Molecular Psychiatry最新文献

Early postnatal development is a critical period for the configuration of neural networks that support social and affective-like behaviors. In this sense, children raised in stressful environments are at high risk to develop maladaptive behaviors immediately or later in life, including anti-social and aggressive behaviors. However, the neurobiological bases of such phenomena remain poorly understood. Here we showed that, at long-term, maternal separation with early weaning (MSEW) decreased the density of somatostatin-expressing (SST+) neurons in the basolateral amygdala (BLA) of females and males, while their activity was only reduced in the medial amygdala (MeA) of males. Interestingly, only MSEW males exhibited long-term behavioral effects, including reduced sociability and social novelty preference in the 3-chamber test (3CH), decreased social interest in the resident-intruder test (RI), and increased aggressivity in both the RI and the tube dominance test (TT). To test whether the manipulation of MeA^SST+ neurons was sufficient to reverse these negative behavioral outcomes, we expressed the chemogenetic excitatory receptor hM3Dq in MSEW adult males. We found that the activation of MeA^SST+ neurons ameliorated social interest in the RI test and reduced aggression traits in the TT and RI assays. Altogether, our results highlight a role for MeA^SST+ neurons in the regulation of aggressivity and social interest and point to the loss of activity of these neurons as a plausible etiological mechanism linking early life stress to these maladaptive behaviors in later life.

Fear extinction leads to a decrease of originally acquired fear responses after the threat is no longer present. Fear extinction is adaptive and critical for organism’s survival, but deficits in extinction may lead to exaggerated fear in animals or post-traumatic stress disorder (PTSD) in humans. Dopamine has recently emerged as essential for fear extinction and PTSD, however the neural circuits serving this dopamine function are only beginning to be investigated, and the dopamine intracellular signaling pathways are unknown. We generated gastrin-releasing peptide gene knockout (Grp^-/-) mice and found that they exhibit enhanced fear memory in a stress-enhanced fear learning (SEFL) paradigm, which combines stress exposure and fear extinction, two features critical for developing PTSD. Using in vivo fiber photometry to record dopamine signals, we found that the susceptibility of Grp^-/- mice to SEFL is paralleled by an increase in basolateral amygdala (BLA) dopaminergic binding during fear conditioning and early extinction. Combined optogenetics and ex vivo electrophysiology showed an increase in presynaptic ventral tegmental area (VTA)-BLA connectivity in Grp^-/- mice, demonstrating a role of dysregulated input from the VTA on BLA function in the absence of the GRP. When examining gene transcription using RNA-seq and qPCR, we discovered concerted down-regulation in dopamine-related genes in the BLA of Grp^-/- mice following long-term SEFL memory recall that was not observed in naïve conditions. These experiments demonstrate that the GRP regulates dopamine function in stress-enhanced fear processing and identify the Grp as the first gene known to regulate dopaminergic control of fear extinction.

Background

Previous studies have implicated hippocampal abnormalities in the neuropathology of psychosis spectrum disorders. Reduced hippocampal volume has been reported across all illness stages, and this atrophy has been hypothesized to be the result of glutamatergic excess. To test this hypothesis, we measured hippocampal subfield volumes and hippocampal glutamate levels in antipsychotic naïve first episode psychosis patients (FEP) and the progression of volume decline and changes in glutamate levels over a 16-week antipsychotic drug (APD) trial. We aimed to determine if subfield volumes at baseline were associated with glutamate levels, and if baseline glutamate levels were predictive of change in subfield volumes over time.

Methods

We enrolled ninety-three medication-naïve FEP participants and 80 matched healthy controls (HC). T1 and T2 weighted images and magnetic resonance spectroscopy (MRS) data from a voxel prescribed in the left hippocampus were collected from participants at baseline and after 6 and 16 weeks of APD treatment. Hippocampal subfield volumes were assessed using FreeSurfer 7.1.1., while glutamate levels were quantified using jMRUI version 6.0. Data were analyzed using linear mixed models.

Results

We found regional subfield volume deficits in the CA1, and presubiculum in FEP at baseline, that further expanded to include the molecular and granule cell layer of the dentate gyrus (GC/ML/DG) and CA4 by week 16. Baseline hippocampal glutamate levels in FEP were not significantly different than those of HC, and there was no effect of treatment on glutamate. Glutamate levels were not related to initial subfield volumes or volume changes over 16 weeks.

Conclusion

We report a progressive loss of hippocampal subfield volumes over a period of 16 weeks after initiation of treatment, suggestive of early progression in neuropathology. Our results do not suggest a role for glutamate as a driving factor. This study underscores the need to further research the mechanism(s) underlying this phenomenon as it has implications for early intervention to preserve cognitive decline in FEP participants.

