Chronic psychosocial stressors are associated with alterations in salience processing and corticostriatal connectivity

Psychosocial stressors including childhood adversity, migration, and living in an urban environment, have been associated with several psychiatric disorders, including psychotic disorders. The neural and psychological mechanisms mediating this relationship remain unclear. In parallel, alterations in corticostriatal connectivity and abnormalities in the processing of salience, are seen in psychotic disorders. Aberrant functioning of these mechanisms secondary to chronic stress exposure, could help explain how common environmental exposures are associated with a diverse range of symptoms. In the current study, we recruited two groups of adults, one with a high degree of exposure to chronic psychosocial stressors (the exposed group, n = 20), and one with minimal exposure (the unexposed group, n = 22). All participants underwent a resting state MRI scan, completed the Aberrant Salience Inventory, and performed a behavioural task - the Salience Attribution Test (SAT). The exposed group showed reduced explicit adaptive salience scores (cohen's d = 0.69, p = 0.03) and increased aberrant salience inventory scores (d = 0.65, p = 0.04). The exposed group also showed increased corticostriatal connectivity between the ventral striatum and brain regions previously implicated in salience processing. Corticostriatal connectivity in these regions negatively correlated with SAT explicit adaptive salience (r = -0.48, p = 0.001), and positively correlated with aberrant salience inventory scores (r = 0.42, p = 0.006). Furthermore, in a mediation analysis there was tentative evidence that differences in striato-cortical connectivity mediated the group differences in salience scores

Mesolimbic Dopamine Function Is Related to Salience Network Connectivity: An Integrative Positron Emission Tomography and Magnetic Resonance Study

BACKGROUND: A wide range of neuropsychiatric disorders, from schizophrenia to drug addiction, involve abnormalities in both the mesolimbic dopamine system and the cortical salience network. Both systems play a key role in the detection of behaviorally relevant environmental stimuli. Although anatomical overlap exists, the functional relationship between these systems remains unknown. Preclinical research has suggested that the firing of mesolimbic dopamine neurons may activate nodes of the salience network, but in vivo human research is required given the species-specific nature of this network. METHODS: We employed positron emission tomography to measure both dopamine release capacity (using the D2/3 receptor ligand 11C-PHNO, n = 23) and dopamine synthesis capacity (using 18F-DOPA, n = 21) within the ventral striatum. Resting-state functional magnetic resonance imaging was also undertaken in the same individuals to investigate salience network functional connectivity. A graph theoretical approach was used to characterize the relationship between dopamine measures and network connectivity. RESULTS: Dopamine synthesis capacity was associated with greater salience network connectivity, and this relationship was particularly apparent for brain regions that act as information-processing hubs. In contrast, dopamine release capacity was associated with weaker salience network connectivity. There was no relationship between dopamine measures and visual and sensorimotor networks, indicating specificity of the findings. CONCLUSIONS: Our findings demonstrate a close relationship between the salience network and mesolimbic dopamine system, and they are relevant to neuropsychiatric illnesses in which aberrant functioning of both systems has been observed

In Vivo Availability of Cannabinoid 1 Receptor Levels in Patients with First-Episode Psychosis

