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.

Childhood adversity is considered a risk factor for neurocognitive development impairments in adulthood, although research evidence for this notion is rather inconclusive. This study aimed to examine the effects of childhood trauma on rudimentary cognitive processes and their neurophysiological underpinnings in non-clinical samples of young adults. Two groups were formed based on scores from the Childhood Trauma Questionnaire: a high early trauma group (high-ACE) and a low early trauma group (low-ACE). All participants performed two versions of the choice reaction time (RT) task, while their brain activity was recorded via electroencephalography (EEG) to reconstruct global network dynamics in response to displayed stimuli. Results indicated that the high-ACE group exhibited greater RTs intra-individual variability and altered functional connectivity (FC) dynamics compared to the low-ACE group, particularly in the short foreperiod block. Performance inconsistency indexes and FC strength values were significantly correlated in the high-ACE group (p < 0.05, Spearman's correlation, FDR-corrected). Our findings showed that adults with higher early trauma exposure demonstrate reduced network flexibility and difficulties in connectivity resource allocation, which is quantified by means of delayed and less dynamic FC responses following stimulus presentation. This study contributes to the understanding of how childhood adversities alter brain functional repertoire and basic cognitive mechanisms, including those that process non-affective stimuli.

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.

Desynchronization of circadian rhythms is a hallmark of major depressive disorder (MDD). Agomelatine is an atypical antidepressant that acts as a melatonin receptor agonist and serotonin receptor antagonist. It has shown efficacy in alleviating symptoms of MDD with a favorable side effect profile. In the brain, agomelatine also modulates the glutamatergic system and in the present study, we investigated the effects of chronic mild stress (CMS) and agomelatine treatment on metabotropic glutamate receptor 5 (mGluR5) and synaptic vesicle glycoprotein 2 A (SV2A) binding in the medial prefrontal cortex (mPFC) and hippocampus (HP) in postmortem brain tissue derived from male rats using autoradiography. To account for diurnal influences, assessments were conducted at two time points: light-on (ZT6) and light-off (ZT18). The sucrose consumption test classified animals into four groups: Control, anhedonic-like, agomelatine responders, and non-responders. CMS increased mGluR5 binding in the prelimbic cortex of the mPFC during the light-on phase, an effect that was normalized by agomelatine treatment in responder rats. Agomelatine also reduced mGluR5 binding in the infralimbic cortex of the mPFC. No changes in mGluR5 binding were detected during the light-off phase or in the HP at either time point. Presynaptic density, assessed by SV2A levels, remained unchanged across all groups and time points. These findings reveal significant region-specific and diurnal alterations in mGluR5, emphasizing the role of time-of-day dependent timing in regulating mGluR5 and its association with depressive-like behaviors. Furthermore, the selective normalization of mGluR5 by agomelatine in responders reinforces its potential as a targeted therapeutic approach for MDD.

Metabolic disturbances are hallmark pathological features of Parkinson's disease (PD) and can be noninvasively captured by arterial spin labeling (ASL). However, the metabolic pattern of disconnections beyond regional alterations remains scarcely documented. We aimed to comprehensively investigate metabolic impairments in PD at the individual network scale by utilizing abundant hemodynamic metrics.

Dopamine receptor inhibition underlies both the therapeutic and adverse effects of antipsychotics, but the mechanisms modulating these effects in patients with schizophrenia remain incompletely understood. Hyperprolactinemia (HPRL), a direct consequence of D2 dopamine receptor blockade, provides a unique clinical model to investigate how genetic variation in glutamatergic signaling influences the downstream effects of dopaminergic disruption. We hypothesized that polymorphisms in GRIN2A and GRIN2B, encoding NMDA glutamate receptor subunits, modify the neuroendocrine consequences of dopamine receptor inhibition. By studying antipsychotic-induced HPRL, we aimed to demonstrate that NMDA receptor genetic variants shape the functional outcomes of dopaminergic perturbation. In a cross-sectional analysis of 536 schizophrenia patients, we measured prolactin levels-a sensitive biomarker of D2 receptor inhibition-and genotyped 23 GRIN2A/GRIN2B variants. Logistic regression assessed gene-drug relationships while controlling for clinical covariates. NMDA receptor genetic variation significantly influenced susceptibility to HPRL, with distinct effects observed between antipsychotic classes with the highest effect for the typical antipsychotics, which are D2 dopamine receptor antagonists. This demonstrates that glutamatergic genotypes predict interindividual variability in the neuroendocrine response to dopamine receptor blockade. These results provide the first clinical evidence in support of the hypothesis that NMDA receptor polymorphisms modulate the effects of dopaminergic inhibition in schizophrenia. Beyond HPRL, this dopamine-glutamate relationships paradigm may extend to other clinical outcomes of antipsychotic treatment, including therapeutic response and neurological side effects. Our findings underscore the importance of glutamatergic pathways in determining the functional consequences of dopamine receptor targeting.

