Biological Psychiatry最新文献

Background: Long-term fear memory storage involves gradual reorganization of supporting brain regions over time, a process termed systems consolidation. Memories initially rely on the hippocampus but gradually shift dependence to the neocortex. Although hippocampal activity drives this transfer, the molecular basis of systems consolidation is largely unknown. DNA methylation changes accompany persistent fear memory formation in the hippocampus and cortex, but its causal role in memory storage and systems consolidation remains unclear.

Methods: We investigated the role of hippocampal DNA methylation in fear memory persistence through multiple approaches. Using rAAV-mediated gene transfer, we overexpressed or knocked down a DNA methyltransferase (Dnmt3a2) in the dorsal hippocampus of mice and assessed its impact on fear memory duration. Engram tagging and manipulation tools were applied to study cortical fear engram stabilization. Finally, RNA-sequencing analysis was used to identify transcriptional changes driven by Dnmt3a2 overexpression.

Results: Overexpression of hippocampal Dnmt3a2 induced a persistent fear memory, while its knockdown impaired remote memory recall. RNA-sequencing revealed that Dnmt3a2 overexpression modifies the expression of synaptic transmission regulatory genes. Furthermore, genetic engram tagging, and manipulation revealed that hippocampal DNA methylation promotes the transfer of the fear memory trace from the hippocampus to the cortex and the stabilization of cortical fear memory traces.

Conclusion: Our findings demonstrate that hippocampal DNA methylation regulates the long-term storage of persistent fear memories by facilitating the transfer of memory traces from the hippocampus to cortex and cortical stabilization. These results highlight DNA methylation as a key molecular mechanism underlying systems consolidation and long-term fear memory storage.

Post-Traumatic Stress Disorder (PTSD) is a debilitating condition caused by exposure to traumatic events, affecting 5-10% of the population, with increased prevalence among women and individuals in war zones. Beyond psychological symptoms, PTSD induces significant physiological changes across systems. Psychoneuroimmunoendocrinology (PNIE) offers a framework to explore these complex interactions between the psyche and the nervous, immune, and endocrine systems. Studies reveal that PTSD entails disruptions in the central and autonomic nervous, immune, and endocrine systems, including gut microbiota imbalances, impairing organ function. Integrative pathways connecting these parts include the microbiota-gut-brain axis, heart-brain axis, neuroinflammation, and hypothalamic-pituitary dysregulation, highlighting bidirectional links between mental and physical health. Viewing PTSD as a entity comprising both psychological and physiological challenges underscores the importance of integrative care strategies, combining pharmacological treatments, psychotherapy, and lifestyle interventions. These approaches align with PNIE principles, which may help identify biomarkers for treatment efficacy. This review discusses the pathophysiology of PTSD through a PNIE lens and its implications for improving patient care, advocating for personalized, multidisciplinary interventions in mental health.

Background: The persistence of cocaine-evoked adaptations relies on gene regulations within the reward circuit, especially in the ventral striatum (i.e., nucleus accumbens (NAc)). Notably, activation of the extracellular signal-regulated kinase (ERK) pathway in the striatum is known to trigger a transcriptional program shaping long-term responses to cocaine. Nuclear calcium signaling has also been shown to control multiple forms of transcription-dependent neuroadaptations but the dynamics and roles of striatal nuclear calcium signaling in preclinical models of addiction remains unknown.

Methods: A genetically-encoded cell-type-specific nuclear calcium probe has been developed to monitor calcium dynamics in the nuclei of striatal neurons, including in freely-moving mice. A cell-type-specific inhibitor of nuclear calcium signaling, combined with 3D imaging of neuronal morphology, immunostaining and behavior, was used to disentangle the roles of nuclear calcium in NAc medium-sized spiny neurons (MSN) expressing the dopamine D1 (D1R) or D2 (D2R) receptor on cocaine-evoked responses.

Results: The D1R-mediated potentiation of calcium influx through glutamate N-methyl-D-aspartate receptors (NMDAR), which shapes cocaine effects, also drives nuclear calcium transients. Fiber photometry revealed that cocaine-treated mice display a sustained nuclear calcium increase in NAc D1R-MSN. Disrupting nuclear calcium in D1R-MSN, but not D2R-MSN, blocks cocaine-evoked morphological changes of MSN and gene expression, and blunts cocaine's rewarding effects.

Conclusions: Our study unravels the dynamics and roles of cocaine-induced nuclear calcium signaling increases in D1R-MSN on molecular, cellular and behavioral adaptations to cocaine, and brings a significant breakthrough as it could contribute to the development of innovative strategies with therapeutic potential to alleviate addiction symptoms.

Background: Meal variety promotes overconsumption by delaying sensory-specific-satiety (SSS), the transient reduction in reward value of a recently consumed food. Despite its role in meal cessation, the neuroendocrine mechanisms underlying SSS are largely unknown.

