2024 01:23:10 +0100

Ketamine (KET) is recognized as rapid-acting antidepressant, but its mechanisms of action remain elusive. Considering the role of endocannabinoids (eCB) in stress and depression, we investigated if S-KET antidepressant effects involve the regulation of the eCB system using an established rat model of depression based on selective breeding: the Flinders Sensitive Line (FSL) and their controls, the Flinders Resistant Line (FRL). S-KET (15mg/kg) effects were assessed in rats exposed to the open field and forced swimming test (FST), followed by analysis of the eCB signaling in the rat prefrontal cortex (PFC), a brain region involved in depression neurobiology. Changes in eCB receptors and enzymes were assessed at mRNA and protein levels (qPCR and western blot), CB1 binding ([ 3H]SR141716A autoradiography) and endocannabinoid content (lipidomics). The results demonstrated that the depressive behavior in FSL was negatively correlated with 2-AG levels, which were restored upon acute S-KET treatment. Although S-KET decreased CB1 and FAAH gene expression in FSL, there were no significant changes at protein levels. [ 3H]SR141716A binding to CB1 receptors was increased by S-KET and in silico analysis suggested that it binds to CB1, CB2, GPR55 and FAAH. Overall, S-KET effects correlated with an increased endocannabinoid signaling in the PFC, but systemic treatment with rimonabant failed to block its behavioral effects. Altogether, our results indicate that S-KET facilitates eCB signaling in the PFC of FSL. The inability of rimonabant to block the antidepressant effect of S-KET highlights the complexity of its interaction with the ECS, warranting further investigation into the molecular pathways.

Effects of mindfulness-based stress reduction on neuropeptide Y plasma levels in stressed individuals

Wed, 01 Jan 2025 01:23:10 +0100

BACKGROUND: Clinical studies have suggested that dysregulation of the neuropeptide Y (NPY) system may play a role in psychiatric disorders, including chronic stress. Meanwhile, Mindfulness Based Stress Reduction (MBSR) has shown promise for stress-related maladies. However, no studies have explored whether MBSR can change plasma NPY concentration in stressed individuals.

METHOD: Individuals with symptoms of chronic stress were randomly assigned to eight weeks of either MBSR (n = 15), a locally-developed stress reduction intervention (LSR) (n = 15) or a wait-list control group (n = 20). Blood samples were collected at baseline and at a twelve-week follow-up to determine the effects of MBSR or LSR compared to the wait-list control group on NPY levels.

RESULTS: The MBSR group had increased plasma NPY levels after the program compared to the waitlist control group, whereas the LSR group was not statistically different from the other groups.

CONCLUSION: This pilot study provides evidence of the feasibility of MBSR to alter plasma NPY.

Predictive utility of artificial intelligence on schizophrenia treatment outcomes

Saboori Amleshi, R., Ilaghi, M., Rezaei, M., et al. — Wed, 04 Dec 2024 01:23:10 +0100

Identifying optimal treatment approaches for schizophrenia is challenging due to varying symptomatology and treatment responses. Artificial intelligence (AI) shows promise in predicting outcomes, prompting this systematic review and meta-analysis to evaluate various AI models' predictive utilities in schizophrenia treatment. A systematic search was conducted, and the risk of bias was evaluated. The pooled sensitivity, specificity, and diagnostic odds ratio with 95 % confidence intervals between AI models and the reference standard for response to treatment were assessed. Diagnostic accuracy measures were calculated, and subgroup analysis was performed based on the input data of AI models. Out of the 21 included studies, AI models achieved a pooled sensitivity of 70 % and specificity of 76 % in predicting schizophrenia treatment response with substantial predictive capacity and a near-to-high level of test accuracy. Subgroup analysis revealed EEG-based models to have the highest sensitivity (89 %) and specificity (94 %), followed by imaging-based models (76 % and 80 %, respectively). However, significant heterogeneity was observed across studies in treatment response definitions, participant characteristics, and therapeutic interventions. Despite methodological variations and small sample sizes in some modalities, this study underscores AI's predictive utility in schizophrenia treatment, offering insights for tailored approaches, improving adherence, and reducing relapse risk.

Comparable glucagon-stimulated amino acid suppression in individuals with and without hepatic steatosis or steatohepatitis

Heebøll, S., Wegener, G., Grønbæk, H., Nielsen, S. — Sun, 01 Dec 2024 01:23:10 +0100

Hepatic amino acid (AA) metabolism and glucagon secretion are linked in a feedback cycle in which circulating AAs stimulate glucagon secretion and alpha-cell proliferation, whereas glucagon stimulates hepatic AA catabolism. It has been proposed that metabolic dysfunction-associated steatotic liver disease (MASLD) leads to hepatic glucagon resistance, which may result in hyperaminoacidemia and hyperglucagonemia. We tested the glucagon effect on AA metabolism in subjects with obesity; 11 with steatohepatitis (MASH), 10 with steatosis (MAS), and 7 subjects [control (CON)] without steatosis. We performed a somatostatin clamp with infusions of insulin and low dose followed by high-dose glucagon. We measured plasma levels of 17 AAs and assessed hepatic fat content (FF%) and body fat distribution (visceral and subcutaneous adipose tissue mass) by MRI. HighGlucagon suppressed plasma total AA equally in all groups; MASH 13% (SD 9%), MAS 14% (7%), and CON 11% (5%), respectively. In univariate regression analyses, visceral adipose tissue mass (b ¼ 0.471, P ¼ 0.011) and AA concentration at LowGlucagon (b ¼ -0.524, P ¼ 0.004), but not FF% (b ¼ -0.243, P ¼ 0.213), were significant predictors of AA reduction. Using a stepwise backward multiple regression approach revealed similar results. Total and specific AA levels (glutamic acid and tyrosine) were higher in both MASLD groups during the study, and FF% was positively correlated to a number of individual AAs. Although finding elevated AA concentrations in subjects with MASLD, we conclude that in patients with MASLD that do not have elevated glucagon at baseline, glucagon suppresses circulating AA levels equally in subjects with and without MASLD. ClinicalTrials.gov: NCT04042142. NEW & NOTEWORTHY The purpose of the study was to investigate the concept of “glucagon resistance” in metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis. We asked if a disruption of the glucagon-mediated suppression of hepatic amino acid (AA) catabolism is present in individuals with MASLD compared with individuals with obesity but no MASLD. Contrary to expectations, we found no disruption of the glucagon-stimulated suppression of plasma AA concentration, which disputes the hypothesis that MASLD causes resistance to glucagon.

