Catecholamines, such as dopamine, are evolutionarily ancient neurotransmitters that play an essential role in mediating behavior. In vertebrates, dopamine is central to the nigrostriatal motor and mesolimbic reward systems. Despite its importance, the distribution of the dopaminergic system has not been well studied in the teleost brain. The African cichlid fish Astatotilapia burtoni has become an important model system in social neuroscience and lends itself to uncovering how social decisions are implemented in the brain. To understand better where dopamine acts to regulate social behavior in this species, we have determined the distribution of putative dopaminergic cells and fibers (by tyrosine hydroxylase immunohistochemistry) and dopamine receptors (by in situ hybridization for the D(1A) and D(2) dopamine receptor subtypes) throughout the forebrain and part of the mesencephalon of A. burtoni. Tyrosine hydroxylase immunoreactivity was evident in several regions of the fore- and midbrain, in support of putative homologies to tetrapods. Additionally, the D(1A) and D(2) receptors were identified in brain regions known to modulate social behavior in other vertebrates, including the proposed teleost homologues of the mammalian amygdalar complex, hippocampus, striatum, preoptic area, anterior hypothalamus, ventromedial hypothalamus, and ventral tegmental area/substantia nigra pars compacta. Tyrosine hydroxylase-immunoreactive fibers as well as D(1A) and D(2) receptor expression overlap almost completely in their distribution. These results significantly extend our understanding of the distribution of the dopaminergic system in the teleost brain and suggest a conserved role of dopamine in modulating behavior across vertebrates.

Turnover and exchange of nucleosomal histones and their variants, a process long believed to be static in post-replicative cells, remains largely unexplored in brain. Here, we describe a novel mechanistic role for HIRA (histone cell cycle regulator) and proteasomal degradation-associated histone dynamics in the regulation of activity-dependent transcription, synaptic connectivity, and behavior. We uncover a dramatic developmental profile of nucleosome occupancy across the lifespan of both rodents and humans, with the histone variant H3.3 accumulating to near-saturating levels throughout the neuronal genome by mid-adolescence. Despite such accumulation, H3.3-containing nucleosomes remain highly dynamic-in a modification-independent manner-to control neuronal- and glial-specific gene expression patterns throughout life. Manipulating H3.3 dynamics in both embryonic and adult neurons confirmed its essential role in neuronal plasticity and cognition. Our findings establish histone turnover as a critical and previously undocumented regulator of cell type-specific transcription and plasticity in mammalian brain.

Abnormal resting state electroencephalogram (EEG) oscillations are reported in schizophrenia (SZ) and bipolar disorder, illnesses with overlapping symptoms and genetic risk. However, less evidence exists on whether similar EEG spectral abnormalities are present in individuals with both disorders or whether these abnormalities are present in first-degree relatives, possibly representing genetic predisposition for these disorders.

Across vertebrates, the mesolimbic reward system is a highly conserved neural network that serves to evaluate the salience of environmental stimuli, with dopamine as the neurotransmitter most relevant to its function. Although brain regions in the dopaminergic reward system have been well characterized in mammals, homologizing these brain areas with structures in teleosts has been controversial, especially for the mesencephalo-diencephalic dopaminergic cell populations. Here we examine the neurochemical profile of five dopaminergic cell groups (Vc, POA, PPr, TPp, pTn) in the model cichlid Astatotilapia burtoni to better understand putative homology relationships between teleosts and mammals. We characterized in the adult brain the expression patterns of three genes (etv5, nr4a2, and pitx3) that either specify dopaminergic cell fate or maintain dopaminergic cell populations. We then determined whether these genes are expressed in dopaminergic cells. We find many striking similarities in these gene expression profiles between dopaminergic cell populations in teleosts and their putative mammalian homologs. Our results suggest that many of these dopaminergic cell groups are indeed evolutionarily ancient and conserved across vertebrates.

