Search Results (29)

Background/Objectives: The dual forces of structured inquiry and serendipitous discovery have long shaped neuropsychiatric research, with groundbreaking treatments such as lithium and ketamine resulting from unexpected discoveries. However, relying on chance is becoming increasingly insufficient to address the rising prevalence of mental health disorders like depression and schizophrenia, which necessitate precise, innovative approaches. Emerging technologies like artificial intelligence, induced pluripotent stem cells, and multi-omics have the potential to transform this field by allowing for predictive, patient-specific interventions. Despite these advancements, traditional methodologies such as animal models and single-variable analyses continue to be used, frequently failing to capture the complexities of human neuropsychiatric conditions. Summary: This review critically evaluates the transition from serendipity to precision-based methodologies in neuropsychiatric research. It focuses on key innovations such as dynamic systems modeling and network-based approaches that use genetic, molecular, and environmental data to identify new therapeutic targets. Furthermore, it emphasizes the importance of interdisciplinary collaboration and human-specific models in overcoming the limitations of traditional approaches. Conclusions: We highlight precision psychiatry’s transformative potential for revolutionizing mental health care. This paradigm shift, which combines cutting-edge technologies with systematic frameworks, promises increased diagnostic accuracy, reproducibility, and efficiency, paving the way for tailored treatments and better patient outcomes in neuropsychiatric care. Full article

Background: Animal models are critical tools in the study of psychiatric disorders; however, none of the current models fully reflect human stress-related disorders, even though most of the knowledge about the mechanisms of depression comes from animal studies. Animal studies are useful in pharmacological research, whereby we can obtain results that translate into patient treatment by controlling environmental factors, especially in behavioural research. The authors systematically reviewed this issue since medical databases provide access to many primary studies. Methods: A systematic review and meta-analysis were conducted based on 25 primary studies. The studies were identified in databases such as PubMed, Embase, and Web of Science (December 2022) according to the inclusion and exclusion criteria established at the beginning of the research and published in the form of a protocol, following the PRISMA and Cochrane Collaboration methodology for secondary studies and CAMARADES (CAMARADES Berlin, QUEST-BIH Charité) for secondary studies on animals. Forest plot analyses were performed (data presented as Mean Difference, Random Model, Inverse Variance), Risk of Bias assessment (Systematic Review Center for Laboratory animal Experimentation (SYRCLE) evaluation), quality assessment of included studies (Animal research: Reporting of In Vivo Experiments (ARRIVE)), and a range of data from source publications were compiled in tabular form. The study analysed the popularity of both animal depression models (ADM) and rat strains used in pharmacological research to test the efficacy of antidepressant drugs based on the immobility time (IT) factor (Forced Swimming Test). The study examined selective serotonin reuptake inhibitors, namely fluoxetine, sertraline, paroxetine, citalopram, and escitalopram. Additionally, the study addressed issues concerning the “data availability statement” because precise IT data analysis was impossible in the case of 212 papers. Results: Our data confirm that the Chronic Unpredictable Mild Stress (CUMS) model is the most popular and versatile model used in preclinical depression research, while the two most popular rat strains were Wistar and Sprague-Dawley. The quality of included papers based on the ARRIVE assessment showed a ratio value equal to 0.63, meaning that studies were of intermediate overall quality. The Risk of Bias assessment based on the SYRCLE tool revealed a high risk related to the blinding and the random outcome assessment. In the meta-analysis, the results indicate that all analysed drugs demonstrated efficacy in reducing IT, and the most analysed drug was fluoxetine (confirmed based on 17 studies (19 models)). The analysis of the efficacy of ADMs showed that the most effective models were CUMS, Flinders Sensitive Line (genetic model), Social Isolation, Restraint Stress, and Low-dose Lipopolysaccharide (pharmacological model). Only 2.35% (5 out of 212) of corresponding authors responded to our data request. Conclusions: The study highlights the dominance of the CUMS model and the Wistar and Sprague-Dawley rat strains in preclinical depression research, affirming the efficacy of SSRIs, particularly fluoxetine, in reducing IT. The findings underscore the need for better data availability and methodological improvements despite intermediate overall study quality and notable bias risks. Enhanced transparency and rigorous assessment standards are essential for advancing the reliability of animal models in depression research. Full article