Experiences of adult patients living with depression-related insomnia

Kristiansen, S. T., Lyhne, C. N., Kragh, M., et al. — Sun, 01 Dec 2024 01:23:10 +0100

Objective: The objective of this review was to identify and synthesize the best available evidence on how adult patients experience living with depression-related insomnia, and their experiences related to pharmacological and non-pharmacological interventions aimed at improving sleep. Introduction: Insomnia affects 80% to 90% of patients with depression. The costs of insomnia are considerable for the individual and society alike. To understand the role and consequences of insomnia for an individual with depression and to optimize sleep interventions, an in-depth understanding of patients' experiences is needed. Therefore, this review addresses how adult patients experience living with depression-related insomnia, along with the experiences of pharmacological and non-pharmacological sleep interventions among patients with depression-related insomnia. Inclusion criteria: Studies focusing on adult patients aged 18 years and older with a diagnosis of depression who had experiences with insomnia and pharmacological and/or non-pharmacological sleep interventions were included. All studies with qualitative research findings from inpatient and outpatient populations were considered. Methods: The following databases were searched: MEDLINE (PubMed), Embase (Elsevier), CINAHL (EBSCOhost), PsycINFO (ProQuest), Cochrane CENTRAL, SveMed+, Scopus, and Web of Science Core Collection. Google Scholar and ProQuest Dissertations and Theses were searched for eligible dissertations and theses. The searches were conducted on May 3-5, 2022, and updated on June 13-19, 2023. Studies published in English, Danish, German, Norwegian, and Swedish were considered. Databases were searched from their inception to the search date. All studies were screened against the inclusion criteria and critically and independently appraised by 2 reviewers for methodological quality. Findings were pooled using meta-aggregation, and a ConQual Summary of Findings was created. Results: Ten qualitative studies were included. The studies were conducted in 6 countries and counted a total of 176 participants. In all, 127 findings were extracted and aggregated into 11 categories. From the 11 categories, 3 synthesized findings were developed: 1) Disruption of sleep challenges coping with everyday life by depleting both physical and mental resources; 2) Sleep is an escape and a protective factor against suicide; and 3) Choices, support, and personalized interventions from non-pharmacological approaches addressing depression-related insomnia are valued. Conclusions: This review underlined the relationship between depression-related insomnia, its profound impact on individuals' lives, and the value of non-pharmacological sleep interventions to address these issues. Specifically, the study revealed the physical and emotional consequences of insomnia while emphasizing how wakefulness during night hours may exacerbate feelings of loneliness and vulnerability to negative thoughts and suicide. Moreover, it provides an overview of patients' experiences of non-pharmacological approaches to address depression-related insomnia and highlights their diverse treatment experiences and preferences. Supplemental Digital Content: A Danish-language version of the abstract of this review is available as Supplemental Digital Content [http://links.lww.com/SRX/A64]. Systematic Review Registration Number: PROSPERO CRD42021276048.

Chronic olanzapine treatment leads to increased opioid receptor expression and changes in feeding regulating neurons in the female rat hypothalamus

Krogsbaek, M., Larsen, N. Y., Yarmahmoudi, F., et al. — Wed, 01 Jan 2025 01:23:10 +0100

Opioid receptor antagonists have shown increasing promise as an adjunct therapy to psychotropic medication. The goal is to reduce the weight gain and metabolic adverse effects that are associated with certain second-generation antipsychotics, such as olanzapine and clozapine. In this study, female rats were treated for 4 weeks with a long-acting injectable formulation of olanzapine to assess effects on hypothalamic feeding regulation. Using quantitative spatial in situ hybridization and receptor autoradiography, expression levels of the mu, kappa and delta opioid receptors were defined in the five hypothalamic areas: paraventricular nucleus (PVN), arcuate nucleus (ARC), ventromedial nucleus (VMN), dorsomedial nucleus (DMN) and lateral hypothalamus (LH). In addition, hypothalamic neuron number and size were estimated using the unbiased optical fractionator and spatial rotator methods. Hyperphagia was observed after only 24 hours of olanzapine treatment, with continued weight gain throughout the duration of the study. In contrast, the observed food intake reversed to control levels after 2 weeks of olanzapine treatment. Chronic olanzapine treatment increased expression of kappa opioid receptor mRNA and receptor availability in the PVN, as well as increased mu opioid receptor availability in the PVN, ARC and VMN. These changes were accompanied by fewer anorexigenic proopiomelanocortin-expressing neurons of the ARC and corticotropin-releasing hormone expressing neurons of the PVN. This study links olanzapine-driven metabolic effects to increased opioid receptor expression in the hypothalamus, thus providing a rationale for the positive effects of using opioid receptor antagonists to relieve olanzapine adverse effects.

Novel drug targets of depression - Focusing on non-coding RNAs

Kaadt, E. — Mon, 01 Jan 2024 01:23:10 +0100

Advancing the understanding of cannabinoids in psychiatry

Wegener, G. — Tue, 01 Oct 2024 01:23:10 +0200

The consequences of childhood maltreatment on dual-diagnosis psychiatric conditions and clinical outcomes in substance use disorders

Stocchero, B. A., Rothmann, L. M., Portolan, E. T., et al. — Sun, 01 Dec 2024 01:23:10 +0100

Background: Evidence suggests that the phenotypic expression of substance use disorders (SUD) may be influenced by exposure to childhood maltreatment (CM). Objective: To assess how CM could impact severity (relapse, treatment dropout, withdrawal), age of substance use onset, psychiatric dual diagnosis (depression, anxiety, PTSD, distress), and self-harm behavior/suicide attempts in adults with SUD, we performed a systematic review and meta-analyses. Methods: We searched PubMed, Web of Science, PsycINFO, and Embase to identify articles examining the association of maltreatment (physical, sexual, or emotional abuse or neglect) before age 18 years with clinical features and course of illness SUD. Multilevel random effects models were performed. Heterogeneity was quantified using the I² statistic. Subgroup/meta-regression analyses were employed to investigate sources of heterogeneity. Risk of bias was assessed using an adapted version of the Newcastle-Ottawa Quality Assessment Scale. Results: Forty-five studies were included. CM was associated with all tested outcomes, such as anxiety (OR = 1.52; 95 % CI = 1.39, 1.65), depression (OR = 1.57; 95 % CI = 1.40, 1.77), PTSD (OR = 1.67; 95 % CI = 1.40, 1.99), psychological distress (OR = 1.49; 95 % CI = 1.24, 1.78), self-harm behavior and suicidal attempts (OR = 1.70; 95 % CI = 1.47, 1.96), SUD severity (OR = 1.15; 95 % CI = 1.04, 1.26), and younger age of onset use (OR = 0.76; 95 % CI = 0.69, 0.84). However, comparisons between outcomes revealed that the association was stronger for dual diagnosis symptoms/conditions than for measures of SUD severity itself. Meta-analyses for some outcomes had large statistical heterogeneity, though these were partly addressed through additional analyses. Gender, mean age of participants, polysubstance use pattern, substance of preference, and CM subtype were found to be moderators of these associations. Conclusions: The consequences of CM on individuals with SUD are more closely linked to co-occurring psychiatric manifestations than to the severity of common clinical indicators (relapse, treatment dropout, withdrawal), and this finding has important implications. Funding: None. Systematic review registration: PROSPERO (CRD42021245936).