Cognitive impairment, a core symptom of psychiatric disorders, is frequently observed in adolescents exposed to early-life stress (ES). However, the underlying neural mechanisms are unclear, and therapeutic efficacy is limited. Targeting parvalbumin-expressing interneurons (PVIs) in the medial prefrontal cortex (mPFC), we report that ES reduces mPFC PVI activity, which causally mediated ES-induced cognitive deficits in adolescent male mice through chemogenetic and optogenetic experiments. To understand the possible causes of PVI activity reduction following ES, we then demonstrated that ES upregulated corticotropin-releasing hormone (CRH) receptor 1 [CRHR1, mainly expressed in pyramidal neurons (PNs)] and reduced activity of local pyramidal neurons (PNs) and their excitatory inputs to PVIs. The subsequent genetic manipulation experiments (CRHR1 knockout, CRH overexpression, and chemogenetics) highlight that ES-induced PVI activity reduction may result from CRHR1 upregulation and PN activity downregulation and that PVIs play indispensable roles in CRHR1- or PN-mediated cognitive deficits induced by ES. These results suggest that ES-induced cognitive deficits could be attributed to the prefrontal CRHR1-PN-PVI pathway. Finally, treatment with antalarmin (a CRHR1 antagonist) and environmental enrichment successfully restored the PVI activity and cognitive deficits induced by ES. These findings reveal the neurobiological mechanisms underlying ES-induced cognitive deficits in adolescent male mice and highlight the therapeutic potentials of PVIs in stress-related cognitive deficits in adolescent individuals.

Longitudinal studies of the effects of adversity on human brain development are complicated by the association of stressful events with confounding variables. To counter this bias, we apply a propensity-weighted analysis of the first two years of The Adolescent Brain Cognitive Development^SM (ABCD) Study® data, employing a machine learning analysis weighted by individuals’ propensity to experience adversity. Data included 338 resting-state functional connections from 7190 youth (46% female), divided into a training group (80%) and an independent testing group (20%). Propensity scores were computed using 390 variables to balance across two-year adverse life event exposures. Using elastic net regularization with and without inverse propensity weighting, we developed linear models in which changes in functional connectivity of brain connections during the two-year period served as predictors of the number of adverse events experienced during that same period. Haufe’s method was applied to forward-transform the backward prediction models. We also tested whether brain changes associated with adverse events correlated with concomitant changes in internalizing or externalizing behaviors or to academic achievement. In the propensity-weighted analysis, brain development significantly predicted the number of adverse events experienced during that period in both the training group (ρ = 0.14, p < 0.001) and the independent testing group (ρ = 0.10, p < 0.001). The predictor indicated a general pattern of decreased functional connectivity between large-scale networks and subcortical brain regions, particularly for cingulo-opercular and sensorimotor networks. These network-to-subcortical functional connectivity decreases inversely associated with the development of internalizing symptoms, suggesting adverse events promoted adaptive brain changes that may buffer against stress-related psychopathology. However, these same functional connections were also associated with poorer grades at the two-year follow-up. Although cortical-subcortical brain developmental responses to adversity potentially shield against stress-induced mood and anxiety disorders, they may be detrimental to other domains such as academic success.

Astrocytes regulate brain functions through gliotransmitters like ATP/ADP and glutamate, but their release patterns and mechanisms remain controversial. Here, we visualized ATP/ADP and glutamate response following astrocyte activation and investigated their mechanisms in vivo. Employing cOpn5-mediated optogenetic stimulation, genetically encoded fluorescent sensors, and two-photon imaging, we observed ATP/ADP released as temporally prolonged and spatially extended flashes that later converted to adenosine. This release occurs via Ca²⁺ and VNUT-dependent vesicular exocytosis. Additionally, astrocytes also release glutamate in flashes through TeNT-sensitive exocytosis, independent of ATP/ADP release. ATP/ADP released by astrocytes triggers further ATP/ADP release from microglia through P2Y12- and VNUT-dependent mechanisms. VNUT in astrocytes and microglia also contributes to ATP/ADP release under LPS-induced brain inflammation. These findings establish Ca²⁺-dependent vesicular exocytosis as a key mode of action, reveal intricate astrocyte-microglia interactions, and suggest a role for gliotransmission in brain inflammation. Furthermore, the methodologies may provide valuable tools for deciphering glial physiology and pathophysiology.