Importance: Experimental and epidemiological studies implicate the cannabinoid 1 receptor (CB1R) in the pathophysiology of psychosis. However, whether CB1R levels are altered in the early stages of psychosis and whether they are linked to cognitive function or symptom severity remain unknown.Objective: To investigate CB1R availability in first-episode psychosis (FEP) without the confounds of illness chronicity or the use of illicit substances or antipsychotics.Design, Setting, and Participants: This cross-sectional, case-control study of 2 independent samples included participants receiving psychiatric early intervention services at 2 independent centers in Turku, Finland (study 1) and London, United Kingdom (study 2). Study 1 consisted of 18 volunteers, including 7 patients with affective or nonaffective psychoses taking antipsychotic medication and 11 matched controls; study 2, 40 volunteers, including 20 antipsychotic-naive or antipsychotic-free patients with schizophrenia or schizoaffective disorder and 20 matched controls. Data were collected from January 5, 2015, through September 26, 2018, and analyzed from June 20, 2016, through February 12, 2019.Main Outcomes and Measures: The availability of CB1R was indexed using the distribution volume (VT, in milliliters per cubic centimeter) of 2 CB1R-selective positron emission tomography radiotracers: fluoride 18–labeled FMPEP-d2 (study 1) and carbon 11–labeled MePPEP (study 2). Cognitive function was measured using the Wechsler Digit Symbol Coding Test. Symptom severity was measured using the Brief Psychiatric Rating Scale for study 1 and the Positive and Negative Syndrome Scale for study 2.Results: A total of 58 male individuals were included in the analyses (mean [SD] age of controls, 27.16 [5.93] years; mean [SD] age of patients, 26.96 [4.55] years). In study 1, 7 male patients with FEP (mean [SD] age, 26.80 [5.40] years) were compared with 11 matched controls (mean [SD] age, 27.18 [5.86] years); in study 2, 20 male patients with FEP (mean [SD] age, 27.00 [5.06] years) were compared with 20 matched controls (mean [SD] age, 27.15 [6.12] years). In study 1, a significant main effect of group on [18F]FMPEP-d2 VT was found in the anterior cingulate cortex (ACC) (t16 = −4.48; P Conclusions and Relevance: The availability of CB1R was lower in antipsychotic-treated and untreated cohorts relative to matched controls. Exploratory analyses indicated that greater reductions in CB1R levels were associated with greater symptom severity and poorer cognitive functioning in male patients. These findings suggest that CB1R may be a potential target for the treatment of psychotic disorders.</p

Rare disruptive variants in the DISC1 Interactome and Regulome : association with cognitive ability and schizophrenia

Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism. Disrupted in schizophrenia 1 (DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWERacross), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWERacross P=0.0339). The burden of singleton disruptive variants in the DISC1 Interactome was associated with low cognitive ability at age 11 (FWERacross P=0.0043). These results identify altered regulation of schizophrenia candidate genes by DISC1 and its core Interactome as an alternate pathway for schizophrenia risk, consistent with the emerging effects of rare copy number variants associated with intellectual disability.Peer reviewe

The impact of Disrupted-in-Schizophrenia 1 (DISC1) on the dopaminergic system: a systematic review

Although the Disrupted-in-Schizophrenia 1 (DISC1) was found as a risk gene that may account for mental symptoms of a specific pedigree in the past, it is now known as a risk biological factor for mental illnesses possibly associated with dopamine impairments. DISC1 is a scaffold protein interacting with proteins involved in the dopamine system. Here, we summarize the impact of DISC1 disruption on the dopamine system in animal models, considering its effects on presynaptic dopaminergic function (tyrosine hydroxylase levels, dopamine transporter levels, dopamine levels at baseline and after amphetamine administration), and post-synaptic dopaminergic function (dopamine D1 and D2 receptor levels, dopamine receptor binding potential, and locomotor activity after amphetamine administration). Our findings show that many, but not all DISC1 models display 1) increased locomotion after amphetamine administration 2) increased dopamine levels after amphetamine administration in the nucleus accumbens 3) inconsistent basal dopamine levels, dopamine receptor levels and binding potentials. There is also limited evidence for decreased tyrosine hydroxylase levels in the frontal cortex and increased dopamine transporter levels in the striatum but not nucleus accumbens, but these conclusions warrant further replication. The main dopaminergic findings are seen across different DISC1 models, providing convergent evidence that DISC1 has a role in regulating dopaminergic function. These results implicate dopaminergic dysregulation as a mechanism underlying the increased rate of schizophrenia seen in DISC1 variant carriers, and provide insights into how Disc1, and potentially DISC1-interacting proteins such as Akt and GSK-3, could be used as novel therapeutic targets for schizophrenia

The relationship between childhood trauma, dopamine release and dexamphetamine-induced positive psychotic symptoms: A [11C]-(+)-PHNO PET study