Acute transcutaneous auricular vagus nerve stimulation modulates presynaptic SV2A density in healthy rat brain

Binda, K. H., Real, C. C., Simonsen, M. T., et al. — Sun, 20 Oct 2024 01:23:10 +0200

Vagus nerve stimulation (VNS) is the subject of exploration as an adjunct treatment for neurological disorders such as epilepsy, chronic migraine, pain, and depression. A non-invasive form of VNS is transcutaneous auricular VNS (taVNS). Combining animal models and positron emission tomography (PET) may lead to a better understanding of the elusive mechanisms of taVNS. We evaluated the acute effect of electrical stimulation of the left vagus nerve via the ear on brain synaptic vesicle glycoprotein 2A (SV2A) as a measure of presynaptic density and glucose metabolism in naïve rats. Female Sprague-Dawley rats were imaged with [11C]UCB-J (n = 11) or [18F]fluorodeoxyglucose ([18F]FDG) PET (n = 13) on two separate days, (1) at baseline, and (2) after acute unilateral left taVNS or sham stimulation (30 min). We calculated the regional volume of distribution (VT) for [11C]UCB-J and standard uptake values (SUV) for [18F]FDG. We observed regional reductions of [11C]UCB-J binding in response to taVNS ranging from 36% to 59%. The changes in taVNS compared to baseline were significantly larger than those induced by sham stimulation. The differences were observed bilaterally in the frontal cortex, striatum, and midbrain. The [18F]FDG PET uptake remained unchanged following acute taVNS or sham stimulation compared to baseline values. This proof-of-concept study shows for the first time that acute taVNS for 30 min can modulate in vivo synaptic SV2A density in cortical and subcortical regions of healthy rats. Preclinical disease models and PET ligands of different targets can be a powerful combination to assess the therapeutic potential of taVNS.

Serotonin-2B receptor (5-HT_2BR) expression and binding in the brain of APP_swe/PS1_dE9 transgenic mice and in Alzheimer's disease brain tissue

Anzalone, M., Karam, S. A., Briting, S. R. R., et al. — Wed, 01 Jan 2025 01:23:10 +0100

Despite well-documented dysregulation in central serotonergic signaling in Alzheimer's disease (AD), knowledge about the potential involvement of the serotonin-2B receptor (5-HT2BR) subtype remains sparse. Here, we assessed the levels of 5-HT2BRs in brain tissue from APPswe/PS1dE9 transgenic (TG) mice, AD patients, and adult microglial cells. 5-HT2BR mRNA was measured by RT-qPCR in ageing TG and wild-type (WT) mice, in samples from the middle frontal gyrus of female, AD and control subjects, and in microglia from the cerebral cortex of WT mice. The density of 5-HT2BRs was measured by autoradiography using [3H]RS 127445. Both mouse and human brains had low levels of 5-HT2BR mRNA. In whole-brain mouse samples, mRNA expression was significantly lower in TG mice compared to WT at > 18 months of age. In the Aβ-plaque-burdened neocortex and hippocampus of old TG mice, however, levels of 5-HT2BR mRNA were two-fold higher over control, with similar elevations observed in the Aβ-plaque-burdened frontal cortex of human AD patients. 5-HT2BR mRNA expression varied widely in adult microglia and was higher compared to other cortical cell subtypes. In mice, specific [3H]RS-127445 binding in the cortex was first detected after 3 months of age. The density of 5-HT2BRs was low and overall reduced in TG, compared to WT mice. Binding was detectable but too low to be reliably quantified in the human cortex. Our results document Aβ-associated increases in 5-HT2BR mRNA expression and suggest reduced receptor binding in the context of AD. Studies investigating the functional involvement of microglial 5-HT2BRs in AD are considered relevant.

Semaglutide reduces cognitive dysfunction in experimental non-alcoholic steatohepatitis through anti-inflammatory and neuroprotective effects

Kjærgaard, K., Mikkelsen, A. C. D., Bay-Richter, C., et al. — Sat, 28 Sep 2024 01:23:10 +0200

Exploring the potential link between ΔFosB and N-acetylcysteine in craving/relapse dynamics: can N-acetylcysteine stand out as a possible treatment candidate?

Thu, 17 Oct 2024 01:23:10 +0200

From a neuroscientific point of view, one of the unique archetypes of substance use disorders is its road to relapse, in which the reward system plays a crucial role. Studies on the neurobiology of substance use disorders have highlighted the central role of a protein belonging to the Fos family of transcription factors, ΔFosB. Relying on the roles ΔFosB plays in the pathophysiology of substance use disorders, we endeavour to present some evidence demonstrating that N-acetylcysteine, a low-cost and well-tolerated over-the-counter medicine, may influence the downstream pathway of ΔFosB, thereby serving as a treatment strategy to mitigate the risk of relapse in cases of substance use.

P2X7 receptors modulate acquisition of cue fear extinction and contextual background memory generalization in male mice

Sun, 15 Dec 2024 01:23:10 +0100

The purinergic P2X7 receptors (P2X7R) are activated by adenosine triphosphate (ATP) in several brain regions, particularly those involved with emotional control and the regulation of fear-related memories. Here, we investigate the role of P2X7R in fear learning memory, specifically in the acquisition and consolidation phases of the cued fear conditioning paradigm. C57Bl/6 wildtype (WT) male mice that received a single i.p. injection of the selective P2X7R antagonist A438079 prior the conditioning session showed generalization of cued fear memory and impaired fear extinction recall in the test session, while those treated prior the extinction session exhibited a similar behavior profile accompanied by resistance in the extinction learning. However, no effects were observed when this drug was administered immediately after the conditioning, extinction, or before the test session. Our results with P2X7R knockout (P2X7 KO) mice showed a behavioral profile that mirrored the collective effects observed across all pharmacological treatment conditions. This suggests that the P2X7R KO model effectively replicates the behavioral changes induced by the pharmacological interventions, demonstrating that we have successfully isolated the role of P2X7R in the fear and extinction phases of memory. These findings highlight the role of P2X7R in the acquisition and recall of extinction memory and supports P2X7R as a promising candidate for controlling abnormal fear processing, with potential applications for stress exposure-related disorders such as post-traumatic stress disorder (PTSD).

Advancing psychiatric nosology through philosophical inquiry

Arjmand, S., Saboori Amleshi, R., Guimarães, F. S., Wegener, G. — Sun, 01 Dec 2024 01:23:10 +0100

Here, we have utilised the concept of fuzzy logic and Karl Popper’s notion of verisimilitude to advocate navigating the complexity of psychiatric nosology, emphasising that psychiatric disorders defy Boolean logic. We underscore the importance of embracing imprecision and collecting extensive data for a more nuanced understanding of psychiatric disorders, asserting that falsifiability is crucial for scientific progress. We encourage the advancement of personalised psychiatric taxonomy, urging the continual accumulation of data to inform emerging advancements like artificial intelligence in reshaping current psychiatric nosology.

All psychiatric disorders are equal, but some are more equal than others! An unconscious bias that calls for precision terminology

Arjmand, S., Guldager, M. B., Wegener, G. — Mon, 02 Sep 2024 01:23:10 +0200

We address the unconsciously biased perception of psychiatric disorders, highlighting a hierarchical perspective that favours certain diagnoses over others. We aim to uncover reasons for these inequities, emphasising the need for a shift toward pathophysiology-based nomenclature that can promote equal support for each disorder, enhance treatment adherence and encourage open discussions.

