DTNPD: A comprehensive database of drugs and targets for neurological and psychiatric disorders.

In response to the shortcomings in data quality and coverage for neurological and psychiatric disorders (NPDs) in existing comprehensive databases, this paper introduces the DTNPD database, specifically designed for NPDs. DTNPD contains detailed information on 30 NPDs types, 1847 drugs, 514 drug targets, 64 drug combinations, and 61 potential target combinations, forming a network with 2389 drug-target associations. The database is user-friendly, offering open access and downloadable data, which is crucial for network pharmacology studies. The key strength of DTNPD lies in its robust networks of drug and target combinations, as well as drug-target networks, facilitating research and development in the field of NPDs. The development of the DTNPD database marks a significant milestone in understanding and treating NPDs. For accessing the DTNPD database, the primary URL is http://dtnpd.cnsdrug.com, complemented by a mirror site available at http://dtnpd.lyhbio.com.

Insights from animal models on insulin signalling disturbances and related diseases in neurological and mental conditions.

There has been a growing awareness of the need for scientific research to focus on somatic and mental comorbidities in recent years due to the emerging evidence showing their substantial overlap at numerous levels. In this special issue, initiated by members of the EU-funded PRIME consortium ("Prevention and Remediation of Insulin Multimorbidity in Europe; www.prime-study.eu), the focus is on the comorbidities of metabolic disturbances, especially related to insulin signalling dysregulation and mental and neurological disorders. Thus, while obesity, type 2 diabetes, and metabolic syndrome are commonly known to be insulin-related disorders, the last decades have shown that neurodegenerative disorders, such as Alzheimer's disease, as well as neurodevelopment disorders, such as obsessive-compulsive disorder (OCD), autism spectrum disorders (ASDs) and attention deficit / hyperactivity disorder (ADHD) also fall into this category. The special issue draws together a series of basic and clinical review articles that describe the current knowledge and future perspectives regarding insulin comorbidities across a multidisciplinary group of experts.

From gut to brain: understanding the role of microbiota in inflammatory bowel disease.

With the proposal of the "biological-psychological-social" model, clinical decision-makers and researchers have paid more attention to the bidirectional interactive effects between psychological factors and diseases. The brain-gut-microbiota axis, as an important pathway for communication between the brain and the gut, plays an important role in the occurrence and development of inflammatory bowel disease. This article reviews the mechanism by which psychological disorders mediate inflammatory bowel disease by affecting the brain-gut-microbiota axis. Research progress on inflammatory bowel disease causing "comorbidities of mind and body" through the microbiota-gut-brain axis is also described. In addition, to meet the needs of individualized treatment, this article describes some nontraditional and easily overlooked treatment strategies that have led to new ideas for "psychosomatic treatment".

UNC5C: Novel Gene Associated with Psychiatric Disorders Impacts Dysregulation of Axon Guidance Pathways.

The UNC-5 family of netrin receptor genes, predominantly expressed in brain tissues, plays a pivotal role in various neuronal processes. Mutations in genes involved in axon development contribute to a wide spectrum of human diseases, including developmental, neuropsychiatric, and neurodegenerative disorders. The NTN1/DCC signaling pathway, interacting with UNC5C, plays a crucial role in central nervous system axon guidance and has been associated with psychiatric disorders during adolescence in humans. Whole-exome sequencing analysis unveiled two compound heterozygous causative mutations within the UNC5C gene in a patient diagnosed with psychiatric disorders. In silico analysis demonstrated that neither of the observed variants affected the allosteric linkage between UNC5C and NTN1. In fact, these mutations are located within crucial cytoplasmic domains, specifically ZU5 and the region required for the netrin-mediated axon repulsion of neuronal growth cones. These domains play a critical role in forming the supramodular protein structure and directly interact with microtubules, thereby ensuring the functionality of the axon repulsion process. We emphasize that these mutations disrupt the aforementioned processes, thereby associating the UNC5C gene with psychiatric disorders for the first time and expanding the number of genes related to psychiatric disorders. Further research is required to validate the correlation of the UNC5C gene with psychiatric disorders, but we suggest including it in the genetic analysis of patients with psychiatric disorders.

