Molecular Psychiatry最新文献

Alterations induced by maternal immune activation (MIA) during gestation impact the subsequent neurodevelopment of progeny, a process that in humans, has been linked to the development of several neuropsychiatric conditions. To undertake a comprehensive examination of the molecular mechanisms governing MIA, we have devised an in vitro model based on neural stem cells (NSCs) sourced from fetuses carried by animals subjected to Poly I:C treatment. These neural progenitors demonstrate proliferative capacity and can be effectively differentiated into both neurons and glial cells. Transcriptomic, proteomic, and phosphoproteomic analyses conducted on these cellular models, in conjunction with counterparts from control treatments, revealed discernible shifts in the expression levels of a specific subset of proteins implicated in neuronal function. Furthermore, the phosphoproteomic data highlighted a discernible discrepancy in the basal phosphorylation of proteins between differentiated cells from both experimental groups, particularly within proteins associated with cytoskeletal architecture and synaptic functionality, notably those belonging to the MAP family. Observed alterations in MAP phosphorylation were found to potentially have functional consequences as they correlate with changes in neuronal plasticity and the establishment of neuronal synapses. Our data agrees with previous published observations and further underscore the importance of MAP2 phosphorylation state on its function and the impact that this protein has in neuronal structure and function.

Laboratory studies show brain maturation involves synaptic pruning and cognitive development. Human studies suggest links between early cognitive performance and later mental health, but inconsistencies remain. It is unclear if specific brain regions mediate this relationship, and the molecular underpinnings are not well understood. Here, our longitudinal analyses in both the Adolescent Brain Cognitive Development and IMAGEN cohorts establish inverted U-shaped relationships between baseline executive function and subsequent symptom trajectories in the high-symptom individuals, whose externalizing (n = 963) or internalizing (n = 1762) symptoms exceed a clinical threshold at any point during the follow-up period, but not in the control group (n = 4291). Volumetric changes in the left lateral occipital cortex (LOC) mediated the relationship with externalizing symptoms (outwardly directed behaviors such as aggression), while changes in the right LOC and pars triangularis mediated the relationship with internalizing symptoms (inwardly directed emotional problems such as anxiety). Transcriptomic and genomic findings highlighted synaptic biology and particularly the gene ADCY1, which is implicated in synaptic pruning, as underlying both moderate executive function and its associated brain mediators. Notably, preadolescent cognitive performance predicts late-onset externalizing symptoms and remitting internalizing symptoms with high accuracies (area under the curve: 0.87 and 0.79). Our findings highlight the predictive value of cognitive performance for adolescent mental health trajectories, and indicate how this is mediated by specific brain regions, and underpinned by particular molecular pathways.

Most of the fear literature on humans and animals tests healthy individuals. However, fear memories can differ between healthy individuals and those previously exposed to traumatic stress, such as a car accident, sexual abuse, military combat and personal assault. Traumatic stress can lead to post-traumatic stress disorder (PTSD) which presents alterations in fear memories, such as an impairment of fear extinction and extinction recall. PTSD-like animal models are exposed to a single highly stressful experience in the laboratory, such as stress immobilization or single-prolonged stress. Some days later, animals exposed to a PTSD-like model can be tested in fear procedures that help uncover molecular mechanisms of fear memories. In this review, there are discussed the molecular mechanisms in stress-induced fear memories of patients with PTSD and PTSD-like animal models. The focus is on the effects of estradiol and cortisol/corticosterone hormones and of different genes, such as FKBP prolyl isomerase 5 gene (FKBP5) - FK506 binding protein 51 (FKBP51), pituitary adenylate cyclase-activating peptide (PACAP) - pituitary adenylate cyclase-activating polypeptide type I receptor (PAC1R), endocannabinoid (eCB) system and the tropomyosin receptor kinase B (TrkB) - brain-derived neurotrophic factor (BDNF). The conclusion is that greater emphasis should be placed on investigating the molecular mechanisms of fear memories in PTSD, through direct testing of patients with PTSD or the use of relevant PTSD-like models.