Plasma Ribonuclease Activity in Antiretroviral Treatment - Naive People with Human Immunodeficiency Virus and Tuberculosis Disease

Olsson, O., Søkilde, R., Tesfaye, F., et al. — Thu, 01 Aug 2024 01:23:10 +0200

Background: The role of ribonucleases in tuberculosis among people with human immunodeficiency virus (HIV; PWH) is unknown. We explored ribonuclease activity in plasma from PWH with and without tuberculosis. Methods: Participants were identified from a cohort of treatment-naive PWH in Ethiopia who had been classified for tuberculosis disease (HIV positive [HIV+]/tuberculosis positive [tuberculosis+] or HIV+/tuberculosis negative [tuberculosis-]). Ribonuclease activity in plasma was investigated by quantification of synthetic spike-in RNAs using sequencing and quantitative polymerase chain reaction and by a specific ribonuclease activity assay. Quantification of ribonuclease 1, 2, 3, 6, 7, and T2 proteins was performed by enzyme-linked immunosorbent assay. Ribonuclease activity and protein concentrations were correlated with markers of tuberculosis and HIV disease severity and with concentrations of inflammatory mediators. Results: Ribonuclease activity was significantly higher in plasma of HIV+/tuberculosis+ (n = 51) compared with HIV+/tuberculosis- (n = 78), causing reduced stability of synthetic spike-in RNAs. Concentrations of ribonucleases 2, 3, and T2 were also significantly increased in HIV+/tuberculosis+ compared with HIV+/tuberculosis-. Ribonuclease activity was correlated with HIV viral load, and inversely correlated with CD4 cell count, mid-upper arm circumference, and body mass index. Moreover, ribonuclease activity was correlated with concentrations of interleukin 27, procalcitonin and the kynurenine-tryptophan ratio. Conclusions: PWH with tuberculosis disease have elevated plasma ribonuclease activity, which is also associated with HIV disease severity and systemic inflammation.

Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression

Guintivano, J., Byrne, E. M., Kiewa, J., et al. — Fri, 01 Dec 2023 01:23:10 +0100

OBJECTIVE: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD.

METHOD: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system.

RESULTS: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD.

CONCLUSIONS: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).

Gas phase production of [¹¹C]methyl iodide-d₃. Synthesis and biological evaluation of S-[N-methyl-¹¹C]citalopram and deuterated analogues

Madsen, J., Elfving, B., Andersen, K., Martiny, L., Knudsen, G. M. — Sat, 01 May 2004 01:23:10 +0200

Three ¹¹C-labelled tracers for the serotonin reuptake site, S-[N-methyl-¹¹C]citalopram ([¹¹C]-4), S-[N-methyl-d ₃-¹¹C]citalopram ([¹¹C]-12), and S-[N-methyl-¹¹C]citalopram-α,α-d₂ ([ ¹¹C]-13) were synthesized and the distribution of radioactivity after injection of radioligand was examined ex vivo in rats. The deuterated analogue of (S)-desmethylcitalopram, (S)-1-(4-fluorophenyl)-1-(3-methylamino-[3-d ₂]-propyl)-1,3-dihydro-isobenzofuran-5-carbonitrile (11), was synthesized in a multi-step synthesis from escitalopram (4) and used as precursor in the synthesis of [¹¹C]-13. In analogy with the reported gas phase synthesis of [¹¹C]methyl iodide the first gas phase synthesis of [¹¹C]Methyl iodide-d₃ is reported. The ¹H/²H kinetic isotope effect related to the synthesized compounds were investigated in ex vivo rat studies, where the brain regions of interest to cerebellum ratios of the tracers [¹¹C]-4, [ ¹¹C]-12 and [¹¹C]-13 were compared. The ex vivo data indicated no significant differences in binding in any of the investigated brain regions after injection of the three tracers.

Dysregulation of circadian clock gene expression patterns in a treatment-resistant animal model of depression

Højgaard, K., Kaadt, E., Mumm, B. H., Pereira, V. S., Elfving, B. — Sun, 01 Sep 2024 01:23:10 +0200

Circadian rhythm (CR) disturbances are among the most commonly observed symptoms during major depressive disorder, mostly in the form of disrupted sleeping patterns. However, several other measurable parameters, such as plasma hormone rhythms and differential expression of circadian clock genes (ccgs), are also present, often referred to as circadian phase markers. In the recent years, CR disturbances have been recognized as an essential aspect of depression; however, most of the known animal models of depression have yet to be evaluated for their eligibility to model CR disturbances. In this study, we investigate the potential of adrenocorticotropic hormone (ACTH)-treated animals as a disease model for research in CR disturbances in treatment-resistant depression. For this purpose, we evaluate the changes in several circadian phase markers, including plasma concentrations of corticosterone, ACTH, and melatonin, as well as gene expression patterns of 13 selected ccgs at 3 different time points, in both peripheral and central tissues. We observed no impact on plasma corticosterone and melatonin concentrations in the ACTH rats compared to vehicle. However, the expression pattern of several ccgs was affected in the ACTH rats compared to vehicle. In the hippocampus, 10 ccgs were affected by ACTH treatment, whereas in the adrenal glands, 5 ccgs were affected and in the prefrontal cortex, hypothalamus and liver 4 ccgs were regulated. In the blood, only 1 gene was affected. Individual tissues showed changes in different ccgs, but the expression of Bmal1, Per1, and Per2 were most generally affected. Collectively, the results presented here indicate that the ACTH animal model displays dysregulation of a number of phase markers suggesting the model may be appropriate for future studies into CR disturbances. (Figure presented.)

Fluoxetine and Ketamine Enhance Extinction Memory and Brain Plasticity by Triggering the p75 Neurotrophin Receptor Proteolytic Pathway

Diniz, C. R. A. F., Crestani, A. P., C Casarotto, P., et al. — Sat, 01 Feb 2025 01:23:10 +0100

Background: Diverse antidepressants were recently described to bind to TrkB (tyrosine kinase B) and drive a positive allosteric modulation of endogenous BDNF (brain-derived neurotrophic factor). Although neurotrophins such as BDNF can bind to p75NTR (p75 neurotrophin receptor), their precursors are the high-affinity p75NTR ligands. While part of an unrelated receptor family capable of inducing completely opposite physiological changes, TrkB and p75NTR feature a crosslike conformation dimer and carry a cholesterol-recognition amino acid consensus in the transmembrane domain. As such qualities were found to be crucial for antidepressants to bind to TrkB and drive behavioral and neuroplasticity effects, we hypothesized that their effects might also depend on p75NTR. Methods: Enzyme-linked immunosorbent assay–based binding and nuclear magnetic resonance spectroscopy were performed to assess whether antidepressants would bind to p75NTR. HEK293T cells and a variety of in vitro assays were used to investigate whether fluoxetine (FLX) or ketamine (KET) would trigger any α- and γ-secretase–dependent p75NTR proteolysis and lead to p75NTR nuclear localization. Ocular dominance shift was performed with male and female p75NTR knockout mice to study the effects of KET and FLX on brain plasticity, in addition to pharmacological interventions to verify how p75NTR signaling is important for the effects of KET and FLX in enhancing extinction memory in male wild-type mice and rats. Results: Antidepressants were found to bind to p75NTR. FLX and KET triggered the p75NTR proteolytic pathway and induced p75NTR-dependent behavioral/neuroplasticity changes. Conclusions: We hypothesize that antidepressants co-opt both BDNF/TrkB and proBDNF/p75NTR systems to induce a more efficient activity-dependent synaptic competition, thereby boosting the brain's ability for remodeling.