General and specific patterns of cortical gene expression as spatial correlates of complex cognitive functioning.

Gene expression varies across the brain. This spatial patterning denotes specialised support for particular brain functions. However, the way that a given gene's expression fluctuates across the brain may be governed by general rules. Quantifying patterns of spatial covariation across genes would offer insights into the molecular characteristics of brain areas supporting, for example, complex cognitive functions. Here, we use principal component analysis to separate general and unique gene regulatory associations with cortical substrates of cognition. We find that the region-to-region variation in cortical expression profiles of 8235 genes covaries across two major principal components: gene ontology analysis suggests these dimensions are characterised by downregulation and upregulation of cell-signalling/modification and transcription factors. We validate these patterns out-of-sample and across different data processing choices. Brain regions more strongly implicated in general cognitive functioning (g; 3 cohorts, total meta-analytic N = 39,519) tend to be more balanced between downregulation and upregulation of both major components (indicated by regional component scores). We then identify a further 29 genes as candidate cortical spatial correlates of g, beyond the patterning of the two major components (|ß| range = 0.18 to 0.53). Many of these genes have been previously associated with clinical neurodegenerative and psychiatric disorders, or with other health-related phenotypes. The results provide insights into the cortical organisation of gene expression and its association with individual differences in cognitive functioning.

Opioid modulation of prefrontal cortex cells and circuits.

Several neurochemical systems converge in the prefrontal cortex (PFC) to regulate cognitive and motivated behaviors. A rich network of endogenous opioid peptides and receptors spans multiple PFC cell types and circuits, and this extensive opioid system has emerged as a key substrate underlying reward, motivation, affective behaviors, and adaptations to stress. Here, we review the current evidence for dysregulated cortical opioid signaling in the pathogenesis of psychiatric disorders. We begin by providing an introduction to the basic anatomy and function of the cortical opioid system, followed by a discussion of endogenous and exogenous opioid modulation of PFC function at the behavioral, cellular, and synaptic level. Finally, we highlight the therapeutic potential of endogenous opioid targets in the treatment of psychiatric disorders, synthesizing clinical reports of altered opioid peptide and receptor expression and activity in human patients and summarizing new developments in opioid-based medications. This article is part of the Special Issue on "PFC circuit function in psychiatric disease and relevant models".

Bradykinin actions in the central nervous system: historical overview and psychiatric implications.

Bradykinin (BK), a well-studied mediator of physiological and pathological processes in the peripheral system, has garnered less attention regarding its function in the central nervous system, particularly in behavioural regulation. This review delves into the historical progression of research focused on the behavioural effects of BK and other drugs that act via similar mechanisms to provide new insights into the pathophysiology and pharmacotherapy of psychiatric disorders. Evidence from experiments with animal models indicates that BK modulates defensive reactions associated with panic symptoms and the response to acute stressors. The mechanisms are not entirely understood but point to complex interactions with other neurotransmitter systems, such as opioids, and intracellular signalling cascades. By addressing the existing research gaps in this field, we present new proposals for future research endeavours to foster a new era of investigation regarding BK's role in emotional regulation. Implications for psychiatry, chiefly for panic and depressive disorders are also discussed.

Modulation of neural circuits by melatonin in neurodegenerative and neuropsychiatric disorders.

