Molecular Psychiatry最新文献

The amygdala-centered functional networks are pivotal to the neuropathology of many psychiatric disorders, yet transdiagnostic abnormalities across disorders remain unclear. This neuroimaging meta-analysis examined convergence in whole and subregion-specific amygdala functional connectivity alterations across major psychiatric disorders. We included 96 amygdala functional connectivity studies comprising 8730 individuals across seven diverse diagnostic groups (depression, bipolar disorder, anxiety, post-traumatic stress disorder, obsessive-compulsive disorder, schizophrenia, and addiction). Our findings revealed that amygdala functional connectivity alterations converged in the regions associated with sensorimotor, emotional, and cognitive processes identified by behavioral decoding analyses, including the medial prefrontal cortex, hippocampus, insula, inferior and middle temporal gyrus, cuneus, postcentral gyrus, and thalamus. More refined disorder-specific analyses suggested that these overall patterns were shared to varying degrees, with notable differences between psychotic disorders versus nonpsychotic disorders, as well as between anxiety-related disorders versus mood disorders. Follow-up meta-analyses of 27 studies on amygdala subregional functional connectivity further indicated lower connectivity of the subregions with their typical target brain regions across disorders. These findings suggest that amygdala connectivity disruptions may represent a transdiagnostic vulnerability factor in psychopathology and a potential target for therapeutic interventions.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis (NMDARE) is a devastating autoimmune disease associated with the presence of autoantibodies targeting NMDAR1 in the cerebrospinal fluid (CSF) and serum of patients. Besides the critical roles of anti-NMDAR1 autoantibodies, studies have implicated other factors such as brain inflammation in NMDARE. To comprehensively uncover the molecular mechanisms underlying NMDARE, here we performed multi-omics analyses based on human forebrain organoids (hFOs). The transcriptomic and metabolomic analyses showed that hFOs exposed to either monoclonal anti-NMDAR1 IgG antibodies or purified patient CSF-derived IgG antibodies alone led to NMDAR hypofunction that caused a reduction of glutamate content and neuroactivities. Interestingly, hFOs exposed to either patient CSF or IgG-depleted patient CSF led to neuronal hyperexcitability rather than hypo neuroactivities. The following proteomic analysis and electrophysiological assays identified that the activated interleukin (IL)-17 signaling pathway in patient CSF accounted for the neuronal hyperexcitability. Neutralizing IL-17 alleviated the neuronal hyperexcitability in hFOs and seizure-like behaviors in mice exposed to CSF from NMDARE patients. Together, this study indicated that the anti-NMDAR1 antibodies and IL-17 signaling pathway shape NMDARE. Inactivating the IL-17 signaling pathway could be a potential therapeutic strategy for NMDARE treatment.

Maintaining appropriate behavioral and physiological responses in the face of challenge is essential for survival. The persistent increase in corticosteroids (CORT) during chronic stress blunts the endocrine response to any subsequent stressors. But the impact of prolonged CORT on behaviors that promote survival in the face of an acute stress is not well understood. Here we used an aerial predator threat model combined with in vivo calcium imaging, whole-cell electrophysiology, chemogenetics and computational modeling to evaluate the effects of short and long-term CORT. We show that in the short term, the activity of the corticotropin releasing hormone neurons of the paraventricular nucleus of the hypothalamus (CRH^PVN) and innate defensive behaviors that rely on these cells, are sensitive to the negative feedback effects of CORT. In response to long-term increases in CORT, however, behaviors recover, even though intrinsic CRH^PVN activity remains low. This escape from negative feedback requires local, homeostatic scaling of glutamate synapses that overcomes the inhibitory effects of CORT. This scaling is sufficient to maintain the output of this system in vivo and preserves innate defensive responses to threat. We propose that homeostatic synaptic scaling functions as a local adaptive mechanism to preserve the reliability of essential survival circuits during times of chronic stress.

Fear promotes rapid detection of threats and appropriate fight-or-flight responses. The endogenous opioid system modulates responses to pain and psychological stressors. Fear and anxiety constitute major psychological stressors for humans, yet the contribution of the opioid system to acute human fear remains poorly characterized. We induced intense unconditioned fear in the subjects by gradually exposing them to a living constrictor snake (threat trials) versus an indoor plant (safety trials). Cerebral haemodynamic responses were recorded from 33 subjects during functional magnetic resonance imaging (fMRI). In addition, 15 subjects underwent brain positron emission tomography (PET) imaging using [¹¹C]carfentanil, a high affinity agonist radioligand for μ-opioid receptors (MORs). Pupillary arousal responses to snake and plant exposure were recorded in 36 subjects. Self-reports and pupillometric responses confirmed significant subjective fear and autonomic activation during the threat trials. fMRI data revealed that proximity of the snake engaged brainstem defense circuits, thalamus, dorsal attention network, and motor and premotor cortices. These effects were diminished during repeated exposures. [¹¹C]carfentanil binding to MORs was higher during the fear versus safety condition, and the acute haemodynamic responses to threat were dependent on baseline MOR binding in the cingulate gyrus and thalamus. Finally, baseline MOR tone predicted dampening of the haemodynamic threat responses during the experiment. Preparatory response during acute fear episodes involves a strong motor component in addition to the brainstem responses. These haemodynamic changes are coupled with a deactivation of the opioidergic circuit, highlighting the role of MORs in modulating the human fear response.