Our understanding of fragile X syndrome (FXS) pathophysiology continues to improve and numerous potential drug targets have been identified. Yet, current prescribing practices are only symptom-based in order to manage difficult behaviors, as no drug to date is approved for the treatment of FXS. Drugs impacting a diversity of targets in the brain have been studied in recent FXS-specific clinical trials. While many drugs have focused on regulation of enhanced glutamatergic or deficient GABAergic neurotransmission, compounds studied have not been limited to these mechanisms. As a single-gene disorder, it was thought that FXS would have consistent drug targets that could be modulated with pharmacotherapy and lead to significant improvement. Unfortunately, despite promising results in FXS animal models, translational drug treatment development in FXS has largely failed. Future success in this field will depend on learning from past challenges to improve clinical trial design, choose appropriate outcome measures and age range choices, and find readily modulated drug targets. Even with many negative placebo-controlled study results, the field continues to move forward exploring both the new mechanistic drug approaches combined with ways to improve trial execution. This review summarizes the known phenotype and pathophysiology of FXS and past clinical trial rationale and results, and discusses current challenges facing the field and lessons from which to learn for future treatment development efforts.

Psychotic disorders including schizophrenia are commonly accompanied by cognitive deficits. Recent studies have reported negative genetic correlations between schizophrenia and indicators of cognitive ability such as general intelligence and processing speed. Here we compare the effect of polygenetic risk for schizophrenia (PRSSCZ) on measures that differ in their relationships with psychosis onset: a measure of current cognitive abilities (the Brief Assessment of Cognition in Schizophrenia, BACS) that is greatly reduced in psychotic disorder patients, a measure of premorbid intelligence that is minimally affected by psychosis onset (the Wide-Range Achievement Test, WRAT); and educational attainment (EY), which covaries with both BACS and WRAT. Using genome-wide single nucleotide polymorphism (SNP) data from 314 psychotic and 423 healthy research participants in the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) Consortium, we investigated the association of PRSSCZ with BACS, WRAT, and EY. Among apparently healthy individuals, greater genetic risk for schizophrenia (PRSSCZ) was significantly associated with lower BACS scores (r = -0.17, p = 6.6 × 10-4 at PT = 1 × 10-4), but not with WRAT or EY. Among individuals with psychosis, PRSSCZ did not associate with variations in any of these three phenotypes. We further investigated the association between PRSSCZ and WRAT in more than 4500 healthy subjects from the Philadelphia Neurodevelopmental Cohort. The association was again null (p > 0.3, N = 4511), suggesting that different cognitive phenotypes vary in their etiologic relationship with schizophrenia.

Central precocious puberty (CPP) has been shown to exert significant effects on psychosocial development. These early puberty-related hormones and psychosocial functional changes are considered to be associated with specific brain development. However, the biological mechanisms underlying the sculpting of human brain architecture and modulation of psychosocial transformation by puberty-related hormonal maturation remain elusive, especially during the early phase of CPP. The current investigation aims to specify the brain regions in which early hormone-related maturation effects occur during CPP and their relationships with psychological functions. 65 young girls (aged 4.3-8.0 years) underwent structural imaging on a 3T MR system, completed psychological tests and performed the gonadotropin-releasing hormone (GnRH) stimulation test to identify hormonal manifestations of hypothalamic-pituitary-gonadal axis (HPG axis) activation. Based on the GnRH test, 28 young girls were identified with CPP, whereas the other 37 girls were identified with non-central precocious puberty (NCPP). Cortical parameters were calculated and compared between the two groups after adjusting for age, weight, and height. Brain regions showing group differences were extracted and correlated with serum hormone levels and psychological parameters. The CPP girls showed thinner cortices primarily in the right rostral middle frontal cortex. This morphological difference was positively correlated with stimulated estradiol (E2) levels. Further, higher E2 levels were significantly associated with higher hyperactivity scores. Premature HPG axis activation in CPP girls at an early stage appears to exert remodeling effects on brain anatomy, primarily in the prefrontal cortex, which may affect psychological development following the emergence of robust changes in sex hormones.