Dysregulation of development, migration, and function of interneurons, collectively termed interneuronopathies, have been proposed as a shared mechanism for autism spectrum disorders (ASDs) and childhood epilepsy. Neuropilin-2 (Nrp2), a candidate ASD gene, is a critical regulator of interneuron migration from the median ganglionic eminence (MGE) to the pallium, including the hippocampus. While clinical studies have identified Nrp2 polymorphisms in patients with ASD, whether selective dysregulation of Nrp2-dependent interneuron migration contributes to pathogenesis of ASD and enhances the risk for seizures has not been evaluated. We tested the hypothesis that the lack of Nrp2 in MGE-derived interneuron precursors disrupts the excitation/inhibition balance in hippocampal circuits, thus predisposing the network to seizures and behavioral patterns associated with ASD. Embryonic deletion of Nrp2 during the developmental period for migration of MGE derived interneuron precursors (iCKO) significantly reduced parvalbumin, neuropeptide Y, and somatostatin positive neurons in the hippocampal CA1. Consequently, when compared to controls, the frequency of inhibitory synaptic currents in CA1 pyramidal cells was reduced while frequency of excitatory synaptic currents was increased in iCKO mice. Although passive and active membrane properties of CA1 pyramidal cells were unchanged, iCKO mice showed enhanced susceptibility to chemically evoked seizures. Moreover, iCKO mice exhibited selective behavioral deficits in both preference for social novelty and goal-directed learning, which are consistent with ASD-like phenotype. Together, our findings show that disruption of developmental Nrp2 regulation of interneuron circuit establishment, produces ASD-like behaviors and enhanced risk for epilepsy. These results support the developmental interneuronopathy hypothesis of ASD epilepsy comorbidity.

With an increasing aging population and Alzheimer’s disease tsunami, it is critical to identify early antecedents of brain aging to target for intervention and prevention. Women and men develop and age differently, thus using a sex differences lens can contribute to identification of early risk biomarkers and resilience. There is growing evidence for fetal antecedents to adult memory impairments, potentially through disruption of maternal prenatal immune pathways. Here, we hypothesized that in utero exposure to maternal pro-inflammatory cytokines will have sex-dependent effects on specific brain circuitry regulating offspring’s memory and immune function that will be retained across the lifespan. Using a unique prenatal cohort, we tested this in 204 adult offspring, equally divided by sex, who were exposed/unexposed to an adverse in utero maternal immune environment and followed into early midlife (~age 50). Functional magnetic resonance imaging results showed exposure to pro-inflammatory cytokines in utero (i.e., higher maternal IL-6 and TNF-α levels) was significantly associated with sex differences in brain activity and connectivity underlying memory circuitry and performance and with a hyperimmune state, 50 years later. In contrast, the anti-inflammatory cytokine, IL-10 alone, was not significantly associated with memory circuitry in midlife. Predictive validity of prenatal exposure was underscored by significant associations with age 7 academic achievement, also associated with age 50 memory performance. Results uniquely demonstrated that adverse levels of maternal in utero pro-inflammatory cytokines during a critical period of the sexual differentiation of the brain produced long-lasting effects on immune function and memory circuitry/function from childhood to midlife that were sex-dependent, brain region-specific, and, within women, reproductive stage-dependent.

We would like to address the results of two recent positron emission tomography (PET) imaging studies and discuss them in relation to our own findings [1]. The first study we would like to refer to is an [¹⁸F]FDOPA PET investigation performed in two independent cohorts of drug-free patients with schizophrenia [2]. [¹⁸F]FDOPA is a direct precursor of dopamine, and its uptake is generally assumed to reflect presynaptic dopamine synthesis and storage capacity. In contrast to earlier [¹⁸F]FDOPA PET studies, Eisenberg et al. failed to find elevated [¹⁸F]FDOPA uptake in patients with schizophrenia. However, the study observed inverse correlations between [¹⁸F]FDOPA uptake rates into the putamen and severity of negative symptoms in both cohorts. Thus, the Eisenberg et al. findings indicate that reduced dopamine transmission in the putamen may be an important element in the formation of negative symptoms of schizophrenia.

The second study we would like to address [3] presents the results of a PET study on the effects of oral methylphenidate (MPH) administration on non-displaceable binding potential (BP_ND) values of the dopamine D_2/3 receptor agonist radioligand [¹¹C]-(+)-PHNO in individuals at clinical high-risk (CHR) for psychosis. Changes in radioligand binding to dopamine D_2/3 receptors after a pharmacological or behavioral challenge provide an indirect measure for the fluctuations in extracellular dopamine levels. The authors aimed to replicate and extend findings on alterations in subcortical availability of dopamine in CHR individuals, as previous studies have shown that subcortical dopamine functioning is elevated in full-blown psychosis, and that enhanced dopamine transmission might be present even before psychosis onset [4, 5]. This, however, was questioned by a more recent meta-analysis [6]. The main finding of the study by Girgis et al. [3] was that, compared to non-CHR controls, CHR subjects showed greater changes in [¹¹C]-(+)-PHNO BP_ND values (∆BP_ND) in response to the MPH challenge. This conforms well with results from earlier challenge-studies in patients with schizophrenia [1, 4, 7,8,9,10,11] and extends the use of this method towards prodromal stages of psychosis (which, of course, can only be termed as such in retrospect). In addition, the study by Girgis et al. observed an inverse relationship between the expression of negative symptoms and [¹¹C]-(+)-PHNO ∆BP_ND in the ventral striatum of CHR subjects.