Search Results (25)

Background/Objectives: G protein-coupled trace amine-associated receptors (TAARs) belong to a family of biogenic amine-sensing receptors. TAAR1 is the best-investigated receptor of this family, and TAAR1 agonists are already being tested in clinical studies for the treatment of schizophrenia, anxiety, and depression. Meanwhile, other TAARs (TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9 in humans) are mostly known for their olfactory function, sensing innate odors. At the same time, there is growing evidence that these receptors may also be involved in brain function. TAAR8 is the least studied TAAR family member, and currently, there is no data on its function in the mammalian central nervous system. Methods: We generated triple knockout (tTAAR8-KO) mice lacking all murine Taar8 isoforms (Taar8a, Taar8b, and Taar8c) using CRISPR-Cas9 technology. In this study, we performed the first phenotyping of tTAAR8-KO mice for behavioral, electrophysiological, and neurochemical characteristics. Results: During the study, we found a number of alterations specific to tTAAR8-KO mice compared to controls. tTAAR8-KO mice demonstrated better short-term memory, more depressive-like behavior, and higher body temperature. Also, we observed changes in the dopaminergic system, brain electrophysiological activity, and adult neurogenic functions in mice lacking Taar8 isoforms. Conclusions: Based on the data obtained, it can be assumed that the physiological TAAR8 role is not limited only to the innate olfactory function, as previously proposed. TAAR8 could be involved in brain function, in particular in dopamine function regulation. Full article

Background/Objectives: Obesity is a major public health challenge of the 21st century, with prevalence rates steadily rising globally. Disordered eating behaviors, particularly emotional eating (EE), complicate the clinical management of obesity and hinder long-term outcomes, such as maintaining weight loss after bariatric surgery. Studies reveal that EE affects 65–75% of overweight or obese adults, and such behavior may stem from a disrupted brain reward system linked to emotional dysregulation and impulsivity. Impulsivity in obesity involves deficient cognitive inhibitory control, creating an imbalance between impulsive and reflective systems. While problematic eating behaviors and obesity are well studied, the role of affective temperaments—innate traits influencing mood, energy, and responses to stimuli—remains underexplored. This study aims to examine the interplay between emotional eating, impulsivity, and affective temperaments in obese patients preparing for bariatric surgery. Methods: A total sample of 304 obese outpatients was consecutively enrolled at the Psychiatry Clinic of the Department of Clinical and Experimental Medicine of the University of Pisa during the presurgical mental health evaluation routinely performed before the bariatric intervention. Sociodemographic and clinical data were collected by psychiatrists during a single consultation. Assessments also included the following psychometric tests: the Structured Clinical Interview (SCID-5), the Emotional Eating Scale (EES), the Barratt Impulsivity Scale-Version 11 (BIS-11), and the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Auto-questionnaire (TEMPS-A). Results: A significant correlation was observed between the EES total score and the BIS total score (p = 0.003), as well as with the sub-dimensions of attentional impulsivity (p < 0.001) and motor impulsivity (p = 0.024). In addition, a significant correlation has been found between the total score of EES and the cyclothymic (p < 0.001), depressive (p < 0.001), irritable (p = 0.013), and anxious (0.020) temperaments. When comparing obese patients with EE and without EE (No-EE), higher rates of both current (p = 0.007) and lifetime (p = 0.024) psychiatric comorbidities were observed in the EE group, namely for anxiety disorders (p = 0.008) and eating disorders (p = 0.014). Conclusions: Our study highlights a significant association between EE in obese patients with the cyclothymic, irritable, anxious, and depressive temperaments, and impulsivity dimension. Thus, problematic eating behaviors and temperamental traits may have a bidirectional psychopathological influence in obese patients and need to be carefully evaluated in subjects seeking bariatric surgery. Full article