Brain dysfunction is prevented by alpha2A adrenergic receptor antagonism in a rodent model of diet-induced metabolic dysfunction-associated steatotic liver disease

Mikkelsen, A. C. D., Kjærgaard, K., Bay-Richter, C., et al. — Mon, 01 Jan 2024 01:23:10 +0100

The effect of antidepressant treatment on blood BDNF levels in depressed patients

Madsen, C. A., Navarro, M. L., Elfving, B., et al. — Tue, 01 Oct 2024 01:23:10 +0200

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder and a leading cause of disability worldwide. Brain-derived neurotrophic factor (BDNF), a signaling protein responsible for promoting neuroplasticity, is highly expressed in the central nervous system but can also be found in the blood. Since impaired brain plasticity is considered a cornerstone in the pathophysiology of MDD, measurement of BDNF in blood has been proposed as a potential biomarker in MDD. The aim of our study is to systematically review the literature for the effects of antidepressant treatments on blood BDNF levels in MDD and the suitability of blood BDNF as a biomarker for depression severity and antidepressant response. We searched Pubmed® and Cochrane library up to March 2024 in a systematic manner using Medical Subject Headings (MeSH). The search resulted in a total of 42 papers, of which 30 were included in this systematic review. Generally, we found that patients with untreated MDD have a lower blood BDNF level than healthy controls. Antidepressant treatments increase blood BDNF levels, and more evidently after pharmacological than non-pharmacological treatment. Neither baseline nor change in the blood BDNF level correlates with depression severity or treatment outcome, which undermines its use as a biomarker in MDD. Our review also highlights the importance of considering factors influencing the accuracy and reproducibility of BDNF measurements. We summarize considerations to help obtain more robust blood BDNF values and compile a list of recommendations to help streamline assessment of blood BDNF levels in future studies.

TMEFF1 is a neuron-specific restriction factor for herpes simplex virus

Dai, Y., Idorn, M., Serrero, M. C., et al. — Thu, 01 Aug 2024 01:23:11 +0200

The brain is highly sensitive to damage caused by infection and inflammation^1,2. Herpes simplex virus 1 (HSV-1) is a neurotropic virus and the cause of herpes simplex encephalitis³. It is unknown whether neuron-specific antiviral factors control virus replication to prevent infection and excessive inflammatory responses, hence protecting the brain. Here we identify TMEFF1 as an HSV-1 restriction factor using genome-wide CRISPR screening. TMEFF1 is expressed specifically in neurons of the central nervous system and is not regulated by type I interferon, the best-known innate antiviral system controlling virus infections. Depletion of TMEFF1 in stem-cell-derived human neurons led to elevated viral replication and neuronal death following HSV-1 infection. TMEFF1 blocked the HSV-1 replication cycle at the level of viral entry through interactions with nectin-1 and non-muscle myosin heavy chains IIA and IIB, which are core proteins in virus–cell binding and virus–cell fusion, respectively^4–6. Notably, Tmeff1^−/− mice exhibited increased susceptibility to HSV-1 infection in the brain but not in the periphery. Within the brain, elevated viral load was observed specifically in neurons. Our study identifies TMEFF1 as a neuron-specific restriction factor essential for prevention of HSV-1 replication in the central nervous system.

Sex differences in sensitivity to fentanyl effects in mice

Kestering-Ferreira, É., Heberle, B. A., Sindermann Lumertz, F., et al. — Thu, 01 Aug 2024 01:23:11 +0200

Purpose: Sex differences play a crucial role in understanding vulnerability to opioid addiction, yet there have been limited preclinical investigations of this effect during the transition from adolescence to adulthood. The present study compared the behaviors of male and female rodents in response to fentanyl treatment and targeted molecular correlates in the striatum and medial prefrontal cortex. Materials and methods: Thirty adolescent C57BL/6J mice underwent a 1-week fentanyl treatment with an escalating dose. In addition to evaluating locomotor activity and anxiety-related parameters, we also assessed naloxone-induced fentanyl acute withdrawal jumps. We employed real-time quantitative PCR (qPCR) to assess overall gene expression of dopaminergic receptors (Drd1, Drd2, Drd4 and Drd5) and the μ-opioid receptor Oprm1. The levels of epigenetic base modifications including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) were assessed on CpG islands of relevant genes. Results: Females had higher locomotor activity than males after chronic fentanyl treatment, and they exhibited higher fentanyl withdrawal jumping behavior induced by naloxone. Females also presented lower Drd4 gene expression and DNA methylation (5mC + 5hmC) in the striatum. We found that locomotor activity and fentanyl withdrawal jumps were negatively correlated with Drd4 methylation and gene expression in the striatum, respectively. Conclusions: The findings suggested that female mice displayed heightened sensitivity to the effects of fentanyl treatment during the transition from adolescence to adulthood. This effect may be associated with molecular alterations related to the Drd4 gene.

Gut microbiota differences in five-year-old children that were born preterm with a history of necrotizing enterocolitis

Magnusson, A., Jabbari Shiadeh, S. M., Ardalan, M., Swolin-Eide, D., Elfvin, A. — Mon, 01 Jul 2024 01:23:11 +0200

The study explores the long-term effects of necrotizing enterocolitis (NEC) on gut microbiota in preterm infants by analyzing stool samples from 5-year-old children using shotgun metagenomic sequencing. It compares children with a history of NEC, treated surgically or medically, to preterm controls without NEC. Findings reveal persistent gut microbiota dysbiosis in NEC children, with reduced species diversity and evenness, especially in those treated surgically. The surgical NEC group had a lower Shannon index, indicating less microbial diversity. Significant differences in taxonomic profiles were observed, mainly influenced by surgical treatment. These results underscore the lasting impact of NEC and its treatment on gut microbiota, suggesting a need for strategies addressing long-term dysbiosis.