Neurodegenerative and neuropsychiatric disorders are two broad categories of neurological disorders characterized by progressive impairments in movement and cognitive functions within the central and peripheral nervous systems, and have emerged as a significant cause of mortality. Oxidative stress, neuroinflammation, and neurotransmitter imbalances are recognized as prominent pathogenic factors contributing to cognitive deficits and neurobehavioral anomalies. Consequently, preventing neurodegenerative and neuropsychiatric diseases has surfaced as a pivotal challenge in contemporary public health. This review explores the investigation of neurodegenerative and neuropsychiatric disorders using both synthetic and natural bioactive compounds. A central focus lies on melatonin, a neuroregulatory hormone secreted by the pineal gland in response to light-dark cycles. Melatonin, an amphiphilic molecule, assumes multifaceted roles, including scavenging free radicals, modulating energy metabolism, and synchronizing circadian rhythms. Noteworthy for its robust antioxidant and antiapoptotic properties, melatonin exhibits diverse neuroprotective effects. The inherent attributes of melatonin position it as a potential key player in the pathophysiology of neurological disorders. Preclinical and clinical studies have demonstrated melatonin's efficacy in alleviating neuropathological symptoms across neurodegenerative and neuropsychiatric conditions (depression, schizophrenia, bipolar disorder, and autism spectrum disorder). The documented neuroprotective prowess of melatonin introduces novel therapeutic avenues for addressing neurodegenerative and psychiatric disorders. This comprehensive review encompasses many of melatonin's applications in treating diverse brain disorders. Despite the strides made, realizing melatonin's full neuroprotective potential necessitates further rigorous clinical investigations. By unravelling the extended neuroprotective benefits of melatonin, future studies promise to deepen our understanding and augment the therapeutic implications against neurological deficits.

Discrete prefrontal neuronal circuits determine repeated stress-induced behavioral phenotypes in male mice.

Chronic stress is a major risk factor for psychiatric disorders, including depression. Although depression is a highly heterogeneous syndrome, it remains unclear how chronic stress drives individual differences in behavioral responses. In this study, we developed a subtyping-based approach wherein stressed male mice were divided into four subtypes based on their behavioral patterns of social interaction deficits and anhedonia, the core symptoms of psychiatric disorders. We identified three prefrontal cortical neuronal projections that regulate repeated stress-induced behavioral phenotypes. Among them, the medial prefrontal cortex (mPFC)→anterior paraventricular thalamus (aPVT) pathway determines the specific behavioral subtype that exhibits both social deficits and anhedonia. Additionally, we identified the circuit-level molecular mechanism underlying this subtype: KDM5C-mediated epigenetic repression of Shisa2 transcription in aPVT projectors in the mPFC led to social deficits and anhedonia. Thus, we provide a set of biological aspects at the cellular, molecular, and epigenetic levels that determine distinctive stress-induced behavioral phenotypes.

TAAR1 as an emerging target for the treatment of psychiatric disorders.

Trace amines, a group of amines expressed at the nanomolar level in the mammalian brain, can modulate monoamine transmission. The discovery of and the functional research on the trace amine-associated receptors (TAARs), especially the most well-characterized TAAR1, have largely facilitated our understanding of the function of the trace amine system in the brain. TAAR1 is expressed in the mammalian brain at a low level and widely distributed in the monoaminergic system, including the ventral tegmental area and substantial nigra, where the dopamine neurons reside in the mammalian brain. Growing in vitro and in vivo evidence has demonstrated that TAAR1 could negatively modulate monoamine transmission and play a crucial role in many psychiatric disorders, including schizophrenia, substance use disorders, sleep disorders, depression, and anxiety. Notably, in the last two decades, many studies have repeatedly confirmed the pharmacological effects of the selective TAAR1 ligands in various preclinical models of psychiatric disorders. Recent clinical trials of the dual TAAR1 and serotonin receptor agonist ulotaront also revealed a potential efficacy for treating schizophrenia. Here, we review the current understanding of the TAAR1 system and the recent advances in the elucidation of behavioral and physiological properties of TAAR1 agonists evaluated both in preclinical animal models and clinical trials. We also discuss the potential TAAR1-dependent signaling pathways and the cellular mechanisms underlying the inhibitory effects of TAAR1 activation on drug addiction. We conclude that TAAR1 is an emerging target for the treatment of psychiatric disorders.

The role of neurotrophic factors in novel, rapid psychiatric treatments.

Neurotrophic factors are a family of growth factors that modulate cellular growth, survival, and differentiation. For many decades, it has been generally believed that a lack of neurotrophic support led to the decreased neuronal synaptic plasticity, death, and loss of non-neuronal supportive cells seen in neuropsychiatric disorders. Traditional psychiatric medications that lead to immediate increases in neurotransmitter levels at the synapse have been shown also to elevate synaptic neurotrophic levels over weeks, correlating with the time course of the therapeutic effects of these drugs. Recent advances in psychiatric treatments, such as ketamine and psychedelics, have shown a much faster onset of therapeutic effects (within minutes to hours). They have also been shown to lead to a rapid release of neurotrophins into the synapse. This has spurred a significant shift in understanding the role of neurotrophins and how the receptor tyrosine kinases that bind neurotrophins may work in concert with other signaling systems. In this review, this renewed understanding of synaptic receptor signaling interactions and the clinical implications of this mechanistic insight will be discussed within the larger context of the well-established roles of neurotrophic factors in psychiatric disorders and treatments.