A significant portion of adolescents suffer from mental illnesses and persistent pain due to repeated stress. The components of the nervous system that link stress and pain in early life remain unclear. Prior studies in adult mice implicated the innate immune system, specifically Toll-like receptors (TLRs), as critical for inducing long-term anxiety and pain-like behaviors in social defeat stress (SDS) models. In this work, we investigated the pain and anxiety behavioral phenotypes of wild-type and TLR4-deficient juvenile mice subjected to repeated SDS and evaluated the engagement of TLR4 by measuring dimerization in the spinal cord, dorsal root ganglia, and prefrontal cortex. Male juvenile (4-week-old) mice (C57BL/6J or Tlr4^-/-) underwent six social defeat sessions with adult aggressor (CD1) mice. In WT mice, SDS promotes chronic mechanical allodynia and thermal hyperalgesia assessed via von Frey testing and the Hargreaves test, respectively. In parallel, the stressed WT mice exhibited transient anxiety-like behavior and long-lasting locomotor activity reduction in the open-field test. Tlr4^-/--stressed animals were resistant to the induction of pain-like behavior but had a remnant of anxious behavior, spending less time in the center of the arena. In WT SDS, there were concordant robust increases in TLR4 dimerization in dorsal root ganglia macrophages and spinal cord microglia, indicating TLR4 activation. These results suggest that the chronic pain phenotype and locomotor impairment induced by SDS in juvenile mice depends on TLR4 engagement evidenced by dimerization in immune cells of the dorsal root ganglia and spinal cord. Full article

Autism spectrum disorder (ASD) is an early-onset neurodevelopmental condition that now impacts 1 in 36 children in the United States and is characterized by deficits in social communication, repetitive behaviors, and restricted interests. Children with ASD also frequently experience co-morbidities including anxiety and ADHD, and up to 80% experience gastrointestinal (GI) symptoms such as constipation, diarrhea, and/or abdominal pain. Systemic immune activation and dysregulation, including increased pro-inflammatory cytokines, are frequently observed in ASD. Evidence has shown that the innate immune system may be impacted in ASD, as altered monocyte gene expression profiles and cytokine responses to pattern recognition ligands have been observed compared to typically developing (TD) children. In humans, circulating monocytes are often categorized into three subpopulations—classical, transitional (or “intermediate”), and nonclassical monocytes, which can vary in functions, including archetypal inflammatory and/or reparative functions, as well as their effector locations. The potential for monocytes to contribute to immune dysregulation in ASD and its comorbidities has so far not been extensively studied. This study aims to determine whether these monocyte subsets differ in frequency in children with ASD and if the presence of GI symptoms alters subset distribution, as has been seen for T cell subsets. Whole blood from ASD children with (ASD⁺GI⁺) and without gastrointestinal symptoms (ASD⁺GI⁻) and their TD counterparts was collected from children enrolled in the Childhood Autism Risk from Genetics and Environment (CHARGE) study. Peripheral blood mononuclear cells were isolated and stained for commonly used subset identifiers CD14 and CD16 as well as activation state markers CCR2, HLA-DR, PD-1, and PD-L1 for flow cytometry analysis. We identified changes in monocyte subpopulations and their expression of surface markers in children with ASD compared to TD children. These differences in ASD appear to be dependent on the presence or absence of GI symptoms. We found that the ASD⁺GI⁺ group have a different monocyte composition, evident in their classical, transitional, and nonclassical populations, compared to the ASD⁺GI⁻ and TD groups. Both the ASD⁺GI⁺ and ASD⁺GI⁻ groups exhibited greater frequencies of classical monocytes compared to the TD group. However, the ASD⁺GI⁺ group demonstrated lower frequencies of transitional and nonclassical monocytes than their ASD⁺GI⁻ and TD counterparts. CCR2⁺ classical monocyte frequencies were highest in the ASD⁺GI⁻ group. HLA-DR⁺ classical, transitional, and nonclassical monocytes were statistically comparable between groups, however, HLA-DR⁻ nonclassical monocyte frequencies were lower in both ASD groups compared to TD. The frequency of classical monocytes displaying exhaustion markers PD-1 and PD-L1 were increased in the ASD⁺GI⁺ group compared to ASD⁺GI⁻ and TD, suggesting potentially impaired ability for clearance of foreign pathogens or debris, typically associated with worsened inflammation. Taken together, the findings of differential proportions of the monocyte subpopulations and altered surface markers may explain some of the characteristics of immune dysregulation, such as in the gastrointestinal tract, observed in ASD. Full article

