Molecular Psychiatry最新文献

The success of ketamine, a dissociative anesthetic and non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, as a rapidly acting antidepressant has ignited efforts to identify other novel depression treatments. In recent years, several clinical trials indicated that nitrous oxide (N₂O), an inhalational dissociative anesthetic in clinical use for over 150 years, also has rapid and durable antidepressant effects in patients with major depressive disorder (MDD) and treatment resistant major depression (TRMD). N₂O is a non-competitive NMDAR inhibitor but acts on NMDARs by mechanisms distinct from ketamine. Cellular and neuronal circuit studies of N₂O-induced psychotropic and antidepressant effects are in their infancy and suggest that N₂O shares at least some downstream mechanisms with ketamine, while also having unique effects on neurophysiology and signaling. Human neuroimaging and brain network connectivity studies of N₂O have begun to identify acute and persisting effects of the drug on brain circuits likely relevant for antidepressant responses. In this review, we highlight the current state of clinical and preclinical research into the effects of N₂O and emphasize major unanswered questions, some of which are currently being explored. We emphasize future directions and potential barriers to clinical use of N₂O for treatment of patients with psychiatric illnesses.

The amygdala is a subcortical brain structure involved in threat processing and implicated in various psychopathology. Previous efforts to map amygdala subnuclei connectivity have been hindered by technological limitations. This study used ultra-high field imaging to investigate the covariance profiles of amygdala subnuclei to better understand their contribution to trauma-related psychopathology and posttraumatic stress disorder (PTSD). Participants included 59 non-trauma-exposed controls (NEC; 51% female), 78 trauma-exposed controls (TEC; 65% female), and 73 individuals with PTSD (93% female) who completed T1-weighted MP2RAGE anatomical scans using a 7-Tesla MRI scanner. FreeSurfer was used to parcellate 105 brain regions including nine bilateral amygdala subnuclei. Pearson's r correlations were computed for each subnuclei-brain region pair, corrected for age, sex, education, and total brain volume. Gray matter volumes, topological connectivity (nodal degree) using graph analysis, and subnuclei-brain region covariances were compared between-groups. There were between-group volumetric differences for the lateral nuclei (left: NEC < PTSD/TEC; right: PTSD < NEC/TEC), and higher nodal degree of the right paralaminar subnucleus for TEC (vs NEC). Covariance patterns differed between-groups, with lower PTSD (vs NEC) structural covariances for left cortical and central nuclei, and higher TEC (vs NEC) covariances for left lateral, basal, cortical, and anterior-amygdaloid-area, right cortico-amygdaloid transition, and bilateral paralaminar nuclei. This study is the first to reveal differences in amygdala subnuclei covariance profiles along the trauma-spectrum using ultra-high field imaging. Findings suggest that amygdala subnuclei could have differential connectivity profiles in trauma-related conditions and ultra-high field imaging studies are needed to more precisely understand their role.

Early life adversities (ELA) can significantly impact brain development and adult behavior, potentially increasing vulnerability to psychopathologies. Evidence shows that ELA exposure is significantly associated with dysfunctional Oxytocin (OXT), a neuropeptide strongly engaged in social behavior and linked to the processing of rewarding stimuli, such as drugs of abuse. Moreover, it has been recently demonstrated that peripheral OXT may be transported to the brain through several mechanisms, including Receptors for Advanced Glycation End-Products (RAGE), and the RAGE-mediated OXT transport has been shown to play a key critical role in mediating some aspects of social behavior, such as social bonding. However, how OXT system alterations induced by ELA could increase vulnerability to psychopathologies is still under investigation. To investigate this link, we exploit our model of early adversity (Repeated Cross-Fostering, RCF), known to increase the sensitivity to cocaine effects in adult C57BL/6 J (C57) female mice acting on the dopaminergic mesocorticolimbic system. Here, we show that in C57 females, RCF manipulation also impairs social recognition and impacts the OXT system by altering i) OXT levels in the brain and plasma; ii) the expression of RAGE; and iii) the expression of OXT receptor (OxtR). Notably, early restoring brain and plasmatic OXT levels via subcutaneous OXT injection during RCF manipulation counteracts the RCF-induced neurobiological alterations of the OXT system and prevents short and long-lasting behavioral alterations. These findings shed light on the mechanisms by which the oxytocinergic system mediates the long-term effects of early-life adversities on drug addiction vulnerability and social behavior.

