The endogenous dynorphin/kappa opioid receptor (KOR) system in the brain mediates the dysphoric effects of stress, and KOR antagonists may have therapeutic potential for the treatment of drug addiction, depression, and psychosis. One class of KOR antagonists, the long-acting norbinaltorphimine (norBNI)–like antagonists, have been suggested to act by causing KOR inactivation through a c-Jun-kinase mechanism

Decades of research have established a critical role of the basolateral complex of the amygdala (BLA) in the encoding and storage of aversive memories. Much of this work has utilized Pavlovian fear conditioning procedures in which animals experience a single aversive event. Although this effort has produced great insight into the neural mechanisms that support fear memories for an isolated aversive

Although childhood trauma is an important risk factor for various diseases, the underlying biological mechanisms remain insufficiently understood. To deepen this understanding, we investigated the wide-spectrum metabolomic signature of childhood trauma exposure in a large adult cohort.

First-episode schizophrenia spectrum disorders (FESSDs) are associated with significant cognitive impairment that affects daily functioning. While these deficits are well documented, the neural mechanisms underlying the cognitive impairment in FESSDs remain limited. Because the structure robustness and resilience of the brain network in healthy populations are reported to be associated with cognitive

The prevalence of stress-induced disorders, including depression, anxiety, posttraumatic stress disorder, and postpartum depression, has been increasing, while current treatment approaches are limited. As a result, researchers are exploring alternative treatments that include ketamine as a prophylactic against these disorders. This review provides an overview of the current knowledge on the use of

There is a pressing need to establish objective measures to improve diagnosis, prediction, prevention, and treatment of bipolar disorder (BD). Multimodal artificial intelligence (AI) tools could provide these means by incorporating various layers of data orthogonally related to BD, including genomics and other omics, environmental exposures, imaging measures, electronic health records, cognition, sensing

Impairment of prefrontal cortex (PFC)–dependent cognition is associated with multiple psychiatric disorders. Development of more effective treatments for this form of cognitive dysfunction is hindered by our limited understanding of the neurobiology underlying PFC-dependent cognition. We previously identified a robust population of corticotropin-releasing factor (CRF) neurons in the caudal dorsomedial

Epigenetic factors (such as DNA methylation) have been widely reported to be associated with schizophrenia (SCZ). However, the causal relationships between epigenetic factors and SCZ remain largely unknown.

In the field of deep brain stimulation (DBS), 2 major themes are currently making significant progress. The first of these is the framework of connectomic DBS, in which circuits that are associated with improvements of specific symptoms are described and targeted to improve and potentially personalize treatment. The second theme is related to the concept of brain sensing and adaptive DBS, which are

Astrocytes in the nucleus accumbens (NAc) play a dynamic role in regulating synaptic plasticity induced by drugs of abuse through modulation of glutamatergic neurotransmission. Astrocyte-secreted factors may also contribute to the reprogramming of brain circuitry that leads to drug-seeking behavior. Here, we investigated the role of astrocyte Ca2+ signals in vivo and of the astrocyte-secreted protein

There has been little examination of the stability and validity of polygenic risk scores (PRSs), i.e., whether individuals identified as high risk for a disorder with one PRS are identified as high risk with another PRS and whether high-risk individuals have the disorder.

Prosocial helping behavior, characterized by voluntary actions taken to benefit others, plays a vital role in promoting cooperation and maintaining social bonds across human and animal social groups. In this review, we examine key conceptual issues surrounding prosocial behavior, focusing specifically on targeted helping and comforting actions. We outline the behavioral paradigms used to study these

There is clinical interest in recognizing copy number variants (CNVs) in children because many have immediate and long-term health implications. Neurodevelopmental (ND) CNVs are associated with intellectual disability, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD), conditions typically diagnosed by medical practitioners. However, ND CNVs may have additional, early

Shorter stature has been phenotypically linked to increased prevalence of schizophrenia (SCZ), but the nature of this association is unknown.

After decades of limited progress in depression treatment, recent advancements have sparked renewed interest in developing novel antidepressants, particularly rapid-acting antidepressants (RAADs). Despite these promising developments, there remains a significant gap in research on bipolar depression. While several antipsychotics have been investigated for their efficacy in bipolar depression due to

Anorexia nervosa (AN) is an eating disorder for which the underlying etiology remains mostly uncharacterized. Large-scale genetic studies of AN suggest a relationship between AN liability and cardiometabolic traits, such as lipid and glycemic biology, which may reveal novel treatment targets through pharmacological or nutritional interventions. However, the role of body mass index (BMI) in the diagnosis

Early-life adversity (ELA) results in detrimental physical and mental health outcomes. The impact of ELA can reverberate across generations, with epigenetic modifications being one of the proposed biological correlates of exposure to ELA. Here, we bridge the translational gap between rodent models and clinical studies by utilizing a nonhuman primate model to study the cross-generational epigenetic

The current study utilized positron emission tomography (PET) imaging to examine how long-term cocaine self-administration (SA) and time off cocaine affected kappa opioid receptor (KOR) availability in the brain of previously cocaine-naïve monkeys. In addition, neuronally derived small extracellular vesicles (NDEs) were measured from plasma to identify peripheral measures of KORs.