A single subanaesthetic dose of the rapid-acting antidepressant S-ketamine raises presynaptic SV2A density in limbic regions of the Wistar Kyoto rat model of depression

Mon, 01 Jan 2024 01:23:11 +0100

The N-methyl-D-aspartate receptor (NMDA-R) antagonist S-ketamine has been approved as a rapid-acting antidepressant for treatment-resistant depression (TRD). The antidepressant mechanisms have not fully been elucidated; however, alterations of synaptic proteins and mechanisms may play a vital role. Here, we study the effect of a single subanaesthetic dose of 15 mg/kg S-ketamine vs saline 1 h after administration in the Wistar Kyoto rat model of depression on the density of synaptic vesicle glycoprotein 2A (SV2A) and the metabotropic glutamate receptor 5 (mGluR5) using [3H]UCB-J and [3H]MPEPγ autoradiography, respectively, compared with control Wistar Hannover rats. In a separate cohort of Wistar Kyoto rats, we investigate the transcriptional regulation of presynaptic markers Sv2a, Syn 1–3, Syt 1–3, Synaptophysin, Vamp1, 2, 5, and 7, postsynaptic markers Homer1-3, Nrg 1, Nlgn 2, Nlgn 3, Psd95, NMDA receptor subunits Nr2a, Nr2b, AMPA receptor subunits Gria1-3, GABA type A receptor-associated protein (Gabarap), glutamate metabotropic receptor subtype 5 (Grm5), and brain-derived neurotrophic factor (Bdnf) using real-time quantitative polymerase chain reaction (qPCR) in hippocampus in response to S-ketamine vs saline injection. In Wistar Kyoto rats, S-ketamine increases [3H]UCB-J binding to SV2A compared to saline-injected controls in the nucleus accumbens and dorsal and ventral hippocampus, an effect absent in the Wistar Hannover strain. No changes were observed in [3H]MPEPγ binding to mGluR5, nor in gene regulation. S-ketamine can regulate presynaptic SV2A density in brain areas relevant to depression in the Wistar Kyoto model, but not in controls, suggesting a role for SV2A in the antidepressant effects of S-ketamine.

Estimating the statistical performance of different approaches to meta-analysis of data from animal studies in identifying the impact of aspects of study design

Wang, Q., Liao, J., Hair, K., et al. — Mon, 01 Jan 2018 01:23:11 +0100

Background: Meta-analysis is increasingly used to summarise the findings identified in systematic reviews of animal studies modelling human disease. Such reviews typically identify a large number of individually small studies, testing efficacy under a variety of conditions. This leads to substantial heterogeneity, and identifying potential sources of this heterogeneity is an important function of such analyses. However, the statistical performance of different approaches (normalised compared with standardised mean difference estimates of effect size; stratified meta-analysis compared with meta-regression) is not known. Methods: Using data from 3116 experiments in focal cerebral ischaemia to construct a linear model predicting observed improvement in outcome contingent on 25 independent variables. We used stochastic simulation to attribute these variables to simulated studies according to their prevalence. To ascertain the ability to detect an effect of a given variable we introduced in addition this "variable of interest" of given prevalence and effect. To establish any impact of a latent variable on the apparent influence of the variable of interest we also introduced a "latent confounding variable" with given prevalence and effect, and allowed the prevalence of the variable of interest to be different in the presence and absence of the latent variable. Results: Generally, the normalised mean difference (NMD) approach had higher statistical power than the standardised mean difference (SMD) approach. Even when the effect size and the number of studies contributing to the meta-analysis was small, there was good statistical power to detect the overall effect, with a low false positive rate. For detecting an effect of the variable of interest, stratified meta-analysis was associated with a substantial false positive rate with NMD estimates of effect size, while using an SMD estimate of effect size had very low statistical power. Univariate and multivariable meta-regression performed substantially better, with low false positive rate for both NMD and SMD approaches; power was higher for NMD than for SMD. The presence or absence of a latent confounding variables only introduced an apparent effect of the variable of interest when there was substantial asymmetry in the prevalence of the variable of interest in the presence or absence of the confounding variable. Conclusions: In meta-analysis of data from animal studies, NMD estimates of effect size should be used in preference to SMD estimates, and meta-regression should, where possible, be chosen over stratified meta-analysis. The power to detect the influence of the variable of interest depends on the effect of the variable of interest and its prevalence, but unless effects are very large adequate power is only achieved once at least 100 experiments are included in the meta-analysis.

Behavioural and molecular effects induced by Cannabidiol in animal models of depression

Silote, G. — Fri, 01 Jan 2021 01:23:11 +0100

Synaptic Vesicle Glycoprotein 2A imaging of non-pharmacological therapies for Pakinson's disease

Henrique Binda, K. — Mon, 01 Jan 2024 01:23:11 +0100

Therapeutic potential of cannabidiol in depression

Guldager, M. B., Chaves Filho, A. M., Biojone, C., Joca, S. — Mon, 01 Jan 2024 01:23:11 +0100

Major depressive disorder (MDD) is a widespread and debilitating condition affecting a significant portion of the global population. Traditional treatment for MDD has primarily involved drugs that increase brain monoamines by inhibiting their uptake or metabolism, which is the basis for the monoaminergic hypothesis of depression. However, these treatments are only partially effective, with many patients experiencing delayed responses, residual symptoms, or complete non-response, rendering the current view of the hypothesis as reductionist. Cannabidiol (CBD) has shown promising results in preclinical models and human studies. Its mechanism is not well-understood, but may involve monoamine and endocannabinoid signaling, control of neuroinflammation and enhanced neuroplasticity. This chapter will explore CBD's effects in preclinical and clinical studies, its molecular mechanisms, and its potential as a treatment for MDD.

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic

Schumacher, A. E., Kyu, H. H., Aali, A., et al. — Wed, 01 May 2024 01:23:11 +0200

Background: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. Methods: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. Findings: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. Interpretation: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic. Funding: Bill & Melinda Gates Foundation.

Variations in seasonal solar insolation are associated with a history of suicide attempts in bipolar I disorder

Bauer, M., Glenn, T., Achtyes, E. D., et al. — Wed, 01 Dec 2021 01:23:11 +0100

Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed.

Pulmonary maternal immune activation does not cross the placenta but leads to fetal metabolic adaptation

Hansen, S. S. K., Krautz, R., Rago, D., et al. — Sat, 01 Jun 2024 01:23:11 +0200

The fetal development of organs and functions is vulnerable to perturbation by maternal inflammation which may increase susceptibility to disorders after birth. Because it is not well understood how the placenta and fetus respond to acute lung- inflammation, we characterize the response to maternal pulmonary lipopolysaccharide exposure across 24 h in maternal and fetal organs using multi-omics, imaging and integrative analyses. Unlike maternal organs, which mount strong inflammatory immune responses, the placenta upregulates immuno-modulatory genes, in particular the IL-6 signaling suppressor Socs3. Similarly, we observe no immune response in the fetal liver, which instead displays metabolic changes, including increases in lipids containing docosahexaenoic acid, crucial for fetal brain development. The maternal liver and plasma display similar metabolic alterations, potentially increasing bioavailability of docosahexaenoic acid for the mother and fetus. Thus, our integrated temporal analysis shows that systemic inflammation in the mother leads to a metabolic perturbation in the fetus.