Both post-mortem and in vivo data argue for dopamine dysfunction in patients with Alzheimer’s Disease (AD). However, the timing and regional progression of dopaminergic systems alterations in AD are still debated. The aim of the study was to investigate in vivo the pattern of dopaminergic changes and connectivity using DAT-SPECT imaging in patients across the AD spectrum. Fifty-nine AD patients (n = 21 AD-MCI; n = 38 AD-DEM) and a control group (CG) of n = 45 age- and sex-matched individuals entered the study and underwent ¹²³I-FP-CIT dopaminergic imaging. The occipital binding was used as reference region to obtain single-subject binding in different brain regions. Between-group differences in ¹²³I-FP-CIT binding in both mesolimbic and nigrostriatal dopaminergic pathways were assessed using an ANCOVA test, adjusting for the effect of center of imaging acquisition, age, and sex. Regions resulting from the voxel-wise direct comparison between AD-MCI and AD-DEM were considered as a seed of interest for a voxel-wise interregional correlation analysis. Both AD-MCI and AD-DEM patients showed dopaminergic depletion within the basal ganglia, whereas cortico-limbic regions (namely hippocampus, amygdala, anterior and middle cingulate, frontal cortex and thalamus) resulted impaired only in the dementia phase. The brain voxel-wise interregional correlation analysis showed a progressive pattern of disruption of caudate/thalamus dopaminergic connectivity to hippocampus and amygdala from AD-MCI to AD-DEM stages. This study indicates basal ganglia dopaminergic alterations and connectivity disruption in the nigrostriatal and mesolimbic systems already in early stage AD, extending to several cortico-limbic regions in dementia phases.

Alzheimer’s disease (AD) is characterized by memory loss and neuropsychiatric symptoms associated with cerebral amyloid-β (Aβ) and tau pathologies, but whether and how these factors differentially disrupt neural circuits remains unclear. Here, we investigated the vulnerability of memory and emotional circuits to Aβ and tau pathologies in mice expressing mutant human amyloid precursor protein (APP), Tau or both APP/Tau in excitatory neurons. APP/Tau mice develop age- and sex-dependent Aβ and phosphorylated tau pathologies, the latter exacerbated at early stages, in vulnerable brain regions. Early memory deficits were associated with hippocampal tau pathology in Tau and APP/Tau mice, whereas anxiety and fear appeared linked to intracellular Aβ in the basolateral amygdala (BLA) of APP and APP/Tau mice. Transcriptome hippocampal profiling revealed gene changes affecting myelination and RNA processing in Tau mice, and inflammation and synaptic-related pathways in APP/Tau mice at 6 months. At 9 months, we detected common and region-specific changes in astrocytic, microglia and 63 AD-associated genes in the hippocampus and BLA of APP/Tau mice. Spatial learning deficits were associated with synaptic tau accumulation and synapse disruption in the hippocampus of Tau and APP/Tau mice, whereas emotional disturbances were linked to Aβ pathology but not synaptic tau in the BLA. Interestingly, Aβ and tau exhibited synergistic detrimental effects in long-term potentiation (LTP) in the hippocampus but they counteract with each other to mitigate LTP impairments in the amygdala. These findings indicate that Aβ and tau pathologies cause region-specific effects and synergize to induce synaptic dysfunction and immune responses, contributing to the differing vulnerability of memory and emotional neural circuits in AD.

The hypothalamic neuropeptide system of orexin (hypocretin) neurons provides projections throughout the neuraxis and has been linked to sleep regulation, feeding and motivation for salient rewards including drugs of abuse. However, relatively little has been done to examine genes associated with orexin signaling and specific behavioral phenotypes in humans. Here, we tested for association of twenty-seven genes involved in orexin signaling with behavioral phenotypes in humans. We tested the full gene set, functional subsets, and individual genes involved in orexin signaling. Our primary phenotype of interest was Externalizing, a composite factor comprised of behaviors and disorders associated with reward-seeking, motivation, and behavioral regulation. We also tested for association with additional phenotypes that have been related to orexin regulation in model organism studies, including alcohol consumption, problematic alcohol use, daytime sleepiness, insomnia, cigarettes per day, smoking initiation, and body mass index. The composite set of 27 genes corresponding to orexin function was highly associated with Externalizing, as well as with alcohol consumption, insomnia, cigarettes per day, smoking initiation and BMI. In addition, all gene subsets (except the OXR2/HCRTR2 subset) were associated with Externalizing. BMI was significantly associated with all gene subsets. The “validated factors for PPOX/HCRT” and “PPOX/HCRT upregulation” gene subsets also were associated with alcohol consumption. Individually, 8 genes showed a strong association with Externalizing, 12 with BMI, 7 with smoking initiation, 3 with alcohol consumption, and 2 with problematic alcohol use, after correction for multiple testing. This study indicates that orexin genes are associated with multiple behaviors and disorders related to self-regulation in humans. This is consistent with prior work in animals that implicated orexin signaling in motivational activation induced by salient stimuli, and supports the hypothesis that orexin signaling is an important potential therapeutic target for numerous behavioral disorders.