Methods: Here, we developed a preclinical model of SSS wherein rats consume more of a different food compared to the same food presented again, leading to greater caloric intake. Using pharmacological and molecular approaches targeting the brainstem, we investigated the involvement of the satiation signal, glucagon-like peptide-1 (GLP-1), in mediating SSS in male rats (n=96) and in female rats (n=85) across their estrous cycle. We also evaluated the sufficiency of the hormone estradiol to modulate GLP-1 and SSS.

Results: In males, brainstem GLP-1 receptors (GLP-1Rs) were necessary for the SSS-induced decrease in same food intake, while agonizing brainstem GLP-1Rs was sufficient to attenuate overconsumption of the different food. Female rats showed SSS in an estrous cycle-dependent manner and did not consume more of the different food in diestrus-to-Proestrus and proestrus-to-Estrus. However, blockade of brainstem GLP-1R restored different food overconsumption. Furthermore, the brainstem's nucleus tractus solitarius and area postrema showed increased expression of the GLP-1 precursor, glucagon (Gcg), during diestrus-to-Proestrus and proestrus-to-Estrus, and greater Glp1r expression in proestrus-to-Estrus. Similarly, 17β-estradiol injections in males not only increased Glp1r and Gcg expression, but also reduced SSS.

Conclusion: We identified a bidirectional role for brainstem GLP-1R signaling in modulating SSS; effects that are estrous cycle-dependent. Moreover, our data indicate that estradiol regulates Glp1r and Gcg expression and likely influences SSS.

Background: Innovative treatments for paranoia, which significantly impairs social functioning in schizophrenia (SCZ), are urgently needed. The pathophysiology of paranoia implicates the amygdala-prefrontal (PFC) circuits; thus, this study systematically investigated whether transcranial direct current stimulation (tDCS) to the ventrolateral PFC can attenuate paranoia and improve social functioning in SCZ.

Methods: A double-blind, within-subjects, crossover design was used to compare active vs. sham tDCS effects in 50 participants with SCZ (ClinicalTrials.gov Identifier: NCT05746494). Participants completed two stimulation visits, each including two tDCS sessions about a week apart, with active (2mA for 20mins) and sham conditions counterbalanced across the two visits. Alongside lab-based measurements of state paranoia and its associated social cognitive biases, Ecological Momentary Assessment (EMA) was used. This involved daily evaluations of paranoia and social functioning, administered three times per day for seven days in each EMA period (EMA-baseline, EMA-active, EMA-sham).

Results: For lab-based assessments, participants showed greater reductions in state paranoia and improvements in paranoia-related social cognitive biases after active stimulation compared to sham, including lower self-reported hostility and hostile attributions in ambiguous situations post-active versus post-sham. Similarly, in the EMA-active period, participants had lower daily paranoia compared to the EMA-sham period and higher social interaction motivation with better attitudes compared to baseline and the EMA-sham period.

Conclusions: Extending our pilot study, the current findings further supported the efficacy of tDCS in SCZ patients in mitigating paranoia and enhancing social functioning. This work sheds light on the neuropathology of paranoia and identifies a promising avenue for future large-scale interventions.

Background: Certain cognitive processes require inhibition provided by the somatostatin (SST) class of gamma-aminobutyric acid (GABA) neurons in the dorsolateral prefrontal cortex (DLPFC). This inhibition onto pyramidal neuron dendrites depends on both SST and GABA signaling. Although SST mRNA levels are lower in the DLPFC in schizophrenia, it is not known if SST neurons exhibit alterations in the capacity to synthesize GABA, principally via the 67-kilodalton isoform of glutamic acid decarboxylase (GAD67).

Methods: GAD67 and SST mRNA levels were quantified in individual SST neurons using fluorescence in situ hybridization in DLPFC layers 2-superficial 3, where SST neurons are enriched, in schizophrenia (n=46) and unaffected comparison (n=46) individuals. Findings were compared to GAD67 and SST mRNA levels quantified by polymerase chain reaction and to final educational attainment, a proxy measure for cognitive functioning.

Results: GAD67 (F_1,84=13.1, p=0.0005, Cohen's d = -0.78) and SST (F_1,84=10.1, p=0.002, Cohen's d = -0.64) mRNA levels in SST neurons were lower in schizophrenia, with no group differences in the relative density of SST neurons (F_1,84=0.21, p=0.65). A presynaptic index of dendritic inhibition, derived by summing the alterations in GAD67 and SST mRNAs, was lower in 80.4% of individuals with schizophrenia and was associated with final educational attainment (adjusted odds ratio=1.44, p=0.022).

Conclusions: Deficits in both GAD67 and SST mRNAs within SST neurons indicate that these neurons have a markedly reduced ability to inhibit postsynaptic pyramidal neuron dendrites in schizophrenia. These alterations likely contribute to cognitive dysfunction in schizophrenia.

Background: Valid scalable biomarkers for predicting longitudinal clinical outcomes in psychiatric research are crucial for optimizing intervention and prevention efforts. Here we recorded spontaneous speech from initially abstinent individuals with cocaine use disorder (iCUD) for use in predicting drug use outcomes.