Approaches to embryonic neurodevelopment

Rafati, A. H., Joca, S., Vontell, R. T., Wegener, G., Ardalan, M. — Mon, 01 Jul 2024 01:23:11 +0200

The development of the human central nervous system initiates in the early embryonic period until long after delivery. It has been shown that several neurological and neuropsychiatric diseases originate from prenatal incidents. Mathematical models offer a direct way to understand neurodevelopmental processes better. Mathematical modelling of neurodevelopment during the embryonic period is challenging in terms of how to 'Approach', how to initiate modelling and how to propose the appropriate equations that fit the underlying dynamics of neurodevelopment during the embryonic period while including the variety of elements that are built-in naturally during the process of neurodevelopment. It is imperative to answer where and how to start modelling; in other words, what is the appropriate 'Approach'? Therefore, one objective of this study was to tackle the mathematical issue broadly from different aspects and approaches. The approaches were divided into three embryonic categories: cell division, neural tube growth and neural plate growth. We concluded that the neural plate growth approach provides a suitable platform for simulation of brain formation/neurodevelopment compared to cell division and neural tube growth. We devised a novel equation and designed algorithms that include geometrical and topological algorithms that could fit most of the necessary elements of the neurodevelopmental process during the embryonic period. Hence, the proposed equations and defined mathematical structure would be a platform to generate an artificial neural network that autonomously grows and develops.

Regulation of mitochondrial dysfunction by estrogens and estrogen receptors in Alzheimer's disease

Arjmand, S., Ilaghi, M., Sisakht, A. K., et al. — Thu, 01 Aug 2024 01:23:11 +0200

Alzheimer's disease (AD) is a neurodegenerative disorder that primarily manifests itself by progressive memory loss and cognitive decline, thus significantly affecting memory functions and quality of life. In this review, we proceed from the understanding that the canonical amyloid-β hypothesis, while significant, has faced setbacks, highlighting the need to adopt a broader perspective considering the intricate interplay of diverse pathological pathways for effective AD treatments. Sex differences in AD offer valuable insights into a better understanding of its pathophysiology. Fluctuation of the levels of ovarian sex hormones during perimenopause is associated with changes in glucose metabolism, as a possible window of opportunity to further understand the roles of sex steroid hormones and their associated receptors in the pathophysiology of AD. We review these dimensions, emphasizing the potential of estrogen receptors (ERs) to reveal mitochondrial functions in the search for further research and therapeutic strategies for AD pharmacotherapy. Understanding and addressing the intricate interactions of mitochondrial dysfunction and ERs potentially pave the way for more effective approaches to AD therapy.

Subanesthetic S-ketamine does not acutely alter striatal dopamine transporter binding in healthy Sprague Dawley female rats

Bærentzen, S. L., Thomsen, J. B., Thomsen, M. B., et al. — Mon, 01 Jul 2024 01:23:11 +0200

Major depressive disorder is one of the most prevalent mental health disorders, posing a global socioeconomic burden. Conventional antidepressant treatments have a slow onset of action, and 30% of patients show no clinically significant treatment response. The recently approved fast-acting antidepressant S-ketamine, an N-methyl-D-aspartate receptor antagonist, provides a new approach for treatment-resistant patients. However, knowledge of S-ketamine's mechanism of action is still being established. Depressed human subjects have lower striatal dopamine transporter (DAT) availability compared to healthy controls. Rodent studies report increased striatal dopamine concentration in response to acute ketamine administration. In vivo [ 18F]FE-PE2I ([ 18F]-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4'-methyl-phenyl) nortropane) positron emission tomography (PET) imaging of the DAT has not previously been applied to assess the effect of acute subanesthetic S-ketamine administration on DAT availability. We applied translational in vivo [ 18F]FE-PE2I PET imaging of the DAT in healthy female rats to evaluate whether an acute subanesthetic intraperitoneal dose of 15 mg/kg S-ketamine alters DAT availability. We also performed [ 3H]GBR-12935 autoradiography on postmortem brain sections. We found no effect of acute S-ketamine administration on striatal DAT binding using [ 18F]FE-PE2I PET or [ 3H]GBR-12935 autoradiography. This negative result does not support the hypothesis that DAT changes are associated with S-ketamine's rapid antidepressant effects, but additional studies are warranted.

The Interplay between the Estrogen Ensemble and Antidepressants

Arjmand, S. — Mon, 01 Jan 2024 01:23:11 +0100

Mice lacking interleukin-18 gene display behavioral changes in animal models of psychiatric disorders: Possible involvement of immunological mechanisms

Lisboa, S. F. S., Issy, A. C., Biojone, C., et al. — Mon, 01 Jan 2018 01:23:11 +0100

Elastase-2 Knockout Mice Display Anxiogenic- and Antidepressant-Like Phenotype: Putative Role for BDNF Metabolism in Prefrontal Cortex

Diniz, C. R. A. F., Becari, C., Lesnikova, A., et al. — Mon, 01 Jan 2018 01:23:11 +0100

Antidepressant-like effect of losartan involves TRKB transactivation from angiotensin receptor type 2 (AGTR2) and recruitment of FYN

Mon, 01 Jan 2018 01:23:11 +0100

Dual mechanism of TRKB activation by anandamide through CB1 and TRPV1 receptors

Diniz, C. R. A. F., Biojone, C., Joca, S., et al. — Tue, 01 Jan 2019 01:23:11 +0100

Reduced P2X receptor levels are associated with antidepressant effect in the learned helplessness model

Ribeiro, D. E., Casarotto, P. ., Stanquini, L., et al. — Tue, 01 Jan 2019 01:23:11 +0100

New insights into the involvement of serotonin and BDNF-TrkB signalling in cannabidiol's antidepressant effect

Sat, 13 Jul 2024 01:23:11 +0200

Cannabidiol (CBD) is a phytocannabinoid devoid of psychostimulant properties and is currently under investigation as a potential antidepressant drug. However, the mechanisms underlying CBD's antidepressant effects are not yet well understood. CBD targets include a variety of receptors, enzymes, and transporters, with different binding-affinities. Neurochemical and pharmacological evidence indicates that both serotonin and BDNF-TrkB signalling in the prefrontal cortex are necessary for the antidepressant effects induced by CBD in animal models. Herein, we reviewed the current literature to dissect if these are independent mechanisms or if CBD-induced modulation of the serotonergic neurotransmission could mediate its neuroplastic effects through subsequent regulation of BDNF-TrkB signalling, thus culminating in rapid neuroplastic changes. It is hypothesized that: a) CBD interaction with serotonin receptors on neurons of the dorsal raphe nuclei and the resulting disinhibition of serotonergic neurons would promote rapid serotonin release in the PFC and hence its neuroplastic and antidepressant effects; b) CBD facilitates BDNF-TRKB signalling, especially in the PFC, which rapidly triggers neurochemical and neuroplastic effects. These hypotheses are discussed with perspectives for new drug development and clinical applications.