Childhood trauma is a risk factor for psychosis. Amphetamine increases synaptic striatal dopamine levels and can induce positive psychotic symptoms in healthy individuals and patients with schizophrenia. Socio-developmental hypotheses of psychosis propose that childhood trauma and other environmental risk factors sensitize the dopamine system to increase the risk of psychotic symptoms, but this remains to be tested in humans. We used [11C]-(+)-PHNO positron emission tomography to measure striatal dopamine-2/3 receptor (D2/3R) availability and ventral striatal dexamphetamine-induced dopamine release in healthy participants (n = 24). The relationships between dexamphetamine-induced dopamine release, dexamphetamine-induced positive psychotic symptoms using the Positive and Negative Syndrome Scale (PANSS), and childhood trauma using the Childhood Trauma Questionnaire (CTQ) were assessed using linear regression and mediation analyses, with childhood trauma as the independent variable, dexamphetamine-induced dopamine release as the mediator variable, and dexamphetamine-induced symptoms as the dependent variable. There was a significant interaction between childhood trauma and ventral striatal dopamine release in predicting dexamphetamine-induced positive psychotic symptoms (standardized β = 1.83, p = 0.003), but a mediation analysis was not significant (standardized β = −0.18, p = 0.158). There were no significant effects of dopamine release and childhood trauma on change in negative (p = 0.280) or general PANSS symptoms (p = 0.061), and there was no relationship between ventral striatal baseline D2/3R availability and positive symptoms (p = 0.368). This indicates childhood trauma and dopamine release interact to influence the induction of positive psychotic symptoms. This is not consistent with a simple sensitization hypothesis, but suggests that childhood trauma moderates the cognitive response to dopamine release to make psychotic experiences more likely

Dispensatorium pharmaceuticum Austriaco-Viennense, in quo hodierna die usualiora medicamenta secundam artis regulas componenda visuntur, ... sumptibus Collegii pharmaceutici Viennensis

Working memory performance is thought to depend on both striatal dopamine 2/3 receptors (D2/3Rs) and task-induced functional organisation in key cortical brain networks. Here, we combine functional magnetic resonance imaging and D2/3R positron emission tomography in 51 healthy volunteers, to investigate the relationship between working memory performance, task-induced default mode network (DMN) functional connectivity changes, and striatal D2/3R availability. Increasing working memory load was associated with reduced DMN functional connectivity, which was itself associated with poorer task performance. Crucially, the magnitude of the DMN connectivity reduction correlated with striatal D2/3R availability, particularly in the caudate, and this relationship mediated the relationship between striatal D2/3R availability and task performance. These results inform our understanding of natural variation in working memory performance, and have implications for understanding age-related cognitive decline and cognitive impairments in neuropsychiatric disorders where dopamine signalling is altered

Computational design of orthogonal membrane receptor-effector switches for rewiring signaling pathways.

Membrane receptors regulate numerous intracellular functions. However, the molecular underpinnings remain poorly understood because most receptors initiate multiple signaling pathways through distinct interaction interfaces that are structurally uncharacterized. We present an integrated computational and experimental approach to model and rationally engineer membrane receptor-intracellular protein systems signaling with novel pathway selectivity. We targeted the dopamine D2 receptor (D2), a G-protein-coupled receptor (GPCR), which primarily signals through Gi, but triggers also the Gq and beta-arrestin pathways. Using this approach, we designed orthogonal D2-Gi complexes, which coupled with high specificity and triggered exclusively the Gi-dependent signaling pathway. We also engineered an orthogonal chimeric D2-Gs/i complex that rewired D2 signaling from a Gi-mediated inhibitory into a Gs-dependent activating pathway. Reinterpreting the evolutionary history of GPCRs in light of the designed proteins, we uncovered an unforeseen hierarchical code of GPCR-G-protein coupling selectivity determinants. The results demonstrate that membrane receptor-cytosolic protein systems can be rationally engineered to regulate mammalian cellular functions. The method should prove useful for creating orthogonal molecular switches that redirect signals at the cell surface for cell-engineering applications