Alterations in cortical thickness have been identified in major depressive disorder (MDD), but findings have been variable and inconsistent. To date, no reliable tools have been available for the meta-analysis of surface-based morphometric (SBM) studies to effectively characterize what has been learned in previous studies, and drug treatments may have differentially impacted findings. We conducted a comprehensive meta-analysis of magnetic resonance imaging (MRI) studies that explored cortical thickness in medication-free patients with MDD, using a newly developed meta-analytic mask compatible with seed-based d mapping (SDM) meta-analytic software. We performed the meta-regression to explore the effects of demographics and clinical characteristics on variation in cortical thickness in MDD. Fifteen studies describing 529 patients and 586 healthy controls (HCs) were included. Medication-free patients with MDD, relative to HCs, showed a complex pattern of increased cortical thickness in some areas (posterior cingulate cortex, ventromedial prefrontal cortex, and anterior cingulate cortex) and decreased cortical thickness in others (gyrus rectus, orbital segment of the superior frontal gyrus, and middle temporal gyrus). Most findings in the whole sample analysis were confirmed in a meta-analysis of studies recruiting medication-naive patients. Using the new mask specifically developed for SBM studies, this SDM meta-analysis provides evidence for regional cortical thickness alterations in MDD, mainly involving increased cortical thickness in the default mode network and decreased cortical thickness in the orbitofrontal and temporal cortex.

Sensory hypersensitivities are common and distressing features of Fragile X Syndrome (FXS). While there are many drug interventions that reduce behavioral deficits in Fmr1 mice and efforts to translate these preclinical breakthroughs into clinical trials for FXS, evidence-based clinical interventions are almost non-existent potentially due to lack of valid neural biomarkers. Local circuit function in sensory networks is dependent on the dynamic balance of activity in inhibitory/excitatory synapses. Studies are needed to examine the association of electrophysiological alterations in neural systems with sensory and other clinical features of FXS to establish their clinical relevance. Adolescents and adults with FXS (n = 38, Mean age = 25.5, std = 10.1; 13 females) and age matched typically developing controls (n = 40, Mean age = 27.7, std = 12.1; 17 females) completed auditory chirp and auditory habituation tasks while undergoing dense array electroencephalography (EEG). Amplitude, latency, and percent change (habituation) in N1 and P2 event-related potential (ERP) components were characterized for the habituation task; time-frequency calculations using Morlet wavelets characterized phase-locking and single trial power for the habituation and chirp tasks. FXS patients showed increased amplitude but some evidence for reduced habituation of the N1 ERP, and reduced phase-locking in the low and high gamma frequency range and increased low gamma power to the chirp stimulus. FXS showed increased theta power in both tasks. While the habituation finding was weaker than previously found, the remaining findings replicate our previous work in a new sample of patients with FXS. Females showed less deficit in the chirp task but not the habituation task. Abnormal increases in gamma power were related to more severe behavioral and psychiatric features as well as reductions in neurocognitive abilities. Replicating electrophysiological deficits in a new group of patients using different EEG equipment at a new data collection site with differing levels of environmental noise that were robust to data processing techniques utilizing multiple researchers, indicates a potential for scalability to multi-site clinical trials. Given the robust replicability, relevance to clinical measures, and preclinical evidence for sensitivity of these EEG measures to pharmacological intervention, the observed abnormalities may provide novel translational markers of target engagement and potentially outcome measures in large-scale studies evaluating new treatments targeting neural hyperexcitability in FXS.

"Resting-state" functional magnetic resonance imaging (rs-fMRI) is widely used to study brain connectivity. So far, researchers have been restricted to measures of functional connectivity that are computationally efficient but undirected, or to effective connectivity estimates that are directed but limited to small networks. Here, we show that a method recently developed for task-fMRI-regression dynamic causal modeling (rDCM)-extends to rs-fMRI and offers both directional estimates and scalability to whole-brain networks. First, simulations demonstrate that rDCM faithfully recovers parameter values over a wide range of signal-to-noise ratios and repetition times. Second, we test construct validity of rDCM in relation to an established model of effective connectivity, spectral DCM. Using rs-fMRI data from nearly 200 healthy participants, rDCM produces biologically plausible results consistent with estimates by spectral DCM. Importantly, rDCM is computationally highly efficient, reconstructing whole-brain networks (>200 areas) within minutes on standard hardware. This opens promising new avenues for connectomics.