Postpartum depression (PPD) affects 174 million women worldwide and is characterized by profound sadness, anxiety, irritability, and debilitating fatigue, which disrupt maternal caregiving and the mother–infant relationship. Limited pharmacological interventions are currently available. Our understanding of the neurobiological pathophysiology of PPD remains incomplete, potentially hindering the development of novel treatment strategies. Recent hypotheses suggest that PPD is driven by a complex interplay of hormonal changes, neurotransmitter imbalances, inflammation, genetic factors, psychosocial stressors, and hypothalamic–pituitary–adrenal (HPA) axis dysregulation. This narrative review examines recent clinical studies on PPD within the past 15 years, emphasizing advancements in neuroimaging findings and blood biomarker detection. Additionally, we summarize recent laboratory work using animal models to mimic PPD, focusing on hormone withdrawal, HPA axis dysfunction, and perinatal stress theories. We also revisit neurobiological results from several brain regions associated with negative emotions, such as the amygdala, prefrontal cortex, hippocampus, and striatum. These insights aim to improve our understanding of PPD’s neurobiological mechanisms, guiding future research for better early detection, prevention, and personalized treatment strategies for women affected by PPD and their families. Full article

Background: Major depressive disorder (MDD) plays a crucial role in the occurrence of heart failure (HF). This investigation was undertaken to explore the possible mechanism of MDD’s involvement in HF pathogenesis and identify candidate biomarkers for the diagnosis of MDD with HF. Methods: GWAS data for MDD and HF were collected, and Mendelian randomization (MR) analysis was performed to investigate the causal relationship between MDD and HF. Differential expression analysis (DEA) and WGCNA were used to detect HF key genes and MDD-associated secretory proteins. Protein–protein interaction (PPI), functional enrichment, and cMAP analysis were used to reveal potential mechanisms and drugs for MDD-related HF. Then, four machine learning (ML) algorithms (including GLM, RF, SVM, and XGB) were used to screen candidate biomarkers, construct diagnostic nomograms, and predict MDD-related HF. Furthermore, the MCPcounter algorithm was used to explore immune cell infiltration in HF, and MR analysis was performed to explore the causal effect of immunophenotypes on HF. Finally, the validation of the association of MDD with reduced left ventricular ejection fraction (LVEF) and the performance assessment of diagnostic biomarkers was accomplished based on animal models mimicking MDD. Results: The MR analysis showed that the MDD was linked to an increased risk of HF (OR = 1.129, p < 0.001). DEA combined with WGCNA and secretory protein gene set identified 315 HF key genes and 332 MDD-associated secretory proteins, respectively. Through PPI and MCODE analysis, 78 genes were pinpointed as MDD-related pathogenic genes for HF. The enrichment analysis revealed that these genes were predominantly enriched in immune and inflammatory regulation. Through four ML algorithms, two hub genes (ISLR/SFRP4) were identified as candidate HF biomarkers, and a nomogram was developed. ROC analysis showed that the AUC of the nomogram was higher than 0.90 in both the HF combined dataset and two external cohorts. In addition, an immune cell infiltration analysis revealed the immune dysregulation in HF, with ISLR/SFRP4 displaying notable associations with the infiltration of B cells, CD8 T cells, and fibroblasts. More importantly, animal experiments showed that the expression levels of ISLR (r = −0.653, p < 0.001) and SFRP4 (r = −0.476, p = 0.008) were significantly negatively correlated with LVEF. Conclusions: The MR analysis indicated that MDD is a risk factor for HF at the genetic level. Bioinformatics analysis and the ML results suggest that ISLR and SFRP4 have the potential to serve as diagnostic biomarkers for HF. Animal experiments showed a negative correlation between the serum levels of ISLR/SFRP4 and LVEF, emphasizing the need for additional clinical studies to elucidate their diagnostic value. Full article