Alterations in excitatory neurotransmitters, involving the glutamate (Glu) and glutamine (Gln) cycle, as well as inhibitory neurotransmission, GABA, are implicated in the pathophysiology of autism spectrum disorder (ASD). Although magnetic resonance spectroscopy (MRS) holds promise for assessing these metabolites, conventional 3 T MRI does not robustly measure them, leaving the neurochemical pathophysiology of ASD insufficiently understood. 7 T MRI enables reliable assessments of these neurometabolites by enhancing the signal-to-noise ratio and improving the spectral resolution, particularly in distinguishing neuroactive Glu from its metabolic precursor, Gln. The current 7 T MRS study has two primary objectives: first, to investigate neurometabolite levels in adults with ASD to elucidate its neurochemical pathophysiology, and second, to examine their association with symptoms of ASD. Thirty-three adults with ASD (mean age = 31 years) and 52 age-matched control adults were included. The neurometabolite levels of Glu, Gln, and GABA were assessed in the anterior cingulate cortex (ACC), thalamus, and right temporo-parietal junction (TPJ), with most quantifications passing quality checks. Analysis of covariance revealed significant effects of diagnosis on Gln in the thalamus (p = 0.008) and right TPJ (p = 0.006), indicating elevated Gln levels in these regions in the ASD group. Among social communication and restricted and repetitive behaviors, significant negative correlations were observed in the ASD group between Gln levels and sensory symptoms. These findings suggest that alterations in the excitatory neurotransmission regulation, presumably increased cycling of the Gln-Glu circuit, may underlie the pathophysiology of ASD.

Aging is the primary risk factor for cognitive decline and neurodegenerative disorders, characterized by impaired circuit plasticity and disrupted gamma oscillations. Non-invasive 40 Hz audiovisual stimulation (AuViS) has emerged as a promising strategy to restore cognition in models of Alzheimer's disease and stroke. Yet, the mechanisms underlying these effects remain unclear. We found that AuViS increased gamma oscillations in the dentate gyrus of middle-aged mice. Control animals displayed scarce neurogenesis, and newborn neurons exhibited limited growth and remained functionally immature. Notably, AuViS triggered the proliferation of neural progenitor cells and shifted the balance from astrocytic towards neuronal differentiation. It also promoted neuronal maturation, leading to the development of complex dendritic trees and axons with large mossy terminals bearing filopodial extensions. These structural modifications were accompanied by increased spiking capacity and spontaneous synaptic activity, indicative of effective circuit integration. These effects were dependent on TrkB signaling, implicating neurotrophin pathways. Our findings demonstrate that AuViS reestablishes neurogenesis and promotes network remodeling in the healthy aging brain, which might aid to ameliorate neurological conditions.

The shared genetic signals between human cerebral cortex and substance use disorders (SUDs) remain largely unknown. Here, we utilized the Human Connectome Project Multi-Modal Parcellation (HCP-MMP) to divide each hemisphere into 180 regions and investigated the genetic overlap between cortical surface area/thickness of these novel regions and four types of SUDs (N > 1 million). We identified 17 and 282 shared genetic loci between global and regional cortical phenotypes and SUDs. The anatomical patterns of genetic overlap were similar for problematic alcohol use and nicotine use, with substantial overlap in the TGd, insula, primary motor cortex, and posterior cingulate cortex. The cortical patterns of SUDs were established along the anatomical and functional hierarchies in the sensorimotor-association (S-A) cortical axis, but were independent of evolutionary hierarchies. Mendelian randomization analyses indicated that genetically predicted reduced surface area of the ventromedial prefrontal cortex (area 25) and frontal opercular area 3 (FOP3), posterior dorsal superior temporal sulcus (STSdp), and posterior insular area 2 (PoI2) were associated with increased risk of cannabis use disorder and opioid use, respectively. Reduced thickness of retrosplenial complex (RSC) was associated with increased risk of problematic alcohol use. However, reduced thickness of fusiform face complex (FFC) was associated with decreased risk of nicotine use. In summary, we provided novel insights into the shared genetic etiology between cortical phenotypes and SUDs under a more refined multimodal cortical parcellation scheme.