Gastrointestinal hormones such as glucagon-like peptide-1 (GLP-1), gastric inhibitory peptide (GIP), glucagon and glicentin are important regulators of appetite and glucose homeostasis. While, agonists of GLP-1 and GIP receptors are approved treatments for type 2 diabetes and obesity, their role in anorexia nervosa (AN) remains largely unknown. In this study, we measured fasting serum levels of GLP-1, GIP, glucagon, and glicentin in 80 female patients with AN before (acAN-T1) and after short-term weight restoration (acAN-T2) compared to 80 age-matched female healthy controls (HC). GIP levels were higher (42.9 %) in acAN-T1 than in HC, while GLP-1, glicentin, and glucagon showed no group differences. Additionally, acAN-T1 patients exhibited lower fasting glucose (-8.4 %) and insulin (-42.6 %) levels than HC. In acAN-T2 GIP, GLP-1, and glicentin levels decreased (-30.4 %, -9.7 %, -15,7 % respectively), with only GIP normalizing. Glucose and insulin levels increased (4.5 % and 41.4 %, respectively), although they remained lower than in HC. Importantly changes in GIP levels after short-term weight restoration negatively correlated (r = -0.279) with changes in glucose levels. Furthermore, GIP levels in acAN-T1, were positively associated with disordered eating and depressive symptoms, independent of BMI-SDS. These results reveal that GIP shows a distinct pattern of dysregulation and normalization in AN, and link GIP levels to both glucose metabolism and symptom severity in AN. Thus, our findings support the rationale for investigating GIP receptor-targeted therapies in AN.

Increasing evidence implicates atypical cerebellar development in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). However, the trajectories of cerebellar subregions from childhood into adulthood-and the impact of ADHD on those trajectories-remain unclear. We analyzed the publicly available ADHD-200 dataset, comprising 871 participants aged 7.09-20.90 years (325 with ADHD, 546 typically developing [TD] controls). High-resolution T1-weighted images were processed with the automated CERES segmentation pipeline to obtain absolute gray matter volumes for the whole cerebellum and 12 lobular subdivisions (lobules I-VI, VIIB, VIIIA, VIIIB, IX-X, and crus I-II). Relative volume is also employed in this study, which refers to the relative proportion of absolute volume to intracranial volume. Age-related change was modeled with linear regression models that included diagnosis-by-age interactions. For absolute volume, a significant age-by-diagnosis interaction was observed in the right lobule I-II and bilateral lobule X. Follow-up analyses revealed that, compared with TD individuals, those with ADHD exhibited a steeper age-related increase in gray matter volume in these regions, indicating smaller volumes at younger ages and a more pronounced age-associated rise across the observed age range. For relative volume, significant age-by-diagnosis interaction effects were found in the bilateral lobule IV and bilateral crus II. Follow-up analyses indicated that both ADHD and TD individuals showed age-related decreases in gray matter volume; however, this decline was more pronounced in the ADHD group. Taken together, the divergent age-related patterns of absolute and relative gray matter volume suggest that overall intracranial volume expansion may lag behind cerebellar growth in ADHD, such that the relative cerebellar differences are proportionally less marked than the global brain differences. These findings unravel normative and ADHD developmental trajectories of cerebellar gray matter volume from childhood through adulthood and provide a neuroanatomical framework for optimizing the cerebellum-focused prevention and intervention strategies in ADHD.

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.

Contrary to a prevailing dogma in twentieth-century neuroscience, emerging evidence suggests that the generation of new neurons continues throughout life, contributing significantly to crucial life functions owing to their robust ability to enhance neuroplasticity. Hippocampal neurogenesis occurs in the subgranular layer of the dentate gyrus, a region characterized by a specific microenvironment conducive to the proliferation of neuronal cells. A substantial body of evidence supports the belief that this phenomenon impacts various functions, including learning, emotional responses, and the formation of new memories. Diseases affecting these areas can significantly disrupt cognition and general behavior. For instance, in mesial temporal lobe epilepsy, aberrant neurogenesis has been observed, leading to increased cell proliferation, altered patterns of cellular integration, errors in information processing, and the formation of abnormal synaptic connections and transmissions. These abnormalities have the potential to generate epileptic seizures, underscoring the profound impact of these diseases on cognitive functions. Conversely, the chronic recurrence of seizures, can result in chronic recurrence of seizures, which can lead to a persistent reduction of neurogenesis in the epileptic brain. This reduction directly impacts various learning processes and the formation of hippocampus-dependent declarative memory. The mechanisms behind these processes remain fully elucidated and involve the delicate balance between neuronal excitation and inhibition, directly influencing brain performance and potentially leading to a decline in cognitive functions. For example, of this are the genetic and epigenetic factors that have been found to significantly influence the etiology of temporal lobe epilepsy, particularly in relation to the processes of neurogenesis. In mesial temporal lobe epilepsy, this condition stands out as one of the most severe disorders affecting the well-being of epileptic patients. While memory is highlighted as one of the most affected functions, it is not the sole cognitive function compromised by this comorbidity. The alterations can extend from language to executive and spatial functions.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Thalamocortical interactions play a critical role in sleep oscillatory activities. However, in individuals with insomnia disorder (ID), the structural organization of these circuits, their relationship with sleep oscillatory coupling, and their potential modulation by repetitive transcranial magnetic stimulation (rTMS) remain unclear.

Stimulant medication is commonly used by children and adolescents with attention-deficit/hyperactivity disorder (ADHD), however its long-lasting effects on the developing brain remain unclear. In a previous randomized controlled trial (RCT) we found that short-term stimulant treatment influences the functional brain response to an acute methylphenidate-challenge in an age-dependent manner, in line with animal studies suggesting persisting effects on brain development.