Osteoarthritis (OA) is a common chronic condition that causes pain and disability, particularly in the elderly, resulting in significant limitations on mobility and overall quality of life. Balneotherapy using peloids (mud therapy) is an effective, non-pharmacological treatment for OA that improves symptoms and function. This pilot study aimed to assess whether a controlled-matured peloid, supplemented with rosmarinic acid (RosA), could enhance clinical outcomes, functional status, and immune response in OA patients. The study involved 42 elderly OA patients (mean age 70), comparing a 10-day balneotherapy cycle using either a RosA-fortified or non-fortified peloid. The effects on pain (Visual Analogue Scale), functional status (WOMAC, knee flexion/extension), quality of life (EUROQOL), and innate immune response (neutrophil phagocytic and microbicidal activity) were evaluated. Both treatments resulted in significant improvements in pain (by approximately 60%), function, and quality of life, but the RosA-fortified peloid led to greater benefits, particularly in the anxiety/depression dimension of the EUROQOL questionnaire and in enhancing neutrophil immune responsiveness. These findings suggest that RosA supplementation may further improve the therapeutic effects of mud therapy for OA management. Full article

Obesity has reached global epidemic proportions, and even though its effects are well-documented, studying the interactions among all influencing factors is crucial for a better understanding of its physiopathology. In a high-fat-diet-induced obesity animal model using C57BL/6J mice, behavioural responses were assessed through a battery of tests, while stress biomarkers and systemic inflammatory cytokines were measured using an Enzyme-Linked ImmunoSorbent Assay and a Bio-Plex Multiplex System. The peritoneal macrophage microbicide capacity was analysed via flow cytometry, and crown-like structures (CLSs) in white adipose tissue (WAT) were evaluated through staining techniques. Results indicated that obese mice exhibited increased body weight, hyperglycaemia, and hyperlipidaemia after 18 weeks on a high-fat diet, as well as worse physical conditions, poorer coordination and balance, and anxiety-like behaviour. Differences in corticosterone and noradrenaline concentrations were also found in obese animals, revealing a stress response and noradrenergic dysregulation, along with a weakened innate immune response characterized by a lower microbicide capacity, and the presence of an underlying inflammation evidenced by more CLSs in WAT. Altogether, these findings indicate that obesity deteriorates the entire stress, inflammatory, metabolic, sensorimotor and anxiety-like behavioural axis. This demonstrates that jointly evaluating all these aspects allows for a deeper and better exploration of this disease and its associated comorbidities, emphasizing the need for individualized and context-specific strategies for its management. Full article

Depression is a common mental illness of great concern. Current therapy for depression is only suitable for 80% of patients and is often associated with unwanted side effects. In this regard, the search for and development of new antidepressant agents remains an urgent task. In this review, we discuss the current available evidence indicating that G protein-coupled trace amine-associated receptors (TAARs) might represent new targets for depression treatment. The most frequently studied receptor TAAR1 has already been investigated in the treatment of schizophrenia, demonstrating antidepressant and anxiolytic properties. In fact, the TAAR1 agonist Ulotaront is currently undergoing phase 2/3 clinical trials testing its safety and efficacy in the treatment of major depressive disorder and generalized anxiety disorder. Other members of the TAAR family (TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9) are not only involved in the innate olfaction of volatile amines, but are also expressed in the limbic brain areas. Furthermore, animal studies have shown that TAAR2 and TAAR5 regulate emotional behaviors and thus may hold promise as potential antidepressant targets. Of particular interest is their connection with the dopamine and serotonin systems of the brain and their involvement in the regulation of adult neurogenesis, known to be affected by the antidepressant drugs currently in use. Further non-clinical and clinical studies are necessary to validate TAAR1 (and potentially other TAARs) as novel therapeutic targets for the treatment of depression. Full article

Compelling evidence indicates that nitric oxide (NO) exerts a significant influence on the central nervous system, participates in the modulation of neurotransmitter release, contributes to the regulation of cognitive functions, and plays a crucial role in modulating various aspects of neural activity. We aimed to explore the influence of two NO donors, molsidomine (MSD) and V-pyrro/NO, on the innate spontaneous psychomotor abilities and short-term memory in rats. Using an actimeter test, the locomotor activity, stress-sensitive behavior, and anxiety level were investigated. The influence on the animal`s cognitive functions was evaluated usingthe Y-maze test to assess the spontaneous alternation percentage, number of arms visited, number of alternations, and the preference index. Four distinct groups of five white male Wistar rats were exposed to the intraperitoneal treatments as follows: Control batch—0.3 mL/100 g of body weight saline solution, Mg batch—200 mg/kbwof magnesium chloride, MSD batch—1 mg/kbw of molsidomine, and V-pyrro/NO batch—5 mg/kbwof V-pyrro/NO. The intraperitoneal administration of MSD resulted in a significant reduction in spontaneous behavior and exploratory skills but was less pronounced than the positive control drug, magnesium chloride. Conversely, treatment with V-pyrro/NO led to only a slight decrease in horizontal movements during the actimeter test. MSD administration, but not V-pyrro/NO, notably increased the rate of spontaneous alternation in the Y-maze test. Additionally, the use of MSD resulted in an increase in the blood level of brain-derived neurotrophic factor and the intensification of the antioxidant enzymes, superoxide dismutase, and glutathione peroxidase activity. In our experimental setup, we demonstrated that MSD exposure led to a decrease in spontaneous behavior, showed anxiolytic effects and antioxidant activity, and improved spatial memory acquisition in rats. Full article

Inflammatory bowel disease (IBD), a common term for Crohn’s disease and ulcerative colitis, is a chronic, relapse-remitting condition of the gastrointestinal tract that is increasing worldwide. Psychiatric comorbidities, including depression and anxiety, are more prevalent in IBD patients than in healthy individuals. Evidence suggests that varying levels of neuroinflammation might underlie these states in IBD patients. Within this context, microglia are the crucial non-neural cells in the brain responsible for innate immune responses following inflammatory insults. Alterations in microglia’s functions, such as secretory profile, phagocytic activity, and synaptic pruning, might play significant roles in mediating psychiatric manifestations of IBD. In this review, we discuss the role played by microglia in IBD-associated comorbidities. Full article

Self-efficacy is one’s awareness of being able to cope optimally with different situations. Perceived self-efficacy is a belief that closely involves emotional and personological functioning. In fact, when one perceives oneself as capable, the likelihood of success increases significantly. The aim of this research was to verify a possible correlation between self-efficacy and the Digit Ratio (2D:4D), referred to as prenatal androgen levels, and whether these correlate with some psychological variables, considering possible gender differences. This study involved 56 sports university students, whose 2D:4D ratio was calculated. Moreover, self-assessment questionnaires: the Self-efficacy Scale (SES), the Big Five Questionnaire-2 (BFQ-2), the Profile of Mood State (POMS), the State–Trait Anxiety Inventory Form Y (STAI-Y) and the Emotional Regulation Questionnaire (ERQ) were administered. The data show that the perceived levels of self-efficacy seem to be influenced by an innate predisposition linked to prenatal androgen values to which the subjects were exposed during uterine life (2D:4D). This negative correlation indicates that the higher the value of the digit ratio, the more likely it is that the level of perceived self-efficacy will be lower. Finally, the degree of perceived self-efficacy also seems to depend on the levels of subjective anxiety, understood both as a personological disposition and a contingent condition, and the latter also seems to be influenced by prenatal androgen levels, particularly in women. Full article