Excessive sucrose consumption reduces synaptic density and increases cannabinoid receptors in Göttingen minipigs

Bærentzen, S. L., Thomsen, M., Alstrup, A. K. O., et al. — Sun, 01 Sep 2024 01:23:11 +0200

Diets high in sucrose and fat are becoming more prevalent the world over, accompanied by a raised prevalence of cardiovascular diseases, cancers, diabetes, obesity, and metabolic syndrome. Clinical studies link unhealthy diets with the development of mental health disorders, particularly depression. Here, we investigate the effects of 12 days of sucrose consumption administered as 2 L of 25% sucrose solution daily for 12 days in Göttingen minipigs on the function of brain receptors involved in reward and motivation, regulating feeding, and pre- and post-synaptic mechanisms. Through quantitative autoradiography of cryostat sections containing limbic brain regions, we investigated the effects of sucrose restricted to a 1-h period each morning, on the specific binding of [³H]raclopride on dopamine D2/3 receptors, [³H]UCB-J at synaptic vesicle glycoprotein 2A (SV2A), [³H]MPEPγ at metabotropic glutamate receptor subtype 5 (mGluR5) and [³H]SR141716A at the cannabinoid receptor 1 (CB1). Compared to control diet animals, the sucrose group showed significantly lower [³H]UCB-J and [³H]MPEPγ binding in the prefrontal cortex. The sucrose-consuming minipigs showed higher hippocampal CB1 binding, but unaltered dopamine D2/3 binding compared to the control group. We found that the sucrose diet reduced the synaptic density marker while increasing CB1 binding in limbic brain structures, which may subserve maladaptive changes in appetite regulation and feeding. Further studies of the effects of diets and lifestyle habits on brain neuroreceptor and synaptic density markers are warranted.

The efficacy of ball blankets on insomnia in depression in outpatient clinics

Sun, 01 Dec 2024 01:23:11 +0100

Many patients with depression report insomnia symptoms that profoundly affect their health and well-being. Non-pharmacological treatments of insomnia may be preferable for some patients. In this randomised crossover trial, we investigated the efficacy of the Protac Ball Blanket® on insomnia among patients with depression. Included patients (n = 45) were diagnosed with unipolar depression, and with subjective insomnia and poor sleep quality (Pittsburgh Sleep Quality Index Score > 5). Each patient slept 2 weeks with a Protac Ball Blanket® and 2 weeks with a control duvet. Randomisation defined the order of the 2-week sleep periods. Patients served as their own control in this design. The primary outcome was changes in total night-time sleep. Secondary outcomes were sleep-onset latency, number of awakenings, wake after sleep onset, daily use of pro necessitate sedatives and hypnotics, subjective sleep quality (Pittsburgh Sleep Quality Index), insomnia severity (Insomnia Severity Index), symptoms of depression (Hamilton Depression Rating Scale, Major Depression Inventory), symptoms of anxiety (Beck Anxiety Index), and patient-reported outcomes concerning interpersonal sensitivity, neurasthenia, anxiety and depression (Self-Reported Symptom State Scale). Paired two-sided t-tests were used to compare the means of the differences of the outcomes. Protac Ball Blanket® increased total night-time sleep by 12.9 min (95% confidence interval: 1.21–24.63, p = 0.031). Among the secondary outcomes, Protac Ball Blanket® decreased Hamilton Depression Rating Scale by 2.78 (95% confidence interval: −5.44; −0.11, p = 0.042) and Insomnia Severity Index by 2.98 (95% confidence interval: −5.45; −0.50, p = 0.020). No changes were observed in sleep-onset latency, number of awakenings, wake after sleep onset, Pittsburgh Sleep Quality Index, Major Depression Inventory, Beck Anxiety Index, Self-Reported Symptom State Scale, and medication use. The results suggest that some patients may benefit from Protac Ball Blanket® as an add-on non-pharmacological treatment to improve sleep in depression.

Novelty-induced Consolidation of Hippocampus-Dependent Memories

Højgaard, K. — Mon, 01 Jan 2024 01:23:11 +0100

Dynamic multi-pinhole collimated brain SPECT of Parkinson’s disease by [¹²³I]FP-CIT

Fredensborg, F. L.H., Thilsing-Hansen, K., Simonsen, J. A., et al. — Fri, 01 Mar 2024 01:23:11 +0100

We investigated the feasibility of using a dopamine transporter (DaT) tracer ligand ([¹²³I]FP-CIT) along with novel multi-pinhole brain collimators for dynamic brain single photon emission computed tomography (SPECT) in suspected Parkinson's disease patients. Thirteen patients underwent dynamic tracer acquisitions before standard imaging. Uptake values were corrected for partial volume effects. Specific binding ratio (SBR_calc) was calculated, reflecting binding potential relative to non-displaceable binding (BP_ND) in the cortex. Additional pharmacokinetic parameters (BP_ND, R₁, k₂) were estimated using the simplified reference tissue model, revealing differences between Kahraman low-score (LS) and high-score (HS) groups. Results showed increasing striatal tracer uptake until 100 min post-injection, with consistent values afterward. Uptake and SBR_calc ratios matched visual assessment. LS patients had lower putamen than caudate nucleus tracer uptake, decreased BP_ND values, while R₁ and k₂ values were comparable to HS patients. In conclusion, dynamic multi-pinhole SPECT using DaT tracer with the extraction of pharmacokinetic parameters is feasible and could help enable early differentiation of reduced and normal DaT values.

Repeated cannabidiol treatment affects neuroplasticity and endocannabinoid signaling in the prefrontal cortex of the Flinders Sensitive Line (FSL) rat model of depression.

Domingos, L. B., Müller, H. K., da Silva, N. R., et al. — Wed, 01 May 2024 01:23:11 +0200

Delayed therapeutic responses and limited efficacy are the main challenges of existing antidepressant drugs, thereby incentivizing the search for new potential treatments. Cannabidiol (CBD), non-psychotomimetic component of cannabis, has shown promising antidepressant effects in different rodent models, but its mechanism of action remains unclear. Herein, we investigated the antidepressant-like effects of repeated CBD treatment on behavior, neuroplasticity markers and lipidomic profile in the prefrontal cortex (PFC) of Flinders Sensitive Line (FSL), a genetic animal model of depression, and their control counterparts Flinders Resistant Line (FRL) rats. Male FSL animals were treated with CBD (10 mg/kg; i.p.) or vehicle (7 days) followed by Open Field Test (OFT) and the Forced Swimming Test (FST). The PFC was analyzed by a) western blotting to assess markers of synaptic plasticity and cannabinoid signaling in synaptosome and cytosolic fractions; b) mass spectrometry-based lipidomics to investigate endocannabinoid levels (eCB). CBD attenuated the increased immobility observed in FSL, compared to FRL in FST, without changing the locomotor behavior in the OFT. In synaptosomes, CBD increased ERK1, mGluR5, and Synaptophysin, but failed to reverse the reduced CB1 and CB2 levels in FSL rats. In the cytosolic fraction, CBD increased ERK2 and decreased mGluR5 expression in FSL rats. Surprisingly, there were no significant changes in eCB levels in response to CBD treatment. These findings suggest that CBD effects in FSL animals are associated with changes in synaptic plasticity markers involving mGluR5, ERK1, ERK2, and synaptophysin signaling in the PFC, without increasing the levels of endocannabinoids in this brain region.