Cognitive and neural mechanisms underlying bipolar disorder (BD) and its treatment are still poorly understood. Here we examined the role of adaptations in risk-taking using a reward-guided decision-making task. We recruited volunteers with high (n = 40) scores on the Mood Disorder Questionnaire, MDQ, suspected of high risk for bipolar disorder and those with low-risk scores (n = 37). We also recruited patients diagnosed with BD who were assigned (randomized, double-blind) to six weeks of lithium (n = 19) or placebo (n = 16) after a two-week baseline period (n = 22 for FMRI). Participants completed mood ratings daily over 50 (MDQ study) or 42 (BD study) days, as well as a risky decision-making task and functional magnetic resonance imaging. The task measured adaptation of risk taking to past outcomes (increased risk aversion after a previous win vs. loss, ‘outcome history’). While the low MDQ group was risk averse after a win, this was less evident in the high MDQ group and least so in the patients with BD. During fMRI, ‘outcome history’ was linked to medial frontal pole activation at the time of the decision and this activation was reduced in the high risk MDQ vs. the low risk MDQ group. While lithium did not reverse the pattern of BD in the task, nor changed clinical symptoms of mania or depression, it changed reward processing in the dorsolateral prefrontal cortex. Participants’ modulation of risk-taking in response to reward outcomes was reduced as a function of risk for BD and diagnosed BD. These results provide a model for how reward may prime escalation of risk-related behaviours in bipolar disorder and how mood stabilising treatments may work.

In this perspective we draw together the data from the genome wide association studies for Alzheimer’s disease, Parkinson’s disease and the tauopathies and reach the conclusion that in each case, most of the risk loci are involved in the clearance of the deposited proteins: in Alzheimer’s disease, the microglial removal of Aβ, in the synucleinopathies, the lysosomal clearance of synuclein and in the tauopathies, the removal of tau protein by the ubiquitin proteasome. We make the point that most loci identified through genome wide association studies are not strictly pathogenic but rather relate to failures to remove age related damage. We discuss these issues in the context of copathologies in elderly individuals and the prediction of disease through polygenic risk score analysis at different ages. Finally, we discuss what analytic approaches are needed now that we have adequately sized case control analyses in white populations.

Age-related dopamine (DA) neuron loss is a primary feature of Parkinson’s disease. However, whether similar biological processes occur during healthy aging, but to a lesser degree, remains unclear. We therefore determined whether midbrain DA neurons degenerate during aging in mice and humans. In mice, we identified no difference in midbrain neuron numbers throughout aging. Despite this, we found age-related decreases in midbrain mRNA expression of tyrosine hydroxylase (Th), the rate limiting enzyme of DA synthesis. Among midbrain glutamatergic cells, we similarly identified age-related declines in vesicular glutamate transporter 2 (Vglut2) mRNA expression. In co-transmitting Th⁺/Vglut2⁺ neurons, Th and Vglut2 transcripts decreased with aging. However, Th and Vglut2 protein levels in striatal synaptic release sites (e.g., terminals and axonal projections) did not differ throughout aging. Similar to the mouse, an initial study of human brain showed no effect of aging on midbrain neuron number with a concomitant decrease in TH and VGLUT2 mRNA expression. Unlike in mice, the density of striatal TH⁺ dopaminergic terminals was lower in aged human subjects. However, TH and VGLUT2 protein levels were unaffected in the remaining striatal boutons. Finally, in contrast to Th and Vglut2 mRNA, expression of most ribosomal genes in Th⁺ neurons was either maintained or even upregulated during aging. This suggests a homeostatic mechanism where age-related declines in transcriptional efficiency are overcome by ongoing ribosomal translation. Overall, we demonstrate species-conserved transcriptional effects of aging in midbrain dopaminergic and glutamatergic neurons that are not accompanied by marked cell death or lower striatal protein expression. This opens the door to novel therapeutic approaches to maintain neurotransmission and bolster neuronal resilience.