Dopamine release at the time of a predicted aversive outcome causally controls the trajectory and expression of conditioned behavior.

Dopamine release in the nucleus accumbens (NAc) is causally linked to adaptive aversive learning, and its dysregulation is a core phenotype in anxiety and stress disorders. Here, we record NAc core dopamine during a task where mice learn to discriminate between cues signaling two types of outcomes: (1) footshock presentation and (2) footshock omission. We show that dopamine release is evoked by footshock omission. This dopamine response is largest when the omission is unexpected and decreases over learning, and artificially increasing this signal disrupts discrimination learning. Conversely, optogenetic inhibition of dopamine responses to the footshock itself impairs learning. Finally, theory-driven computational modeling suggests that these effects can be explained by dopamine signaling the perceived saliency of predicted aversive events. Together, we elucidate the role of NAc dopamine in aversive learning and offer potential avenues for understanding the neural mechanisms involved in anxiety and stress disorders.

Sex and cell-specific gene expression in corticolimbic brain regions associated with psychiatric disorders revealed by bulk and single-nuclei RNA sequencing.

BACKGROUND: There are sex-specific differences in the prevalence, symptomology and course of psychiatric disorders. However, preclinical models have primarily used males, such that the molecular mechanisms underlying sex-specific differences in psychiatric disorders are not well established. METHODS: In this study, we compared transcriptome-wide gene expression profiles in male and female rats within the corticolimbic system, including the cingulate cortex, nucleus accumbens medial shell (NAcS), ventral dentate gyrus and the basolateral amygdala (n = 22-24 per group/region). FINDINGS: We found over 3000 differentially expressed genes (DEGs) in the NAcS between males and females. Of these DEGs in the NAcS, 303 showed sex-dependent conservation DEGs in humans and were significantly enriched for gene ontology terms related to blood vessel morphogenesis and regulation of cell migration. Single nuclei RNA sequencing in the NAcS of male and female rats identified widespread sex-dependent expression, with genes upregulated in females showing a notable enrichment for synaptic function. Female upregulated genes in astrocytes, Drd3+MSNs and oligodendrocyte were also enriched in several psychiatric genome-wide association studies (GWAS). INTERPRETATION: Our data provide comprehensive evidence of sex- and cell-specific molecular profiles in the NAcS. Importantly these differences associate with anxiety, bipolar disorder, schizophrenia, and cross-disorder, suggesting an intrinsic molecular basis for sex-based differences in psychiatric disorders that strongly implicates the NAcS. FUNDING: This work was supported by funding from the Hope for Depression Research Foundation (MJM).

Sex Differences in Long-term Outcome of Prenatal Exposure to Excess Glucocorticoids-Implications for Development of Psychiatric Disorders.

Exposure to prenatal insults, such as excess glucocorticoids (GC), may lead to pathological outcomes, including neuropsychiatric disorders. The aim of the present study was to investigate the long-term effects of in utero exposure to the synthetic GC analog dexamethasone (Dex) in adult female offspring. We monitored spontaneous activity in the home cage under a constant 12 h/12 h light/dark cycle, as well as the changes following a 6-h advance of dark onset (phase shift). For comparison, we re-analysed data previously recorded in males. Dex-exposed females were spontaneously more active, and the activity onset re-entrained slower than in controls. In contrast, Dex-exposed males were less active, and the activity onset re-entrained faster than in controls. Following the phase shift, control females displayed a transient reorganisation of behaviour in light and virtually no change in dark, while Dex-exposed females showed limited variations from baseline in both light and dark, suggesting weaker photic entrainment. Next, we ran bulk RNA-sequencing in the suprachiasmatic nucleus (SCN) of Dex and control females. SPIA pathway analysis of ~ 2300 differentially expressed genes identified significantly downregulated dopamine signalling, and upregulated glutamate and GABA signalling. We selected a set of candidate genes matching the behaviour alterations and found consistent differential regulation for ~ 73% of tested genes in SCN and hippocampus tissue samples. Taken together, our data highlight sex differences in the outcome of prenatal exposure to excess GC in adult mice: in contrast to depression-like behaviour in males, the phenotype in females, defined by behaviour and differential gene expression, is consistent with ADHD models.

