Publications - All publications

Sex differences in sensitivity to fentanyl effects in mice

Kestering-Ferreira, É., Heberle, B. A., Sindermann Lumertz, F., et al. — Thu, 01 Aug 2024 12:41:33 +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 12:41:33 +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 12:41:33 +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 12:41:33 +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 12:41:33 +0100

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

Henrique Binda, K. — Mon, 01 Jan 2024 12:41:34 +0100

Therapeutic potential of cannabidiol in depression

Guldager, M. B., Chaves Filho, A. M., Biojone, C., Joca, S. — Mon, 01 Jan 2024 12:41:34 +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 12:41:34 +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 12:41:34 +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 12:41:34 +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 12:41:34 +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. — Mon, 27 May 2024 12:41:34 +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 12:41:34 +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: A Search for Therapeutic Insights

Arjmand, S. — Mon, 01 Jan 2024 12:41:34 +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 12:41:34 +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 12:41:34 +0100

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

Mon, 01 Jan 2018 12:41:34 +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 12:41:34 +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 12:41:34 +0100

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

Sat, 13 Jul 2024 12:41:34 +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 12:41:34 +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

Mon, 01 Jan 2024 12:41:34 +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. — Sun, 01 Jan 2023 12:41:34 +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 12:41:34 +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 12:41:34 +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.

Sildenafil, alone and in combination with imipramine or escitalopram, display antidepressant-like effects in an adrenocorticotropic hormone-induced (ACTH) rodent model of treatment-resistant depression

Bernardus Saayman, J. L., Harvey, B. H., Wegener, G., Brink, C. B. — Mon, 01 Apr 2024 12:41:34 +0200

Background: Major depressive disorder (MDD) represents a challenge with high prevalence and limited effectiveness of existing treatments, particularly in cases of treatment-resistant depression (TRD). Innovative strategies and alternative drug targets are therefore necessary. Sildenafil, a selective phosphodiesterase type 5 (PDE5) inhibitor, is known to exert neuroplastic, anti-inflammatory, and antioxidant properties, and is a promising antidepressant drug candidate. Aim: To investigate whether sildenafil monotherapy or in combination with a known antidepressant, can elicit antidepressant-like effects in an adrenocorticotropic hormone (ACTH)-induced rodent model of TRD. Methods: ACTH-naïve and ACTH-treated male Sprague-Dawley (SD) rats received various sub-acute drug treatments, followed by behavioural tests and biochemical analyses conversant with antidepressant actions. Results: Sub-chronic ACTH treatment induced significant depressive-like behaviour in rats, evidenced by increased immobility during the forced swim test (FST). Sub-acute sildenafil (10 mg/kg) (SIL-10) (but not SIL-3), and combinations of imipramine (15 mg/kg) (IMI-15) and sildenafil (3 mg/kg) (SIL-3) or escitalopram (15 mg/kg) (ESC-15) and SIL-3, exhibited significant antidepressant-like effects. ACTH treatment significantly elevated hippocampal levels of brain-derived neurotrophic factor (BDNF), serotonin, norepinephrine, kynurenic acid (KYNUA), quinolinic acid (QUINA), and glutathione. The various mono- and combined treatments significantly reversed some of these changes, whereas IMI-15 + SIL-10 significantly increased glutathione disulfide levels. ESC-15 + SIL-3 significantly reduced plasma corticosterone levels. Conclusion: This study suggests that sildenafil shows promise as a treatment for TRD, either as a stand-alone therapy or in combination with a traditional antidepressant. The neurobiological mechanism underlying the antidepressant-like effects of the different sildenafil mono- and combination therapies reflects a multimodal action and cannot be explained in full by changes in the individually measured biomarker levels.