Obsessive-compulsive disorder (OCD) is a debilitating and disabling neuropsychiatric disorder, whose neurobiological basis remains unclear. Although traditional static resting-state magnetic resonance imaging (rfMRI) studies have found aberrant functional connectivity (FC) in OCD, alterations in whole-brain FC and topological properties in the context of brain dynamics remain relatively unexplored. The rfMRI data of 29 patients with OCD and 40 healthy controls were analyzed using group independent component analysis to obtain independent components (ICs) and a sliding-window approach to generate dynamic functional connectivity (dFC) matrices. dFC patterns were clustered into three reoccurring states, and state transition metrics were obtained. Then, graph-theory methods were applied to dFC matrices to calculate the variability of network topological organization. The occurrence of a state (State 1) with the highest modularity index and lowest mean FC between networks was increased significantly in OCD, and the fractional time in brain State 1 was positively correlated with anxiety level in patients. State 1 was characterized by having positive connections within default mode (DMN) and salience networks (SAN), and negative coupling between the two networks. Additionally, ICs belonging to DMN and SAN showed lower temporal variability of nodal degree centrality and efficiency in patients, which was related to longer illness duration and higher current obsession ratings. Our results provide evidence of clinically relevant aberrant dynamic brain activity in OCD. Increased functional segregation among networks and impaired functional flexibility in connections among brain regions in DMN and SAN may play important roles in the neuropathology of OCD.

Previous studies have demonstrated relations between spontaneous neural activity evaluated by resting-state functional magnetic resonance imaging (fMRI) and symptom severity in post-traumatic stress disorder. However, few studies have used brain-based measures to identify imaging associations with illness severity at the level of individual patients. This study applied connectome-based predictive modeling (CPM), a recently developed data-driven and subject-level method, to identify brain function features that are related to symptom severity of trauma survivors. Resting-state fMRI scans and clinical ratings were obtained 10-15 months after the earthquake from 122 earthquake survivors. Symptom severity of post-traumatic stress disorder features for each survivor was evaluated using the Clinician Administered Post-traumatic Stress Disorder Scale (CAPS-IV). A functionally pre-defined atlas was applied to divide the human brain into 268 regions. Each individual's functional connectivity 268 × 268 matrix was created to reflect correlations of functional time series data across each pair of nodes. The relationship between CAPS-IV scores and brain functional connectivity was explored in a CPM linear model. Using a leave-one-out cross-validation (LOOCV) procedure, findings showed that the positive network model predicted the left-out individual's CAPS-IV scores from resting-state functional connectivity. CPM predicted CAPS-IV scores, as indicated by a significant correspondence between predicted and actual values (r = 0.30, P = 0.001) utilizing primarily functional connectivity between visual cortex, subcortical-cerebellum, limbic, and motor systems. The current study provides data-driven evidence regarding the functional brain features that predict symptom severity based on the organization of intrinsic brain networks and highlights its potential application in making clinical evaluation of symptom severity at the individual level.

A vivid sense of motion can be inferred from static pictures of objects in motion. Like perception of real motion (RM), viewing photographs with implied motion (IM) can also activate the motion-sensitive visual cortex, including the middle temporal complex (hMT+) of the human extrastriate cortex. Moreover, extrastriate cortical activity also increases with motion coherence. Based on these previous findings, this study examined whether similar coherence level-dependent activity in motion-sensitive human extrastriate cortex is seen with IM stimuli of varying coherence. Photographic stimuli showing a human moving in four directions (left, right, toward, or away from the viewer) were presented to 15 participants. The coherence of the stimuli was manipulated by changing the percentage of pictures implying movement in one direction. Electroencephalographic data were collected while participants viewed IM or counterpart non-IM stimuli. The P2 response of extrastriate visual cortex (source located at hMT+) increased bilaterally with coherence level in the IM conditions but not in the non-IM conditions. This finding demonstrates that extrastriate visual cortical responses are progressively activated as motion coherence increases, even when motion is inferred, providing new support for the view that the activity of human motion-sensitive extrastriate visual cortex can be modulated by top-down perceptual influences in addition to its well-established role in processing bottom-up sensory signals.