ADRA2B and HTR1A: An Updated Study of the Biogenic Amine Receptors Reveals Novel Conserved Motifs Which Play Key Role in Mental Disorders.

Mental disorders are strongly connected with several psychiatric conditions including depression, bipolar disorder, schizophrenia, eating disorder, and suicides. There are many biological conditions and pathways that define these complicated illnesses. For example, eating disorders are complex mental health conditions that require the intervention of geneticists, psychiatrists, and medical experts in order to alleviate their symptoms. A patient with suicidal ideation should first be identified and consequently monitored by a similar team of specialists. Both genetics and epigenetics can shed light on eating disorders and suicides as they are found in the main core of such investigations. In the present study, an analysis has been performed on two specific members of the GPCR family toward drawing conclusions regarding their functionality and implementation in mental disorders. Specifically, evolutionary and structural studies on the adrenoceptor alpha 2b (ADRA2B) and the 5-hydroxytryptamine receptor 1A (HTR1A) have been carried out. Both receptors are classified in the biogenic amine receptors sub-cluster of the GPCRs and have been connected in many studies with mental diseases and malnutrition conditions. The major goal of this study is the investigation of conserved motifs among biogenic amine receptors that play an important role in this family signaling pathway, through an updated evolutionary analysis and the correlation of this information with the structural features of the HTR1A and ADRA2B. Furthermore, the structural comparison of ADRA2B, HTR1A, and other members of GPCRs related to mental disorders is performed.

Co-Aggregation and Parallel Aggregation of Specific Proteins in Major Mental Illness.

BACKGROUND: Disrupted proteostasis is an emerging area of research into major depressive disorder. Several proteins have been implicated as forming aggregates specifically in the brains of subsets of patients with psychiatric illnesses. These proteins include CRMP1, DISC1, NPAS3 and TRIOBP-1. It is unclear, however, whether these proteins normally aggregate together in the same individuals and, if so, whether each protein aggregates independently of each other ("parallel aggregation") or if the proteins physically interact and aggregate together ("co-aggregation"). MATERIALS AND METHODS: Post mortem insular cortex samples from major depressive disorder and Alzheimer's disease patients, suicide victims and control individuals had their insoluble fractions isolated and tested by Western blotting to determine which of these proteins are insoluble and, therefore, likely to be aggregating. The ability of the proteins to co-aggregate (directly interact and form common aggregate structures) was tested by systematic pairwise expression of the proteins in SH-SY5Y neuroblastoma cells, which were then examined by immunofluorescent microscopy. RESULTS: Many individuals displayed multiple insoluble proteins in the brain, although not enough to imply interaction between the proteins. Cell culture analysis revealed that only a few of the proteins analyzed can consistently co-aggregate with each other: DISC1 with each of CRMP1 and TRIOBP-1. DISC1 was able to induce aggregation of full length TRIOBP-1, but not individual domains of TRIOBP-1 when they were expressed individually. CONCLUSIONS: While specific proteins are capable of co-aggregating, and appear to do so in the brains of individuals with mental illness and potentially also with suicidal tendency, it is more common for such proteins to aggregate in a parallel manner, through independent mechanisms. This information aids in understanding the distribution of protein aggregates among mental illness patients and is therefore important for any future diagnostic or therapeutic approaches based on this aspect of mental illness pathology.

Sex- and Lifestyle-Related Factors are Associated with Altered Hepatic CYP Protein Levels in People Diagnosed with Mental Disorders.