Major depressive disorder (MDD) is a leading cause of disability worldwide, with available treatments often showing limited efficacy. Recent research suggests that targeting specific subtypes of depression and understanding the underlying brain mechanisms can improve treatment outcomes. This study investigates the potential of the potassium KCNQ (Kv7) channel opener ezogabine to modulate the resting-state

Alcohol use disorder (AUD) is a prevalent neuropsychiatric disorder that is a major global health concern, affecting millions of people worldwide. Previous studies of AUD used underpowered single-cell analysis or bulk homogenates of postmortem brain tissue, which obscure gene expression changes in specific cell types. Therefore, we sought to conduct the largest-to-date single-nucleus RNA sequencing

Substantial interindividual differences exist in the vulnerability to develop posttraumatic stress disorder (PTSD) symptoms following trauma exposure. Identification of neurocognitive risk markers for PTSD symptoms could aid early assessment and identification of preventive intervention targets for PTSD, particularly in high-risk professionals. Therefore, large prospective longitudinal studies with

Hallucinations and delusions are often grouped together as positive symptoms of psychosis. However, recent evidence suggests that they may be driven by distinct computational and neural mechanisms. Examining the time course of their emergence may provide insights into the relationship between these underlying mechanisms.

Given the increasingly large number of loci discovered by psychiatric genome-wide association studies (GWASs), specification of the key biological pathways that underlie these loci has become a priority for the field. We have previously leveraged the pleiotropic genetic relationships between schizophrenia (SCZ) and 2 cognitive phenotypes (educational attainment and cognitive task performance) to differentiate

Autoimmune encephalitis (AE) is a rapidly evolving topic in both neurology and psychiatry. A recent international consensus article defined criteria for possible, probable, and definite autoimmune psychosis (AP) inspired by the principles established in neurology for the definition of AE. This has stimulated much clinical research on AP but also criticism of the validity of the criteria for possible

In this study, we investigated the interplay between molecular measures of polygenic risk scores (PRSs) and conventional measures of family history (FH) on the risk of 4 psychiatric disorders: schizophrenia (SCZ), bipolar disorder (BPD), major depressive disorder (MDD), and obsessive-compulsive disorder (OCD) in community samples of East Asian populations. We examined the individual and joint associations

Psychiatric disorders have complex genetic architectures with substantial genetic overlap across conditions, which may partially explain their high levels of comorbidity. This presents significant challenges to research. Genome-wide association studies (GWASs) have uncovered hundreds of loci associated with single disorders, but the genetic landscape of psychiatric disorders has remained largely obscure

Bipolar disorder (BD) and schizophrenia (SCZ) are uniquely human disorders with a complex pathophysiology that involves adverse neuropathological events in brain development. High disease polygenicity and limited access to live human brain tissue make these disorders exceedingly challenging to study mechanistically. Cellular cultures and brain organoids generated from human-derived pluripotent stem

As global gene discovery efforts move away from a historic Eurocentric focus and advance toward embracing more diverse populations, consideration of sociocultural aspects of bipolar disorder (BD) become critical to their success. Diversity can be leveraged to accelerate gene discovery, via different patterns of linkage disequilibrium that lead to greater resolution of mapping association signals, and

Neuroimaging is a powerful noninvasive method for studying brain alterations in bipolar disorder (BD). To date, most neuroimaging studies of BD have included smaller cross-sectional samples reporting case versus control comparisons, revealing small to moderate effect sizes. In this narrative review, we discuss the current state of structural neuroimaging studies using magnetic resonance imaging, which

Echoes of natural and anthropogenic stressors not only reverberate within the physiology, biology, and neurobiology of the generation directly exposed to them but also within the biology of future generations. With the intent of understanding this phenomenon, significant efforts have been made to establish how exposure to psychosocial stress, chemicals, over- and undernutrition, and chemosensory experiences

COVID-19 lockdowns were linked to a surge in unhealthy food–related behaviors, potentially as an attempt to cope with disrupted social homeostasis. Here, we tested bidirectional associations between momentary psychological states and prospective food consumption and the moderation of these associations by quality and quantity of social interactions.

Long-term pharmacological treatment is the cornerstone of the management of bipolar disorder (BD). Clinicians typically select mood-stabilizing medications from among several options through trial and error. This process could be optimized by using robust predictors of treatment response. We review clinical features and biological markers studied in relation to outcome of long-term treatment of BD

Researchers have begun to use the synergy of psychiatry and neuroscience to identify biomarkers that can be used to diagnose mental health disorders, predict their progression, and forecast treatment efficacy. However, biomarkers have achieved limited success to date, potentially due to a narrow focus on specific aspects of brain signals. This highlights a critical need for methodologies that can fully

The brain integrates multiple scales of description, from the level of cells and molecules to large-scale networks and behavior. Understanding relationships across these scales may be fundamental to advancing understanding of brain function in health and disease. Recent neuroimaging research has shown that functional brain alterations that are associated with schizophrenia spectrum disorders (SSDs)

Repeated use of addictive drugs produces long-lasting and prepotent drug-cue associations that increase vulnerability for relapse in individuals with a substance use disorder. Epigenetic factors, such as HDAC5 (histone deacetylase 5), play a key role in regulating the formation of drug-cue associations, but the underlying mechanisms remain unclear.