Stress promotes negative affective states, which include anhedonia and passive coping. While these features are in part mediated by neuroadaptations in brain reward circuitry, a comprehensive framework of how stress-induced negative affect may be encoded within key nodes of this circuit is lacking. Here, we show in a mouse model for stress-induced anhedonia and passive coping that these phenomena are associated with increased synaptic strength of ventral hippocampus (VH) excitatory synapses onto D1 medium spiny neurons (D1-MSNs) in the nucleus accumbens medial shell (NAcmSh), and with lateral hypothalamus (LH)-projecting D1-MSN hyperexcitability mediated by decreased inwardly rectifying potassium channel (IRK) function. Stress-induced negative affective states are prevented by depotentiation of VH to NAcmSh synapses, restoring Kir2.1 function in D1R-MSNs, or disrupting co-participation of these synaptic and intrinsic adaptations in D1-MSNs. In conclusion, our data provide strong evidence for a disynaptic pathway controlling maladaptive emotional behavior.

Jet lag is commonly experienced when travelers cross multiple time zones, leaving the wake-sleep cycle and intrinsic biological "clocks" out of synchrony with the current environment. The effect of jet lag on intrinsic cortical function remains unclear. Twenty-two healthy individuals experiencing west-to-east jet lag flight were recruited. Brain structural and functional magnetic resonance studies, as well as psychological and neurohormonal tests, were carried out when participants returned from travel over six time zones and 50 days later when their jet lag symptoms had resolved. During jet lag, the functional brain network exhibited a small-world topology that was shifted toward regularity. Alterations during jet lag relative to recovery included decreased basal ganglia-thalamocortical network connections and increased functional connectivity between the medial temporal lobe subsystem and medial visual cortex. The lower melatonin and higher thyroid hormone levels during jet lag showed the same trend as brain activity in the right lingual gyrus. Although there was no significant difference between cortisol measurements during and after jet lag, cortisol levels were associated with temporal lobe activity in the jet lag condition. Brain and neuroendocrine changes during jet lag were related to jet lag symptoms. Further prospective studies are needed to explore the time course over which jet lag acts on the human brain.

Numerous novel neuroscience-based drug targets have been identified in recent years. However, it remains unclear how these targets relate to the expression of symptoms in central nervous system (CNS) disorders in general and psychiatric disorders in particular. To discuss this issue, a New Frontiers Meetings of European College of Neuropsychopharmacology (ECNP) was organized to address the challenges in translational neuroscience research that are impeding the effective development of new treatments. The main aim of this meeting was to discuss scientific insights, concepts and methodologies in order to improve drug development for psychiatric disorders. The meeting was designed to bring together stakeholders from academia, pharmaceutical industry, and regulatory agencies. Here we provide a synopsis of the proceedings from the meeting entitled 'New approaches to psychiatric drug development'. New views on psychiatric drug development were presented to address the challenges and pitfalls as identified by the different stakeholders. The general conclusion of the meeting was that drug discovery could be stimulated by designing new classification and sensitive assessment tools for psychiatric disorders, which bear closer relationships to neuropharmacological and neuroscientific developments. This is in line with the vision of precision psychiatry in which patients are clustered, not merely on symptoms, but primarily on biological phenotypes that represent pathophysiological relevant and 'drugable' processes. To achieve these goals, a closer collaboration between all stakeholders in early stages of development is essential to define the research criteria together and to reach consensus on new quantitative biological methodologies and etiology-directed treatments.

Hippocampal disturbances are important in the pathophysiology of both schizophrenia and major depressive disorder (MDD). Imaging studies have shown selective volume deficits across hippocampal subfields in both disorders. We aimed to investigate whether these volumetric alterations in hippocampal subfields are shared or divergent across disorders.

Convergent evidence is increasing to indicate progressive brain abnormalities in schizophrenia. Knowing the brain network features over the illness course in schizophrenia, independent of effects of antipsychotic medications, would extend our sight on this question.

Questions of whether and how cortical thickness (CTh) alterations differ over the course of schizophrenia (SCZ) have yet to be resolved.

Fragile X syndrome (FXS) is the most common inherited form of neurodevelopmental disability. It is often characterized, especially in males, by intellectual disability, anxiety, repetitive behavior, social communication deficits, delayed language development, and abnormal sensory processing. Recently, we identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS.