This study aimed to compare the local gyrification index (LGI) between first-episode drug-naive major depressive disorder (MDD) patients and healthy controls (HC), to investigate associated alterations in functional connectivity (FC) and effective connectivity (EC), and to examine the relationships of neuroimaging alterations to cognitive performances and to neurotransmitter profiles.

Adolescent major depressive disorder (AMDD) emerges during a period of significant neurobiological reorganization, yet its specific pathophysiological mechanisms remain poorly understood. This study investigated structural-functional brain coupling (SC-FC coupling) in AMDD and its relationship with neurotransmitter systems and molecular profiles.

Recent evidence suggests that psychedelics hold promise in treating a range of neuropsychiatric disorders, highlighting the need to better understand their broader behavioral effects. Many animal-based behavioral assays related to mood, like anxiety and despair-like behavior, highly depend on locomotor activity. However, the influence of psychedelics on movement, especially in emotionally salient contexts, remains underexplored. While general locomotor activity can be monitored in the home cage, assessing movement in novel environments is critical for interpreting behaviors shaped by context and novelty. In this study, we examine the effects of the serotonergic psychedelic, DOI, on locomotor activity using the elevated plus maze (EPM), a conventionally used conflict-based anxiety maze. We find that DOI alters locomotor behavior in rats in a dose-dependent manner, and these changes are closely correlated with changes in anxiety-like behavior on the EPM. Notably, we observe species- and strain-specific differences in the DOI-evoked influence on spontaneous motor activity. While Sprague-Dawley rats and 129S6/SvEv mice exhibit reduced movement in response to 1 mg/kg DOI, C57BL/6J mice show increased movement at the same dose. The modulation of locomotor activity, like the observed anxiety-related effects, appears to be driven by the serotonin 2A receptor (5-HT R), as noted by the absence of DOI-evoked locomotor changes in 5-HT R knockout (KO) mice. These findings highlight the importance of considering the impact of serotonergic psychedelics on both spontaneous and context-dependent locomotion whilst interpreting mood-related behavioral responses in novelty-dependent, conflict-based approach-avoidance tasks.

Post-traumatic stress disorder (PTSD) is a severe mental illness characterized by increased arousal, intrusion, avoidance, and negative cognitive alterations following exposure to fatal stresses or psychological trauma. In this study, we explored the ameliorating effects of spinosin on PTSD-like behaviors in PTSD model mice induced by single prolonged stress (SPS). A single dose of spinosin (3 mg/kg, p.o.) ameliorated PTSD-like behaviors as assessed using the elevated plus-maze test, marble burying test, Y-maze test, tail suspension test, and fear extinction test. Furthermore, we discovered that spinosin promotes fear extinction through 5-HT receptor activation. We also verified that spinosin normalizes the increased phosphorylation levels of PKA and CREB, which are downstream signaling pathways of the 5-HT receptor, in the amygdala of mice modeling PTSD. Our findings suggest that spinosin could be an effective treatment for PTSD via 5-HT receptor activation, addressing the limitations of current PTSD medications.

Difficulties in interpersonal interactions have been related to Social Cognition (SC) impairments in eating disorders (EDs). However, results do not account for differences between restrictive (rED) and purgative (pED) profiles and are just based on decoding tasks. This study assessed SC by Theory of Mind (ToM) abilities in ToM decoding and inference tasks between rED and pED patients and healthy women and its relationship with clinical variables.

Individuals with autism spectrum disorder (ASD) exhibit aberrant intrinsic connectivity and altered mismatch negativity responses. Both mismatch negativity and intrinsic connectivity are associated with pre-attentive mechanisms. However, the potential link between mismatch negativity and alterations in intrinsic connectivity in ASD has not been thoroughly explored. This study aimed to investigate the resting-state functional connectivity of the auditory network in ASD and examine its association with mismatch negativity and set-shifting performance.

Procrastination is a problematic behavior that negatively affects both physical and mental well-being. While extant research has established a negative association between psychological resilience and procrastination, the cognitive and neural basis underlying this relationship remain poorly characterized. To address this issue, current study asked college student participants (n = 430, M = 19.288 years, SD = 1.675) to undergo the MRI scanning and complete the Resilience Scale for Chinese Adolescents (RSCA) and General Procrastination Scale (GPS). The network model found that the negative relationship between psychological resilience and procrastination was primarily driven by goal planning and affect control which were two subcomponents of psychological resilience. VBM results showed that the gray matter volume (GMV) of the left Inferior Frontal Gyrus (IFG) and right Middle Frontal Gyrus (MFG) were positively correlated with goal planning, while the GMV of the right Inferior Temporal Gyrus (ITG) was positively correlated with the affect control. Importantly, the structural equation modeling (SEM) results indicated that the left IFG and the right ITG were associated with procrastination via goal planning and affect control, respectively. Taken together, these findings suggest that high psychological resilience reduces procrastination primarily through brain regions supporting goal planning and affect control.

Early life stress (ELS) has been widely recognized as a major risk factor for the development of depression and anxiety in humans. While clinical studies have established this association, the underlying neural mechanisms remain elusive. To address this gap, rodent models such as maternal separation have been employed to mimic ELS and to explore its long-term effects on the brain and behavior. Environmental enrichment (EE) has further been proposed as a potential intervention to counteract the detrimental consequences of ELS, but its efficacy and underlying mechanisms remain insufficiently characterized. In this study, we utilized multi-parametric magnetic resonance imaging combined with behavioral tests to systematically evaluate the long-term effects of ELS exposure and subsequent EE intervention on brain signatures and behavioral changes in adult male and female ELS mice. ELS mice exhibited depressive- and anxiety-like behaviors, along with increased brain activity in the striatum. These behavioral changes were accompanied by reductions in gray matter volume, white matter integrity and metabolite ratios in the striatum. Importantly, EE intervention effectively reversed the behavioral impairments by restoring the alterations in brain function, structure, and metabolism, especially in the striatum. This study provides comprehensive insights into the detrimental effects of early life stress on brain and behavioral outcomes and reveals that these negative effects can be mitigated by EE intervention. Our findings identify the striatum as a critical region involved in these processes.

Aging and unhealthy eating habits independently and synergistically disrupt central nervous system (CNS) homeostasis, increasing susceptibility to neurological and behavioral disorders. Mitochondria plays a critical role in maintaining neuronal survival and activity, representing a central player in the pathogenesis of neurodegenerative diseases. Here, we used zebrafish as a model to investigate how aging and a high-fat diet (HFD) affect brain bioenergetics and behavior. Young (4-6 months) and aged (17-22 months) male zebrafish were fed either a standard diet or an HFD based on boiled chicken egg yolk for 14 days. Brain mitochondria was evaluated using high-resolution respirometry, transmission electron microscopy (TEM), and qRT-PCR. HFD impaired the metabolic health of both young and aged animals, promoting weight gain, increased abdominal length, and elevated fasting glucose levels. Aging intensified the HFD detrimental effects on behavior: aged HFD-fed zebrafish displayed increased anxiety-like behavior in the novel tank test, and impaired cognitive performance in the T-maze test. Notably, HFD had no significant effect on aggressive behavior regardless of age. Mitochondrial responses to HFD differed by age: while cerebral bioenergetic function declined in young fish, aged animals showed an opposite trend. TEM analysis revealed increased accumulation of fragmented mitochondria in HFD group, indicating potential mitochondrial dysfunction. RT-qPCR showed upregulation of genes involved in the electron transport chain, especially in aged zebrafish. In conclusion, our findings demonstrate an age-dependent vulnerability to the effects of HFD on both neurobehavioral and mitochondrial parameters.

Flavonoid-based phytomedicines are emerging as promising therapies for combating various disorders, including depression. Depression is a common and serious medical illness that negatively affects the quality of life. It has become a leading cause of disability worldwide. Flavonoids are ubiquitous biologically active phytochemicals in medicinal plants, herbs, fruits, vegetables, teas, and wines. There is a negative association between total flavonoid intake and depression symptoms in humans. This review aims to discuss the recent in vivo and in vitro studies on the effects of dietary flavonoids in depression models and assays to identify the molecular pathways that underlie their actions. Here, we briefly introduce the pathophysiology of depression, the diagnosis of depression, and the models for studying depression. The discovered potential antidepressant flavonoids include flavonols (quercetin, quercitrin, kaemferol, and heptamethoxyflavone), flavones (luteolin, baicalin, apigenin, and cymaroside), isoflavones (ononin), flavanones (pinocembrin), and anthocyanins (callistephin). These plant-derived flavonoids have been shown to reduce neuronal damage in the hippocampus, decrease neurotransmitter depletion, attenuate hypothalamic-pituitary-adrenal axis hyperactivation, inhibit inflammation in the central nervous system, and regulate gut microbiota. The key signaling pathways regulated by flavonoids include brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB), and nuclear factor kappa-B (NF-κB). Clearly, there is a need to conduct human dietary intervention studies to validate the beneficial physiological functions of flavonoids on the prevention and management of depression.

Cognitive difficulties within treatment-resistant unipolar and bipolar depression (TRD; TRBD) often do not improve with conventional pharmacotherapies. Psilocybin-assisted psychotherapy (PAP) has shown promise as a novel intervention for TRD; however, few studies have assessed its effects on cognition in this population.

Major depressive disorder (MDD) is a recurrent episodic mood disorder characterized by persistent low mood and loss of interest. The pathogenesis of major depressive disorder (MDD) involves a neuroinflammatory response, neurotransmitter dysfunction, blood-brain barrier disruption, oxidative stress, and mitochondrial dysfunction. Neuroinflammation, caused by the overactivation of microglia, is considered a key factor in the development of the disease. Metabolic reprogramming has been shown to play a crucial role in microglial activation and executive function. In MDD, microglia have the potential to become activated and transform into either pro-inflammatory or anti-inflammatory phenotypes. These variations in cellular phenotypes lead to differences in cellular energy metabolism. Mitochondria are involved in the energy metabolism of microglia and have intricate connections with microglia-mediated metabolic reprogramming and neuroinflammation. However, the specific changes in the metabolic reprogramming of microglia in depression, the numerous signaling pathways and cytokines involved, and the mechanisms by which they mediate phenotypic transitions remain unclear. Therefore, this review summarizes the metabolic reprogramming of microglia in MDD, as well as the involved signaling pathways, mitochondrial involvement and cytokines, and elaborates on their interaction with phenotypic transformation. The effects of drugs on regulating immune metabolic reprogramming to suppress neuroinflammation were summarized, providing potential for new research approaches in the treatment of MDD.

Nitric oxide synthase (NOS) plays a role in substance use related neurotoxicity and addictive phenotypes. Inhibition of nitric oxide (NO) production can prevent negative phenotypes associated with drugs intake. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NOS. ADMA levels are regulated by dimethylarginine dimethylaminohydrolase type 1 (DDAH1). Numerous evidence suggests that drugs of abuse can increase DDAH1 levels, leading to reduction of ADMA levels, and in turn, causing neurotoxicity associated with NO overproduction. Yet, this data is sparse, and very little mechanistic evidence exists. Here, we review the literature on the impact of substances of abuse and social stress, as a condition implicated in addictive phenotypes, on DDAH1 levels in the brain. This review highlights five things: first, psychostimulants can increase brain DDAH1 levels and DDAH1-ADMA-NOS signaling axis could underlay neurotoxicity and addictive behaviors driven by psychostimulants. Second, opioids can also significantly increase brain DDAH1 levels, yet currently no mechanistic studies exist to determine the consequences of that increase. Three, the nicotine and alcohol studies are inconclusive as results are often complicated with comorbidities associated with cardiovascular impairments, liver toxicity and aging. Four, studies on cannabinoids are insufficient, more data is needed. Finally, social stress affects DDAH1 levels and anti-depressants can reverse this effect, but mechanistic data is lacking. In conclusion, proteomic, metabolomic and functional studies suggest that DDAH1 may play a role in addiction and conditions related to social stress. Further investigation is necessary to elucidate the specific function of DDAH1 in addiction and social stress phenotypes.

While the harmful effects of alcohol use during pregnancy are well recognized, less is understood about how maternal alcohol consumption during adolescence, prior to reproduction, may affect offspring. This is especially concerning given the high prevalence of adolescent alcohol use, particularly in females. This study investigates how maternal pre-reproductive alcohol exposure, combined with a maternal immune activation (MIA) during pregnancy, a well-established neurodevelopmental risk factor, affects offspring. Female Wistar rats were subjected to intermittent binge-like alcohol consumption during adolescence and later mated with naïve males. On gestational day 15, dams received either saline or a mild dose of the viral mimic Poly I:C. Maternal care was monitored, and stress axis components were analyzed in both dams and their offspring. Adult offspring underwent behavioral testing, MRI, neurochemical and neuroimmune analyses, metabolic profiling, and voluntary alcohol consumption assessments. Maternal alcohol exposure prior to reproduction led to increased offspring body weight, memory impairments, altered HPA axis function, microglial reductions, and enlarged cerebellar volumes, with most outcomes showing sex-specific differences, including opposing neurochemical responses. Interestingly, MIA, but not maternal alcohol, induced elevated alcohol intake in offspring and disrupted sensorimotor gating. MIA-exposed dams also showed impaired maternal care and reproductive HPA axis dysregulation. These findings demonstrate that adolescent alcohol use before reproduction has significant intergenerational consequences and that even mild immune challenges during pregnancy can independently disrupt offspring development. Results underscore the importance of sex as a biological variable and call for targeted preventive strategies.

Aripiprazole, brexpiprazole and cariprazine represent a new generation of atypical antipsychotics with partial agonist activity at dopamine D and D receptors. So far, the functional activity of these partial agonists has mainly been studied at G-protein-dependent cyclic adenosine monophosphate (cAMP) signaling pathways of D and D receptors. While their effects at D receptor-mediated β-arrestin translocation were relatively well characterized the comparative investigation at D-dependent β-arrestin translocation is still largely missing. Moreover, antagonism of these partial agonists either at D or D receptors has not been studied at multiple cellular signaling pathways. In this study, we compared the agonist and antagonist features of aripiprazole, brexpiprazole, cariprazine on dopamine receptor-mediated cAMP and β-arrestin pathways in multiple cell lines expressing recombinant human D or D receptors using homogeneous time-resolved fluorescence and luminescent enzyme fragment complementation technologies. We demonstrated that the three partial agonists display qualitatively similar functional profile at D receptor-mediated cAMP and β-arrestin pathways. While cariprazine showed partial agonism and partial antagonism at D receptor-mediated β-arrestin translocation, aripiprazole and brexpiprazole displayed only weak or no agonist but potent antagonist activity. These data suggest differentiated mechanism of action of cariprazine at the D receptor signaling compared to aripiprazole and brexpiprazole.

Obsessive-compulsive disorder (OCD) is characterized by disruptions in large-scale brain networks. However, the role of high-frequency neural synchrony in these abnormalities remains unclear. Elucidating frequency-specific alterations may offer critical insights into the neurophysiological mechanisms underlying brain network dysfunction in OCD.

Insomnia disorder is a heterogeneous psychiatric condition characterized by differences in psychological traits and neurobiological mechanisms, necessitating precise phenotyping for targeted interventions. This clinical control study, part of a two-year multicenter research project, examined differences in sleep parameters, psychological characteristics, and morphometric similarity (MS) patterns between insomnia phenotypes classified by objective total sleep time (oTST). The study enrolled 997 adult patients with insomnia disorder, of whom 270 underwent MRI scanning. Participants were categorized into insomnia with objective normal sleep duration (INSD) and insomnia with objective short sleep duration (ISSD) based on oTST measured using a wearable forehead sleep recorder. Primary outcomes included sleep parameters (e.g., wake after sleep onset and rapid eye movement percentage), psychological characteristics (e.g., rumination), and MS patterns assessed through MS mapping. Results showed that the ISSD phenotype showed shorter wake after sleep onset, lower eye movement sleep (REM) percentage, and higher non-REM stage 2 percentage, whereas the INSD phenotype exhibited greater sleep perception bias and more fragmented sleep. Additionally, ISSD showed higher global MS and distinct regional MS patterns, including lower MS in the right middle temporal gyrus and higher MS in the right postcentral gyrus. It also exhibited decoupling with the visual network and de-differentiation with the ventral attention and default mode networks. These findings reveal distinct neurobiological mechanisms underlying insomnia phenotypes and highlight the need for phenotype-based interventions.

Depression, characterized by sustained low moods and even suicidal tendencies, has been intimately linked with mitochondrial dysfunction. This dysfunction is significantly connected with various psychiatric disorders, suggesting its potential role in the pathogenesis and progression of depression. Sirtuin 3 (SIRT3), a potent deacetylase enzyme primarily located within mitochondria, orchestrates mitochondrial function and mitigates various dysfunctions, e.g., insufficient cellular energy supply and oxidative stress. Insufficient cellular energy supply and oxidative stress disrupt normal neuroplasticity and neuroinflammation in the nervous system, as well as disturbances of the hypothalamic-pituitary-adrenal axis in peripheral systems. This review aims to elucidate that SIRT3 can be a potential target for depression, thereby summarizing the mechanisms by which SIRT3 is involved in the pathogenesis and progression of depression by regulating mitochondrial function.

Treating people with schizophrenia still represents a major challenge for neuropsychiatric drug development companies. While available atypical antipsychotics are mainly effective on positive symptoms of schizophrenia, their effects on cognitive and social-cognitive deficits remain insufficient and poorly characterized. For instance, a modest improvement of cognitive functions has been described following clozapine treatment. Nevertheless, it remains unclear whether this outcome is due to a direct effect on the neural circuits underlying cognition or to an indirect effect mediated by an overall reduction in positive symptoms. To address this question, we sought to measure mismatch negativity (MMN) responses in telemetered rats. MMN constitutes an electroencephalography-based biomarker of sensory, pre-attentional and predictive coding processes, functions whose disruptions highly influence certain aspects of patients' cognitive symptoms. MMN was measured under N-methyl-d-aspartate receptor (NMDAr) pharmacological inhibition by MK-801 (dizocilpine), a model based on the glutamatergic hypothesis of schizophrenia, and we tested whether clozapine could improve MMN under this condition or not. We found that MK-801 dose-dependently reduced the MMN peak amplitude in rats, aligning with the MMN response deficit seen in schizophrenia patients. Strikingly, clozapine was able to mitigate this electrophysiological deficit, an unprecedented observation that has the potential to inspire new treatment strategies aimed towards unaddressed schizophrenia symptoms.

Preterm birth involves structural brain changes and increases the risk of neurodevelopmental disorders, including social cognitive dysfunction as implicated in autism spectrum disorder (ASD). However, it remains unclear whether or how volumetric brain changes may impact the risk of social cognitive dysfunction in toddlers of preterm birth.