A series of behavioral detection paradigms have been developed for zebrafish (Danio rerio) to examine anxiety-like behavioral responses. Among them, the novel tank diving test is rapidly gaining popularity in translational neuroscience and behavioral research for the investigation of psychopharmacological activity focusing on stress. Zebrafish respond to conspecific epidermal-released alarm substances with antipredator reactions. Although the alarm responses of zebrafish were well characterized in a novel tank diving experiment, the relationship between the intensity of the alarm behavior and the concentration of the alarm substance needed to be understood more adequately. In the current paper, we investigated the behavioral phenotypes and potencies of zebrafish elicited by the serial dilution of an alarm substance in the novel tank diving test. Using a video-tracking assisted behavioral quantification approach, we demonstrated no linear concentration-dependent relationship between antipredator behavior and skin extracts, suggesting that an optimal concentration induced each typical behavioral response. The results showed that the freezing duration (%) significantly increased when stimulated with 10⁴-fold times dilutions of skin extract (equivalent 5 × 10⁻⁵ fish/L), while erratic movements (%), time in the bottom half (%), and latency to the upper half (s) significantly elevated when stimulated with 10³-fold times dilutions (equivalent 5 × 10⁻⁴ fish/L). Therefore, the concentration threshold for an alarm substance that elicited innate fear behavior in zebrafish was presumed to be an equivalent concentration of approximately 5 × 10⁻⁴ fish/L. The conclusions may fill a knowledge gap between the innate fear response triggered by injured skin and a novel tank diving paradigm that provides insights into the characterization of alarm substance, behavioral responses, and physiological response mechanisms in zebrafish. Full article

Gut microbes and their metabolites are actively involved in the development and regulation of host immunity, which can influence disease susceptibility. Herein, we review the most recent research advancements in the gut microbiota–immune axis. We discuss in detail how the gut microbiota is a tipping point for neonatal immune development as indicated by newly uncovered phenomenon, such as maternal imprinting, in utero intestinal metabolome, and weaning reaction. We describe how the gut microbiota shapes both innate and adaptive immunity with emphasis on the metabolites short-chain fatty acids and secondary bile acids. We also comprehensively delineate how disruption in the microbiota–immune axis results in immune-mediated diseases, such as gastrointestinal infections, inflammatory bowel diseases, cardiometabolic disorders (e.g., cardiovascular diseases, diabetes, and hypertension), autoimmunity (e.g., rheumatoid arthritis), hypersensitivity (e.g., asthma and allergies), psychological disorders (e.g., anxiety), and cancer (e.g., colorectal and hepatic). We further encompass the role of fecal microbiota transplantation, probiotics, prebiotics, and dietary polyphenols in reshaping the gut microbiota and their therapeutic potential. Continuing, we examine how the gut microbiota modulates immune therapies, including immune checkpoint inhibitors, JAK inhibitors, and anti-TNF therapies. We lastly mention the current challenges in metagenomics, germ-free models, and microbiota recapitulation to a achieve fundamental understanding for how gut microbiota regulates immunity. Altogether, this review proposes improving immunotherapy efficacy from the perspective of microbiome-targeted interventions. Full article