Absence epilepsy is a non-convulsive type of epilepsy characterized by the sudden loss of awareness. It is associated with thalamo-cortical impairment, which may cause neuropsychiatric and neurocognitive problems. Rats with spontaneous absence-like seizures are widely used as in vivo genetic models for absence epilepsy; they display behavioral and cognitive problems similar to epilepsy in humans, such as genetic absence epilepsy rats from Strasbourg (GAERS) and Wistar Albino rats from Rijswijk (WAG/Rij). Both GAERS and WAG/Rij rats exhibited depression-like symptoms, but there is uncertainty regarding anxiety-related symptoms. Deficits in executive functions and memory impairment in WAG/Rij rats, i.e., cognitive comorbidities, are linked to the severity of epilepsy. Wistar rats can develop spontaneous seizures in adulthood, so caution is advised when using them as a control epileptic strain. This review discusses challenges in the field, such as putative high emotionality in genetically prone rats, sex differences in the expression of cognitive comorbidities, and predictors of cognitive problems or biomarkers of cognitive comorbidities in absence epilepsy, as well as the concept of “the cognitive thalamus”. The current knowledge of behavioral and cognitive comorbidities in drug-naive rats with spontaneous absence epilepsy is beneficial for understanding the pathophysiology of absence epilepsy, and for finding new treatment strategies. Full article

This study provides estimates on genetic parameters, inbreeding depression and purging for meat performance measures from 25 German sheep breeds. All German meat, merino sheep breeds and breeds of other breeding directions with a sufficient number of pedigree and performance data were included in this study. Phenotypic traits retrieved from the national database OviCap were evaluated: daily weight gain, meatiness score and ultrasound measurements for muscle and fat thickness. We employed animal models to estimate heritability, variance and covariance components for these meat performance traits as well as inbreeding depression and purging. The heritabilities, on average, reached estimates of 0.55, 0.34, 0.53 and 0.61 for daily weight gain, meatiness score and ultrasound measurements for muscle and fat thickness, respectively. We estimated the linear regression slopes for the individual rate of inbreeding, new and ancestral inbreeding, as well as the inbreeding coefficient and its interaction with the inbreeding coefficient of Ballou, employing animal models with non-genetic effects and the additive genetic effect of the animal. Across all breeds, inbreeding was only significant for daily weight gain, whereas for all other traits, estimates were not significant. Within sheep breeds, we found significant inbreeding depression for daily weight gain in German Mutton Merino and German Blackheaded Mutton as well as for the meatiness score in German Whiteheaded Mutton. Significant effects for purging, based on ancestral inbreeding and the interaction effect of the classical inbreeding coefficient with the inbreeding coefficient of Ballou, were not obvious either across or within any sheep breed. A 1% increase in inbreeding significantly decreased the phenotypic trait median of daily weight gain across all sheep breeds by 0.50% and 0.70% of phenotypic and genetic standard deviation, respectively. Purging effects due to ancestral inbreeding were not significant in any breed or across breeds. The results of this study may indicate that inbreeding depression may be more harmful in traits under stronger selection than in traits that exert low selection pressure. The results of this study demonstrate the different effects that result in meat performance traits due to inbreeding. With increasing rates of inbreeding and critical effective population sizes, selection intensity for breeding objectives has to be critically reviewed for each sheep breed. Inbreeding depression and purging should be evaluated in order to prevent a decrease in trait means due to inbreeding and to determine whether detrimental alleles are eliminated. Full article

This study provides comprehensive results on the current status of inbreeding depression for traits upon which sheep are selected for the herdbook in Germany. A total of 30 sheep breeds from the OviCap national database met the inclusion criteria for the present analysis regarding the depth and completeness of pedigrees and the number of animals with phenotypic data. We analyzed heritabilities and inbreeding depression for the three breeding objective traits of wool quality, muscling conformation and exterior. Heritabilities were across all breeds of moderate size, with estimates of 0.18 for wool quality and muscling conformation and of 0.14 for exterior. The models employed to estimate linear regression slopes for individual and ancestral inbreeding rates also account for non-genetic effects and the additive genetic effect of the animal. Inbreeding depression was obvious for all three traits when we averaged the estimates across all 30 sheep breeds. Inbreeding depression was significant for wool quality for only a few breeds, whereas for muscling conformation, 14/30 breeds achieved significant estimates. A 1% increase in inbreeding decreased the mean of all three traits across all sheep breeds by 0.33% of their standard deviation. Positive effects due to ancestral inbreeding were only significant in very few breeds in the different traits. Across all 30 sheep breeds, there were indications that purging effects (a reduction in negative effects of inbreeding depression due to selection for heterozygotes) may play a role for the exterior. The results of this study should help for reviewing breeding programs, particularly for sheep breeds with critical effective population sizes and increasing rates of inbreeding, with regard to the selection policy and selection intensity applied. Full article

Attention deficit-hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high incidence in children and adolescents characterized by motor hyperactivity, impulsivity, and inattention. Magnetic resonance imaging (MRI) has revealed that neuroanatomical abnormalities such as the volume reduction in the neocortex and hippocampus are shared by several neuropsychiatric diseases such as schizophrenia, autism spectrum disorder and ADHD. Furthermore, the abnormal development and postnatal pruning of dendritic spines of neocortical neurons in schizophrenia, autism spectrum disorder and intellectual disability are well documented. Dendritic spines are dynamic structures exhibiting Hebbian and homeostatic plasticity that triggers intracellular cascades involving glutamate receptors, calcium influx and remodeling of the F-actin network. The long-term potentiation (LTP)-induced insertion of postsynaptic glutamate receptors is associated with the enlargement of spine heads and long-term depression (LTD) with spine shrinkage. Using a murine model of ADHD, a delay in dendritic spines’ maturation in CA1 hippocampal neurons correlated with impaired working memory and hippocampal LTP has recently reported. The aim of this review is to summarize recent evidence that has emerged from studies focused on the neuroanatomical and genetic features found in ADHD patients as well as reports from animal models describing the molecular structure and remodeling of dendritic spines. Full article

Despite enormous global efforts within clinical research and medical practice to reduce cardiovascular disease(s) (CVD), it still remains the leading cause of death worldwide. While genetic factors clearly contribute to CVD etiology, the preponderance of epidemiological data indicate that a major common denominator among diverse ethnic populations from around the world contributing to CVD is the composite of Western lifestyle cofactors, particularly Western diets (high saturated fat/simple sugar [particularly high fructose and sucrose and to a lesser extent glucose] diets), psychosocial stress, depression, and altered sleep/wake architecture. Such Western lifestyle cofactors are potent drivers for the increased risk of metabolic syndrome and its attendant downstream CVD. The central nervous system (CNS) evolved to respond to and anticipate changes in the external (and internal) environment to adapt survival mechanisms to perceived stresses (challenges to normal biological function), including the aforementioned Western lifestyle cofactors. Within the CNS of vertebrates in the wild, the biological clock circuitry surveils the environment and has evolved mechanisms for the induction of the obese, insulin-resistant state as a survival mechanism against an anticipated ensuing season of low/no food availability. The peripheral tissues utilize fat as an energy source under muscle insulin resistance, while increased hepatic insulin resistance more readily supplies glucose to the brain. This neural clock function also orchestrates the reversal of the obese, insulin-resistant condition when the low food availability season ends. The circadian neural network that produces these seasonal shifts in metabolism is also responsive to Western lifestyle stressors that drive the CNS clock into survival mode. A major component of this natural or Western lifestyle stressor-induced CNS clock neurophysiological shift potentiating the obese, insulin-resistant state is a diminution of the circadian peak of dopaminergic input activity to the pacemaker clock center, suprachiasmatic nucleus. Pharmacologically preventing this loss of circadian peak dopaminergic activity both prevents and reverses existing metabolic syndrome in a wide variety of animal models of the disorder, including high fat-fed animals. Clinically, across a variety of different study designs, circadian-timed bromocriptine-QR (quick release) (a unique formulation of micronized bromocriptine—a dopamine D2 receptor agonist) therapy of type 2 diabetes subjects improved hyperglycemia, hyperlipidemia, hypertension, immune sterile inflammation, and/or adverse cardiovascular event rate. The present review details the seminal circadian science investigations delineating important roles for CNS circadian peak dopaminergic activity in the regulation of peripheral fuel metabolism and cardiovascular biology and also summarizes the clinical study findings of bromocriptine-QR therapy on cardiometabolic outcomes in type 2 diabetes subjects. Full article