In this study, we used human postmortem tissue to investigate hepatic protein expression levels of cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 by LC-MS/MS in a population of people suffering from mental disorders (n = 171). We report hepatic protein levels of these six CYP isoforms in 171 individuals in total, and define a focused population dataset of 116 individuals after excluding 55 samples due to low microsomal protein per gram of liver (MPPGL) yield. Postmortem decay was most likely the reason for the low MPPGL yield in the 55 samples. In the focused population, we found women to have significantly higher protein levels of CYP3A4 than men in addition to decreased CYP3A4 protein levels among obese individuals. Furthermore, MPPGL was negatively correlated with body mass index (BMI). An increase in CYP1A2 protein levels was observed among smokers, and increased CYP2E1 protein levels were observed among individuals with a history of alcohol abuse. Finally, individuals who received phenobarbital (CYP3A4 inducer) had significantly higher CYP3A4 levels. In conclusion, lifestyle-related factors prevalent among people suffering from mental disorders are associated with altered CYP protein levels, which may alter drug metabolism and affect the efficacy of commonly prescribed drugs. Furthermore, this investigation demonstrates that postmortem hepatic tissue can be used to study how lifestyle and effectors affect hepatic CYP-levels in a large cohort of patients. SIGNIFICANCE STATEMENT: Using a large number of postmortem hepatic tissue specimens (n=116) originating from the autopsy of individuals diagnosed with mental disorders, we were able to show that hepatic CYP-levels were affected by alcohol, smoking, BMI, and sex and that MPPGL was affected by BMI. These lifestyle-related changes may alter drug metabolism and affect the efficacy of commonly prescribed drugs. It is a novel approach to use a large postmortem cohort to investigate how lifestyle and effectors affect hepatic CYP-levels.

Connecting Dots between Mitochondrial Dysfunction and Depression.

Mitochondria are the prime source of cellular energy, and are also responsible for important processes such as oxidative stress, apoptosis and Ca2+ homeostasis. Depression is a psychiatric disease characterized by alteration in the metabolism, neurotransmission and neuroplasticity. In this manuscript, we summarize the recent evidence linking mitochondrial dysfunction to the pathophysiology of depression. Impaired expression of mitochondria-related genes, damage to mitochondrial membrane proteins and lipids, disruption of the electron transport chain, higher oxidative stress, neuroinflammation and apoptosis are all observed in preclinical models of depression and most of these parameters can be altered in the brain of patients with depression. A deeper knowledge of the depression pathophysiology and the identification of phenotypes and biomarkers with respect to mitochondrial dysfunction are needed to help early diagnosis and the development of new treatment strategies for this devastating disorder.

Epigenetic Alterations of Brain Non-Neuronal Cells in Major Mental Diseases.

The tissue-specific expression and epigenetic dysregulation of many genes in cells derived from the postmortem brains of patients have been reported to provide a fundamental biological framework for major mental diseases such as autism, schizophrenia, bipolar disorder, and major depression. However, until recently, the impact of non-neuronal brain cells, which arises due to cell-type-specific alterations, has not been adequately scrutinized; this is because of the absence of techniques that directly evaluate their functionality. With the emergence of single-cell technologies, such as RNA sequencing (RNA-seq) and other novel techniques, various studies have now started to uncover the cell-type-specific expression and DNA methylation regulation of many genes (e.g., TREM2, MECP2, SLC1A2, TGFB2, NTRK2, S100B, KCNJ10, and HMGB1, and several complement genes such as C1q, C3, C3R, and C4) in the non-neuronal brain cells involved in the pathogenesis of mental diseases. Additionally, several lines of experimental evidence indicate that inflammation and inflammation-induced oxidative stress, as well as many insidious/latent infectious elements including the gut microbiome, alter the expression status and the epigenetic landscapes of brain non-neuronal cells. Here, we present supporting evidence highlighting the importance of the contribution of the brain's non-neuronal cells (in particular, microglia and different types of astrocytes) in the pathogenesis of mental diseases. Furthermore, we also address the potential impacts of the gut microbiome in the dysfunction of enteric and brain glia, as well as astrocytes, which, in turn, may affect neuronal functions in mental disorders. Finally, we present evidence that supports that microbiota transplantations from the affected individuals or mice provoke the corresponding disease-like behavior in the recipient mice, while specific bacterial species may have beneficial effects.