Antibiotics (AB) are widely abused in medicine and may be a risk factor for mental health. To better understand their effects, we observed mental disorder symptoms in AB-treated mice and patients, and investigated possible mechanisms. Using AB-treated mice, we found obvious anxiety-like behaviors, along with differential gut microbiota (mainly Firmicutes and Bacteroidota), reduced short-chain fatty acids (SCFAs), and disrupted gut-brain lipid metabolism. Acetylcholine decreased in feces, colon wall, serum, and hippocampus of AB-treated mice, and this reduction was significantly correlated with anxiety-like behaviors. Moreover, using AB-treated patients (n = 55), AB-naïve patients (n = 60), and healthy controls (n = 60), we also observed the obvious anxiety symptoms in AB-treated patients, along with differential gut microbiota (mainly Firmicutes), reduced SCFAs, and disrupted lipid metabolism in feces and serum. AB-treated patients showed consistently lower serum and fecal acetylcholine, which was highly correlated with anxiety symptoms. In both AB-treated mice and patients, co-occurrence analysis indicated that the "Bacteroides-acetylcholine" pair may play an important role in AB-induced anxiety. At the species levels, Bacteroides_caecimuris in AB-treated mice and Bacteroides_plebeius in AB-treated patients were both decreased and significantly correlated with acetylcholine. Furthermore, exogenous methacholine (an acetylcholine derivative) intervention effectively alleviated anxiety-like behaviors and suppressed hippocampal microglial activation in AB-treated mice. Together, our findings highlight the harmful effects of aggressive AB treatment on mood and show the potential of acetylcholine or its derivative to reverse this effect.

Postoperative delirium (POD) following cardiac surgery is a severe complication. There is evidence of a link between neuroinflammation and neurodegeneration in POD. We investigated the preoperative proinflammatory interleukin-6 (IL-6) and neuronal damage marker phosphorylated tau protein 181 (p-tau181) to POD while considering preoperative heart-brain axis related factors. The prospective FINd DElirium RIsk factors (FINDERI) is an observational study in patients undergoing cardiac surgery. Biomarkers IL-6 and p-tau181 were measured in blood samples. For statistics, we utilized multiple logistic regression analyses and advanced machine learning techniques. In 491 patients, 106 (21.6%) developed POD. The age of patients with POD was significantly higher than that of patients without POD (p < 0.001). Preoperative IL-6 and p-tau181 levels independently predicted POD [IL-6: area under the curve (AUC) = 0.605, p < 0.005; p-tau181: AUC = 0.641, p < 0.0001)]. A multiple logistic regression analysis of preoperative log-transformed biomarkers levels (p-tau181, IL-6), female sex and cognitive performance increased the AUC (0.710, p < 0.0001) in predicting POD. We created a decision tree prediction model including preoperative p-tau181, IL-6, and the severity of mitral valve disease (training data: AUC = 0.672, p < 0.0001; validation data: AUC = 0.642, p < 0.05). The LASSO regression showed an increased AUC in the training (0.751, p < 0.0001) and validation dataset (0.652, p < 0.05). Our results demonstrate that the combined assessment of preoperatively measured p-tau181 and IL-6, preoperative mitral valve disease, cognitive performance and female sex, significantly predicts POD. These findings provide evidence that neuroinflammation and neuronal cell damage are associated with POD.

Recent studies highlight the promising use of psychedelic therapies for psychiatric disorders, including depression. The persisting clinical effects of psychedelics such as psilocybin are commonly attributed to activation of the serotonin 2A receptor (5-HT2AR) based on its role in the acute hallucinatory effects. However, the active metabolite of psilocybin binds to many serotonin receptor subtypes, including the serotonin 1B receptor (5-HT1BR). Given the known role of 5-HT1BR in mediating depressive phenotypes and promoting neural plasticity, we hypothesized that it mediates the effects of psilocybin on neural activity and behavior. We first examined the acute neural response to psilocybin in mice lacking 5-HT1BR. We found that 5-HT1BR expression influenced brain-wide activity following psilocybin administration, measured by differences in the patterns of the immediate early gene c-Fos, across regions involved in emotional processing and cognitive function, including the amygdala and other subcortical limbic structures. Functionally, we demonstrated that 5-HT1BR mediates some of the acute and persisting behavioral effects of psilocybin. Although there was no effect of 5-HT1BR expression on the acute head twitch response, mice lacking 5-HT1BRs had attenuated hypolocomotion to psilocybin. We also measured the persisting effects of psilocybin on anhedonia and anxiety-like behavior using transgenic and pharmacological 5-HT1BR loss-of-function models. Although there were effects of sex and stress paradigms, we found that 5-HT1B is involved in mediating some of the longer-lasting behavioral responses to psilocybin. Finally, using a network analysis, we identified neural circuits through which 5-H1BR may modulate the response to psilocybin. Overall, our research implicates the 5-HT1BR, a non-hallucinogenic serotonin receptor, as a mediator of the behavioral and neural effects of psilocybin in mice.