Appropriate dilated cardiomyopathy (DCM) animal models are highly desirable considering the pathophysiological and clinical heterogeneity of DCM. Genetically modified mice are the most widely and intensively utilized research animals for DCM. However, to translate discoveries from basic science into new and personalized medical applications, research in non-genetically based DCM models remains a key issue. Here, we characterized a mouse model of non-ischemic DCM induced by a stepwise pharmacologic regime of Isoproterenol (ISO) high dose bolus followed by a low dose systemic injection of the chemotherapy agent, 5-Fluorouracil (5-FU). C57BL/6J mice were injected with ISO and, 3 days after, were randomly assigned to saline or 5-FU. Echocardiography and a strain analysis show that ISO + 5FU in mice induces progressive left ventricular (LV) dilation and reduced systolic function, along with diastolic dysfunction and a persistent global cardiac contractility depression through 56 days. While mice treated with ISO alone recover anatomically and functionally, ISO + 5-FU causes persistent cardiomyocyte death, ensuing in cardiomyocyte hypertrophy through 56 days. ISO + 5-FU-dependent damage was accompanied by significant myocardial disarray and fibrosis along with exaggerated oxidative stress, tissue inflammation and premature cell senescence accumulation. In conclusions, a combination of ISO + 5FU produces anatomical, histological and functional cardiac alterations typical of DCM, representing a widely available, affordable, and reproducible mouse model of this cardiomyopathy. Full article

The pathophysiology of major depressive disorder (MDD) is diverse and multi-factorial, yet treatment strategies remain limited. While women are twice as likely to develop the disorder as men, many animal model studies of antidepressant response rely solely on male subjects. The endocannabinoid system has been linked to depression in clinical and pre-clinical studies. Cannabidiolic Acid-Methyl Ester (CBDA-ME, EPM-301) demonstrated anti-depressive-like effects in male rats. Here, we explored acute effects of CBDA-ME and some possible mediating mechanisms, using a depressive-like genetic animal model, the Wistar–Kyoto (WKY) rat. In Experiment 1, Female WKY rats underwent the Forced swim test (FST) following acute CBDA-ME oral ingestion (1/5/10 mg/kg). In Experiment 2, Male and female WKY rats underwent the FST after injection of CB1 (AM-251) and CB2 (AM-630) receptor antagonists 30 min before acute CBDA-ME ingestion (1 mg/kg, males; 5 mg/kg, females). Serum levels of Brain-Derived Neurotrophic Factor (BDNF), numerous endocannabinoids and hippocampal Fatty Acid Amide Hydrolase (FAAH) levels were assessed. Results indicate that females required higher doses of CBDA-ME (5 and 10 mg/kg) to induce an anti-depressive-like effect in the FST. AM-630 blocked the antidepressant-like effect in females, but not in males. The effect of CBDA-ME in females was accompanied by elevated serum BDNF and some endocannabinoids and low hippocampal expression of FAAH. This study shows a sexually diverse behavioral anti-depressive response to CBDA-ME and possible underlying mechanisms in females, supporting its potential use for treating MDD and related disorders. Full article

The etiology of autism spectrum disorder (ASD) is genetic, environmental, and epigenetic. In addition to sex differences in the prevalence of ASD, which is 3–4 times more common in males, there are also distinct clinical, molecular, electrophysiological, and pathophysiological differences between sexes. In human, males with ASD have more externalizing problems (i.e., attention-deficit hyperactivity disorder), more severe communication and social problems, as well as repetitive movements. Females with ASD generally exhibit fewer severe communication problems, less repetitive and stereotyped behavior, but more internalizing problems, such as depression and anxiety. Females need a higher load of genetic changes related to ASD compared to males. There are also sex differences in brain structure, connectivity, and electrophysiology. Genetic or non-genetic experimental animal models of ASD-like behavior, when studied for sex differences, showed some neurobehavioral and electrophysiological differences between male and female animals depending on the specific model. We previously carried out studies on behavioral and molecular differences between male and female mice treated with valproic acid, either prenatally or early postnatally, that exhibited ASD-like behavior and found distinct differences between the sexes, the female mice performing better on tests measuring social interaction and undergoing changes in the expression of more genes in the brain compared to males. Interestingly, co-administration of S-adenosylmethionine alleviated the ASD-like behavioral symptoms and the gene-expression changes to the same extent in both sexes. The mechanisms underlying the sex differences are not yet fully understood. Full article