The prevalence of Alzheimer’s disorder (AD) is increasing worldwide, and the co-morbid anxiety is an important, albeit often neglected problem, which might appear early during disease development. Animal models can be used to study this question. Mice, as prey animals, show an innate defensive response against a predator odor, providing a valuable tool for anxiety research. Our aim was to test whether the triple-transgenic mice model of AD shows signs of innate anxiety, with specific focus on the temporal appearance of the symptoms. We compared 3xTg-AD mice bearing human mutations of amyloid precursor protein, presenilin 1, and tau with age-matched controls. First, separate age-groups (between 2 and 18 months) were tested for the avoidance of 2-methyl-2-thiazoline, a fox odor component. To test whether hypolocomotion is a general sign of innate anxiety, open-field behavior was subsequently followed monthly in both sexes. The 3xTg-AD mice showed more immobility, approached the fox odor container less often, and spent more time in the avoidance zone. This effect was detectable already in two-month-old animals irrespective of sex, not visible around six months of age, and was more pronounced in aged females than males. The 3xTg-AD animals moved generally less. They also spent less time in the center of the open-field, which was detectable mainly in females older than five months. In contrast to controls, the aged 3xTg-AD was not able to habituate to the arena during a 30-min observation period irrespective of their sex. Amyloid beta and phospho-Tau accumulated gradually in the hippocampus, amygdala, olfactory bulb, and piriform cortex. In conclusion, the early appearance of predator odor- and open space-induced innate anxiety detected already in two-month-old 3xTg-AD mice make this genetically predisposed strain a good model for testing anxiety both before the onset of AD-related symptoms as well as during the later phase. Synaptic dysfunction by protein deposits might contribute to these disturbances. Full article

Citrullinemia type I (CTLN1) is a rare autosomal recessive disorder caused by mutations in the gene encoding argininosuccinate synthetase 1 (ASS1) that catalyzes the third step of the urea cycle. CTLN1 patients suffer from impaired elimination of nitrogen, which leads to neurotoxic levels of circulating ammonia and urea cycle byproducts that may cause severe metabolic encephalopathy, death or irreversible brain damage. Standard of care (SOC) of CTLN1 consists of daily nitrogen-scavenger administration, but patients remain at risk of life-threatening decompensations. We evaluated the therapeutic efficacy of a recombinant adeno-associated viral vector carrying the ASS1 gene under the control of a liver-specific promoter (VTX-804). When administered to three-week-old CTLN1 mice, all the animals receiving VTX-804 in combination with SOC gained body weight normally, presented with a normalization of ammonia and reduction of citrulline levels in circulation, and 100% survived for 7 months. Similar to what has been observed in CTLN1 patients, CTLN1 mice showed several behavioral abnormalities such as anxiety, reduced welfare and impairment of innate behavior. Importantly, all clinical alterations were notably improved after treatment with VTX-804. This study demonstrates the potential of VTX-804 gene therapy for future clinical translation to CTLN1 patients. Full article

Neuroinflammation is discussed to play a role in specific subgroups of different psychiatric disorders, including anxiety disorders. We have previously shown that a mouse model of trait anxiety (HAB) displays enhanced microglial density and phagocytic activity in key regions of anxiety circuits compared to normal-anxiety controls (NAB). Using minocycline, we provided causal evidence that reducing microglial activation within the dentate gyrus (DG) attenuated enhanced anxiety in HABs. Besides pharmacological intervention, “positive environmental stimuli”, which have the advantage of exerting no side-effects, have been shown to modulate inflammation-related markers in human beings. Therefore, we now investigated whether environmental enrichment (EE) would be sufficient to modulate upregulated neuroinflammation in high-anxiety HABs. We show for the first time that EE can indeed attenuate enhanced trait anxiety, even when presented as late as adulthood. We further found that EE-induced anxiolysis was associated with the attenuation of enhanced microglial density (using Iba-1 as the marker) in the DG and medial prefrontal cortex. Additionally, EE reduced Iba1 + CD68+ microglia density within the anterior DG. Hence, the successful attenuation of trait anxiety by EE was associated in part with the normalization of neuro-inflammatory imbalances. These results suggest that pharmacological and/or positive behavioral therapies triggering microglia-targeted anti-inflammatory effects could be promising as novel alternatives or complimentary anxiolytic therapeutic approaches in specific subgroups of individuals predisposed to trait anxiety. Full article