Unravelling the complex tapestry of addiction

Wegener, G. — Mon, 01 Apr 2024 12:41:34 +0200

Mutation in the TRKB Cholesterol Recognition Site that blocks Antidepressant Binding does not Influence the Basal or BDNF-Stimulated Activation of TRKB

Biojone, C., Cannarozzo, C., Seiffert, N., et al. — Sun, 01 Dec 2024 12:41:34 +0100

Brain-derived neurotrophic factor (BDNF) acting upon its receptor Neurotrophic tyrosine kinase receptor 2 (NTRK2, TRKB) plays a central role in the development and maintenance of synaptic function and activity- or drug-induced plasticity. TRKB possesses an inverted cholesterol recognition and alignment consensus sequence (CARC), suggesting this receptor can act as a cholesterol sensor. We have recently shown that antidepressant drugs directly bind to the CARC domain of TRKB dimers, and that this binding as well as biochemical and behavioral responses to antidepressants are lost with a mutation in the TRKB CARC motif (Tyr433Phe). However, it is not clear if this mutation can also compromise the receptor function and lead to behavioral alterations. Here, we observed that Tyr433Phe mutation does not alter BDNF binding to TRKB, or BDNF-induced dimerization of TRKB. In this line, primary cultures from embryos of heterozygous Tyr433Phe mutant mice (hTRKB.Tyr433Phe) are responsive to BDNF-induced activation of TRKB, and samples from adult mice do not show any difference on TRKB activation compared to wild-type littermates (TRKB.wt). The behavioral phenotype of hTRKB.Tyr433Phe mice is indistinguishable from the wild-type mice in cued fear conditioning, contextual discrimination task, or the elevated plus maze, whereas mice heterozygous to BDNF null allele show a phenotype in context discrimination task. Taken together, our results indicate that Tyr433Phe mutation in the TRKB CARC motif does not show signs of loss-of-function of BDNF responses, while antidepressant binding to TRKB and responses to antidepressants are lost in Tyr433Phe mutants, making them an interesting mouse model for antidepressant research.

Long-term impact of maternal obesity on the gliovascular unit and ephrin signaling in the hippocampus of adult offspring

Thu, 01 Feb 2024 12:41:34 +0100

Background: Children born to obese mothers are at increased risk of developing mood disorders and cognitive impairment. Experimental studies have reported structural changes in the brain such as the gliovascular unit as well as activation of neuroinflammatory cells as a part of neuroinflammation processing in aged offspring of obese mothers. However, the molecular mechanisms linking maternal obesity to poor neurodevelopmental outcomes are not well established. The ephrin system plays a major role in a variety of cellular processes including cell–cell interaction, synaptic plasticity, and long-term potentiation. Therefore, in this study we determined the impact of maternal obesity in pregnancy on cortical, hippocampal development, vasculature and ephrin-A3/EphA4-signaling, in the adult offspring in mice. Methods: Maternal obesity was induced in mice by a high fat/high sugar Western type of diet (HF/HS). We collected brain tissue (prefrontal cortex and hippocampus) from 6-month-old offspring of obese and lean (control) dams. Hippocampal volume, cortical thickness, myelination of white matter, density of astrocytes and microglia in relation to their activity were analyzed using 3-D stereological quantification. mRNA expression of ephrin-A3, EphA4 and synaptic markers were measured by qPCR in the brain tissue. Moreover, expression of gap junction protein connexin-43, lipocalin-2, and vascular CD31/Aquaporin 4 were determined in the hippocampus by immunohistochemistry. Results: Volume of hippocampus and cortical thickness were significantly smaller, and myelination impaired, while mRNA levels of hippocampal EphA4 and post-synaptic density (PSD) 95 were significantly lower in the hippocampus in the offspring of obese dams as compared to offspring of controls. Further analysis of the hippocampal gliovascular unit indicated higher coverage of capillaries by astrocytic end-feet, expression of connexin-43 and lipocalin-2 in endothelial cells in the offspring of obese dams. In addition, offspring of obese dams demonstrated activation of microglia together with higher density of cells, while astrocyte cell density was lower. Conclusion: Maternal obesity affects brain size, impairs myelination, disrupts the hippocampal gliovascular unit and decreases the mRNA expression of EphA4 and PSD-95 in the hippocampus of adult offspring. These results indicate that the vasculature–glia cross-talk may be an important mediator of altered synaptic plasticity, which could be a link between maternal obesity and neurodevelopmental/neuropsychiatric disorders in the offspring. Graphical Abstract: (Figure presented.).

The arterial blood sampling associated with PET imaging studies can lead to post-scan complications in Göttingen minipigs

Alstrup, A. K. O., Lillethorup, T. P., Landau, A., Afzelius, P. — Sat, 01 Jun 2024 12:41:34 +0200

Göttingen minipigs, due to their low adult body weight, are frequently used for longitudinal imaging studies investigating disease progression or treatment effects. We recently showed that prolonged anesthesia, with intensive blood sampling and road transportation, affects internal organs in non-recovery positron emission tomography (PET) imaging studies in domestic pigs. In the current study, we examined if repeated non-invasive PET scans per se affect internal organs using computed tomography (CT). We then examined post-scan complications using clinical observations following PET imaging of Göttingen minipigs with (n=14) and without (n=4) invasive blood sampling. We report that non-invasive CT scans show no organ damage in minipigs (n=4) placed in sternal recumbence for PET scanning last-ing a few hours. Furthermore, upon reviewing medical records of other Göttingen minipigs positioned in sternal recumbence during PET scans, two cases (5 % of scans) with minor post-scan complications were found during the first two weeks after scanning. Minipigs in dorsal recumbence with the surgical placement of femoral catheters for blood sampling were more frequently (6 cases, 43 % of scans) associated with minor-to-moderate post-scan complications. A reduced daily gain in body weight was also observed after minipigs were placed in dorsal recumbence with blood sampling compared to pre-scan daily weight gain. The results suggest anesthetized Göttingen minipigs are somewhat affected by short-term PET scanning procedures, and blood sampling should be reduced when possible. Post-operative care should be improved due to the higher incidence of post-scan complications in minipigs with femo-ral artery catheterization.

Automated behavioral phenotyping of ouabain-treated flinders sensitive line rats: toward an animal model for the mixed state?

Arjmand, S., Andreatini, R., Wegener, G. — Sun, 01 Jan 2023 12:41:34 +0100

An acute thrombus formation in the left coronary artery of an atypical Kawasaki patient

Bagheri, M. M., Arjmand, S., Torabinejad, M. H., Behzadi, M. — Mon, 01 Jan 2018 12:41:34 +0100

Evaluation and awareness of over the counter use of non-steroidal anti-inflammatory drugs

Amirimoghadam, P., Zihayat, B., Dabaghzadeh, F., et al. — Wed, 01 Mar 2017 12:41:34 +0100

Attenuation Effect of Cannabinoid Type 1 Receptor Activation on Methamphetamine-Induced Neurodegeneration and Locomotion Impairments among Male Rats

Ramshini, E., Dabiri, S., Arjmand, S., et al. — Sun, 01 Jan 2017 12:41:34 +0100

Bipolar disorder and the endocannabinoid system

Arjmand, S., Behzadi, M., Kohlmeier, K. A., Mazhari, S., Sabahi, A., Shabani, M. — Thu, 01 Aug 2019 12:41:34 +0200

OBJECTIVE: Bipolar disorder (BD) is a debilitating, lifelong neuropsychiatric illness characterised by unsteady mood states which vacillate from (hypo)mania to depression. Despite the availability of pharmaceutical agents which can be effective in ameliorating the acute affective symptoms and prevent episodic relapse, BD is inadequately treated in a subset of patients. The endocannabinoid system (ECS) is known to exert neuromodulatory effects on other neurotransmitter systems critical in governing emotions. Several studies ranging from clinical to molecular, as well as anecdotal evidence, have placed a spotlight on the potential role of the ECS in the pathophysiology of BD. In this perspective, we present advantages and disadvantages of cannabis use in the management of illness course of BD and provide mechanistic insights into how this system might contribute to the pathophysiology of BD.

RESULTS: We highlight the putative role of selective cannabinoid receptor 2 (CB2) agonists in BD and briefly discuss findings which provide a rationale for targeting the ECS to assuage the symptoms of BD. Further, data encourage basic and clinical studies to determine how cannabis and cannabinoids (CBs) can affect mood and to investigate emerging CB-based options as probable treatment approaches.

CONCLUSION: The probable role of the ECS has been almost neglected in BD; however, from data available which suggest a role of ECS in mood control, it is justified to support conducting comprehensive studies to determine whether ECS manipulation could positively affect BD. Based on the limited available data, we suggest that activation of CB2 may stabilise mood in this disorder.

Comparing Copper Serum Level and Cognitive Functioning in Patients With Schizophrenia and Healthy Controls

Mazhari, S., Arjmand, S., Eslami Shahrbabaki, M., Karimi Ghoughari, E. — Wed, 01 Jan 2020 12:41:34 +0100

Cannabinoids and Tremor Induced by Motor-related Disorders: Friend or Foe?

Thu, 01 Oct 2015 12:41:34 +0200

Contribution of CB1Rs in anxiety-related behaviors but not locomotor deficits induced by methamphetamine

Thu, 01 Feb 2018 12:41:34 +0100

Modulation of sphingosine-1-phosphate receptor ameliorates harmaline-induced essential tremor in rat

Sat, 01 Jul 2017 12:41:34 +0200

Nitric oxide pathway presumably does not contribute to antianxiety and memory retrieval effects of losartan

Aghaei, I., Arjmand, S., Yousefzadeh Chabok, S., Tondar, M., Shabani, M. — Fri, 01 Sep 2017 12:41:34 +0200

A Brain on a Roller Coaster: Can the Dopamine Reward System Act as a Protagonist to Subdue the Ups and Downs of Bipolar Disorder?

Arjmand, S., Behzadi, M., Stephens, G. J., et al. — Thu, 01 Jun 2017 12:41:34 +0200

A road to bring Brij52 back to attention: Shear stress sensitive Brij52 niosomal carriers for targeted drug delivery to obstructed blood vessels

Arjmand, S., Pardakhty, A., Forootanfar, H., Khazaeli, P. — Sat, 01 Dec 2018 12:41:34 +0100

Role of anxiety and depression in association with migraine and myofascial pain temporomandibular disorder

Shabani, M., Nazeri, M., Ghahrechahi, H., et al. — Mon, 01 Jan 2018 12:41:34 +0100

Laccase-Mediated Treatment of Pharmaceutical Wastes

Forootanfar, H., Arjmand, S., Behzadi, M., Faramarzi, M. A. — Mon, 01 Jan 2018 12:41:34 +0100

Validity and reliability of a Persian version of the Dissociative Experiences Scale II (DES-II) on Iranian patients diagnosed with schizophrenia and mood disorders

Ghaffarinejad, A., Sattari, N., Raaii, F., Arjmand, S. — Tue, 01 Oct 2019 12:41:34 +0200

When Thoughts Are in a Race: Area 10 and Bipolar Disorders

Arjmand, S., Sabahi, A., Sheibani, V. — Tue, 01 Oct 2019 12:41:34 +0200

Looking into a Deluded Brain through a Neuroimaging Lens

Arjmand, S., Kohlmeier, K. A., Behzadi, M., Ilaghi, M., Mazhari, S., Shabani, M. — Wed, 01 Jul 2020 12:41:34 +0200

Delusions are irrational, tenacious, and incorrigible false beliefs that are the most common symptom of a range of brain disorders including schizophrenia, Alzheimer’s, and Parkinson’s disease. In the case of schizophrenia and other primary delusional disorders, their appearance is often how the disorder is first detected and can be sufficient for diagnosis. At this time, not much is known about the brain dysfunctions leading to delusions, and hindering our understanding is that the complexity of the nature of delusions, and their very unique relevance to the human experience has hampered elucidation of their underlying neurobiology using either patients or animal models. Advances in neuroimaging along with improved psychiatric and cognitive modeling offers us a new opportunity to look with more investigative power into the deluded brain. In this article, based on data obtained from neuroimaging studies, we have attempted to draw a picture of the neural networks involved when delusion is present and evaluate whether different manifestations of delusions engage different regions of the brain.

Prenatal cocaine exposure and its influence on pediatric epigenetic clocks and epigenetic scores in humans

Viola, T. W., Danzer, C., Mardini, V., et al. — Mon, 01 Jan 2024 12:41:34 +0100

The investigation of the effects of prenatal cocaine exposure (PCE) on offspring has been inconsistent, with few studies investigating biological outcomes in humans. We profiled genome-wide DNA methylation (DNAm) of umbilical cord blood (UCB) from newborns with (n = 35) and without (n = 47) PCE. We used DNAm data to (1) assess pediatric epigenetic clocks at birth and (2) to estimate epigenetic scores (ES) for lifetime disorders. We generated gestational epigenetic age estimates (DNAmGA) based on Knight and Bohlin epigenetic clocks. We also investigated the association between DNAmGA and UCB serum brain-derived neurotrophic factor (BDNF) levels. Considering the large-scale DNAm data availability and existing evidence regarding PCE as a risk for health problems later in life, we generated ES for tobacco smoking, psychosis, autism, diabetes, and obesity. A gene ontology (GO) analysis on the CpGs included in the ES with group differences was performed. PCE was associated with lower DNAmGA in newborns, and this effect remained significant when controlling for potential confounders, such as blood cell type composition predicted by DNAm and obstetric data. DNAmGA was negatively correlated with BDNF levels in the serum of UCB. Higher tobacco smoking, psychosis, and diabetes ES were found in the PCE group. The GO analysis revealed GABAergic synapses as a potential pathway altered by PCE. Our findings of decelerated DNAmGA and ES for adverse phenotypes associated with PCE, suggest that the effects of gestational cocaine exposure on the epigenetic landscape of human newborns are detectable at birth.

From hormones to behavior through microglial mitochondrial function

Ardalan, M., Mallard, C. — Fri, 01 Mar 2024 12:41:34 +0100

A molecular perspective on mGluR5 regulation in the antidepressant effect of ketamine

Elmeseiny, O. S. A., Müller, H. K. — Thu, 01 Feb 2024 12:41:34 +0100

Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, has received much attention for its rapid antidepressant effects. A single administration of ketamine elicits rapid and sustained antidepressant effects in both humans and animals. Current efforts are focused on uncovering molecular mechanisms responsible for ketamine's antidepressant activity. Ketamine primarily acts via the glutamatergic pathway, and increasing evidence suggests that ketamine induces synaptic and structural plasticity through increased translation and release of neurotrophic factors, activation of mammalian target of rapamycin (mTOR), and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR)-mediated synaptic potentiation. However, the initial events triggering activation of intracellular signaling cascades and the mechanisms responsible for the sustained antidepressant effects of ketamine remain poorly understood. Over the last few years, it has become apparent that in addition to the fast actions of the ligand-gated AMPARs and NMDARs, metabotropic glutamate receptors (mGluRs), and particularly mGluR5, may also play a role in the antidepressant action of ketamine. Although research on mGluR5 in relation to the beneficial actions of ketamine is still in its infancy, a careful evaluation of the existing literature can identify converging trends and provide new interpretations. Here, we review the current literature on mGluR5 regulation in response to ketamine from a molecular perspective and propose a possible mechanism linking NMDAR inhibition to mGluR5 modulation.