Mating between related animals is an inevitable consequence of a closed population structure especially when it coincides with a small population size. As a result, inbreeding depression may be encountered especially when considering fitness traits. However, under certain circumstances, the joint effects of inbreeding and selection may at least partly purge the detrimental genes from the population. In the course of this study, our objective was to determine the status of purging and to quantify the magnitude of the eliminated genetic load for the survival at birth of Pannon White rabbit kits maintained in a closed nucleus population. The evolution of the survival at birth was evaluated by applying the PurgeR R package based on the inbreeding-purging model. In the period from 1992 to 2017, 22.718 kindling records were analyzed. According to the heuristic approach, the purging coefficient reached the maximum possible value of 0.5 when estimating between 1992 and 1997. Based on the expected fitness over generations and on the expressed opportunity of purging, the beneficial effects of purging could be expected after 10 generations. The proportion of the purged genetic load could be between 20% and 60%. While the results obtained are not entirely conclusive, they do raise the possibility that some of the inbreeding load was caused, at least in part, by genes that could be successfully removed from the population by purging. Full article

Macrophage migration inhibitory factor (MIF) is a controversially discussed inflammatory marker in major depressive disorder (MDD). While some studies show an association of high MIF protein levels with depression, animal models have yielded conflicting results. Thus, it remains elusive as to whether MIF plays an anti- or pro-depressive role. Therefore, we aimed to examine the potential of MIF at the genetic, expression and protein levels as a risk factor and biomarker to diagnose, monitor, or predict the course of MDD. Patients with a current major depressive episode (n = 66 with, and n = 63 without, prior medication) and remitted patients (n = 39) were compared with healthy controls (n = 61). Currently depressed patients provided a second blood sample after three weeks of therapy. Depression severity was assessed by self-evaluation and clinician rating scales. We genotyped for three MIF polymorphisms and analyzed peripheral MIF expression and serum levels. The absence of minor allele homozygous individuals in the large group of 96 female patients compared with 10–16% in female controls suggests a protective effect for MDD, which was not observed in the male group. There were no significant group differences of protein and expression levels, however, both showed predictive potential for the course of depression severity in some subgroups. While MIF protein levels, but not MIF expression, decreased during treatment, they were not associated with changes in depression severity. This project is the first to investigate three biological levels of MIF in depression. The data hint toward a genetic effect in women, but do not provide robust evidence for the utility of MIF as a biomarker for the diagnosis or monitoring of MDD. The observed predictive potential requires further analysis, emphasizing future attention to confounding factors such as sex and premedication. Full article

The prodromal phase of Parkinson’s disease (PD) is characterised by many non-motor symptoms, and these have recently been posited to be predictive of later diagnosis. Genetic rodent models can develop non-motor phenotypes, providing tools to identify mechanisms underlying the early development of PD. However, it is not yet clear how reproducible non-motor phenotypes are amongst genetic PD rodent models, whether phenotypes are age-dependent, and the translatability of these phenotypes has yet to be explored. A systematic literature search was conducted on studies using genetic PD rodent models to investigate non-motor phenotypes; cognition, anxiety/depressive-like behaviour, gastrointestinal (GI) function, olfaction, circadian rhythm, cardiovascular and urinary function. In total, 51 genetic models of PD across 150 studies were identified. We found outcomes of most phenotypes were inconclusive due to inadequate studies, assessment at different ages, or variation in experimental and environmental factors. GI dysfunction was the most reproducible phenotype across all genetic rodent models. The mouse model harbouring mutant A53T, and the wild-type hα-syn overexpression (OE) model recapitulated the majority of phenotypes, albeit did not reliably produce concurrent motor deficits and nigral cell loss. Furthermore, animal models displayed different phenotypic profiles, reflecting the distinct genetic risk factors and heterogeneity of disease mechanisms. Currently, the inconsistent phenotypes within rodent models pose a challenge in the translatability and usefulness for further biomechanistic investigations. This review highlights opportunities to improve phenotype reproducibility with an emphasis on phenotypic assay choice and robust experimental design. Full article