The current study aimed to identify classes of cognitively impaired older individuals based on their neuropsychiatric symptoms (NPSs) and to investigate the contribution of NPS class to cognitive decline and Alzheimer’s disease (AD) risk in mild cognitive impairment (MCI).

Cannabis use is common, particularly during emerging adulthood when brain development is ongoing, and its use is associated with harmful outcomes for a subset of people. An improved understanding of the neural mechanisms underlying risk for problem-level use is critical to facilitate the development of more effective prevention and treatment approaches.

Tourette disorder (TS) is characterized by motor hyperactivity and tics that are believed to originate in the basal ganglia. Postmortem immunocytochemical analyses has revealed decreases in cholinergic (CH), as well as parvalbumin and somatostatin GABA (gamma-aminobutyric acid) interneurons (INs) within the caudate/putamen of individuals with TS.

Alcohol use disorder (AUD) is a leading cause of death and disability worldwide. There has been substantial progress in identifying genetic variants that underlie AUD. However, whole-exome sequencing studies of AUD have been hampered by the lack of available samples.

Chronic social isolation alters behavior across animal species. Genetic model organisms such as mice and flies provide crucial insight into the molecular and physiological effects of social isolation on brain cells and circuits. Here, we comparatively review recent findings regarding the function of conserved neuropeptides in social isolation in mice and flies. Analogous functions of 3 classes of

Longitudinal changes in cognitive function may be crucial in predicting clinical outcomes in clinical high-risk (CHR) individuals. In this study, we aimed to investigate the predictive value of baseline cognitive impairment and short-term cognitive changes for nonremission and conversion to psychosis in individuals at CHR for psychosis compared with healthy control individuals (HCs).

Long-term fear memory storage involves gradual reorganization of supporting brain regions over time, a process termed systems consolidation. Memories initially rely on the hippocampus but gradually shift dependence to the neocortex. Although hippocampal activity drives this transfer, the molecular basis of systems consolidation is largely unknown. DNA methylation changes accompany persistent fear memory

Posttraumatic stress disorder (PTSD) is a debilitating condition caused by exposure to traumatic events that affects 5% to 10% of the population, with increased prevalence among women and individuals in war zones. Beyond psychological symptoms, PTSD induces significant physiological changes across systems. Psychoneuroimmunoendocrinology (PNIE) offers a framework to explore these complex interactions

The persistence of cocaine-evoked adaptations relies on gene regulations within the reward circuit, especially in the ventral striatum (i.e., nucleus accumbens [NAc]). Notably, activation of the ERK (extracellular signal-regulated kinase) pathway in the striatum is known to trigger a transcriptional program shaping long-term responses to cocaine. Nuclear calcium signaling has also been shown to control

Meal variety promotes overconsumption by delaying sensory-specific satiety (SSS), the transient reduction in reward value of a recently consumed food. Despite its role in meal cessation, the neuroendocrine mechanisms that underlie SSS are largely unknown.

Innovative treatments for paranoia, which significantly impairs social functioning in schizophrenia spectrum disorders (SSDs), are urgently needed. The pathophysiology of paranoia implicates the amygdala–prefrontal cortex (PFC) circuits; thus, in this study, we systematically investigated whether transcranial direct current stimulation (tDCS) to the ventrolateral PFC can attenuate paranoia and improve

Certain cognitive processes require inhibition provided by the somatostatin (SST) class of GABA (gamma-aminobutyric acid) neurons in the dorsolateral prefrontal cortex (DLPFC). This inhibition onto pyramidal neuron dendrites depends on both SST and GABA signaling. Although SST messenger RNA (mRNA) levels are lower in the DLPFC in schizophrenia, it is not known whether SST neurons exhibit alterations

Valid scalable biomarkers for predicting longitudinal clinical outcomes in psychiatric research are crucial for optimizing intervention and prevention efforts. Here, we recorded spontaneous speech from initially abstinent individuals with cocaine use disorder (iCUDs) for use in predicting drug use outcomes.

Eating disorders (EDs) are serious psychiatric disorders with an estimated 3.3 million healthy life-years lost worldwide yearly. Understanding the course of illness, diagnostic transitions and remission, and their associated genetic correlates could inform both ED etiology and treatment. We investigated occurrences of ED transitions and presumed remission and their genetic correlates as captured by

Bipolar disorder (BD) is a severe psychiatric condition with unclear etiology and no established biomarkers. Here, we aimed to characterize the cerebrospinal fluid (CSF) proteome in euthymic individuals with BD to identify potential protein biomarkers.