Methods: At baseline, 88 iCUD provided 5-minute speech samples describing the positive consequences of quitting drug use and negative consequences of using drugs. Outcomes, including withdrawal, craving, abstinence days, and recent cocaine use, were assessed at three-month intervals up to one year (57 iCUD included in analyses). Predictive modeling compared natural language processing (NLP) techniques, specifically sentence embeddings with established inventories as targets, with models utilizing standard demographic and baseline psychometric variables.

Results: At short time intervals, maximal predictive power was obtained with non-NLP models that also incorporated the same drug use measures (as the outcomes) obtained at baseline, potentially reflecting their slow rate of change, which could be estimated by linear functions. However, for longer-term predictions, speech samples alone demonstrated statistically significant results, with Spearman r ≥ 0.46 and 80% accuracy for predicting abstinence. Hence speech samples may capture non-linear dynamics over extended intervals more effectively than traditional measures. These results need to be replicated in larger and independent samples.

Conclusions: Compared to the common outcome measures used in clinical trials, speech-based measures could be leveraged as better predictors of longitudinal drug use outcomes in initially abstinent iCUD, as potentially generalizable to other subgroups with cocaine addiction, and to additional substance use disorders and related comorbidity.

Background: Bipolar disorder (BD) is a severe psychiatric condition with unclear etiology and no established biomarkers. Here, we aimed to characterize the cerebrospinal fluid (CSF) proteome in euthymic BD individuals to identify potential protein biomarkers.

Methods: We employed nano-flow liquid chromatography coupled to high-resolution mass spectrometry to quantify over 2,000 CSF proteins in 374 individuals from two independent clinical cohorts (n=164+89 and 66+55 cases and controls, respectively). A subset of the cases was followed longitudinally and reexamined after a median of 6.5 years.

Results: Differential abundance analysis revealed 41 proteins with robust case-control association in both cohorts. These included lower levels of synaptic proteins (e.g., APP, CLSTN1, NPTX2, NRXN1), axon guidance and cell adhesion molecules (e.g., NEO1, NCAM1, SEMA7A), higher levels of blood-brain-barrier integrity proteins (e.g., VTN, SERPIN3), and complement components (e.g., C1RL, C3, C5). The findings were consistently driven by the BD type 1 subtype. Comparing BD type 1 with controls increased discoverability, revealing 86 replicated associations despite a loss of statistical power. Moreover, longitudinal analyses of co-expression modules revealed dynamic changes in the CSF proteome composition that correlated with clinical outcomes, including disease severity, future manic episodes, and symptom improvement. Finally, we conducted association analyses of CSF proteins with genetic risk loci for bipolar disorder and schizophrenia.

Conclusions: This study represents the first large-scale untargeted profiling of the CSF proteome in BD, unveiling potential biomarkers and providing in vivo support for altered synaptic and brain connectivity processes, impaired neurovascular integrity, and complement activation in the pathology of BD.

Objective: Eating disorders (EDs) are serious psychiatric disorders with an estimated 3.3 million healthy life-years lost worldwide yearly. Understanding the course of illness, diagnostic transitions and remission, and their associated genetic correlates could inform both ED etiology and treatment. The authors investigated occurrences of ED transitions and presumed remission and their genetic correlates as captured by polygenic scores (PGSs) in a large Danish register-based cohort.

Methods: The sample was compromised of 10,565 individuals with a diagnosis of anorexia nervosa (AN), bulimia nervosa (BN), or eating disorder not otherwise specified (EDNOS) with at least two registered hospital contacts between 1995 and 2018. Based on medical records, occurrence of diagnostic transitions and periods of presumed remission were identified. Associations between 422 PGS and diagnostic transitions and presumed remission were evaluated using Cox proportional hazard models.

Results: A minority of ED cases (14.1%-23.1%) experienced a diagnostic transition. Presumed remission ranged between 86.9%-89.8%. Higher (one SD increase) PGS for major depressive disorder and multisite chronic pain were positively associated with transitioning from AN to either BN or EDNOS. Higher PGS on a measure of body fat percentage and financial difficulties were positively associated with presumed remission from AN. Higher PGS for mood swings was positively associated with presumed remission from EDNOS whereas higher PGS for health rating showed the opposite.

Conclusions: The authors found that most ED patients did not experience diagnostic transitions but were more likely to experience a period of presumed remission. Both diagnostic transitions and presumed remission have significant polygenic component.

Persisting symptoms and disability remain a problem for an appreciable proportion of people with schizophrenia despite treatment with antipsychotic medication. Improving outcomes requires an understanding of the nature and mechanisms of the pathological processes underlying persistence. Classical features of schizophrenia, which include disorganization and impoverishment of mental activity, are well-recognized early clinical features that predict poor long-term outcome. Substantial evidence indicates that these features reflect imprecise predictive coding. Predictive coding provides an overarching framework for understanding efficient functioning of the nervous system. Imprecise predictive coding also has the potential to precipitate acute psychosis characterized by reality distortion (delusions and hallucinations) at times of stress. On the other hand, substantial evidence indicates that persistent reality distortion itself gives rise to poor occupational and social function in the long term. Furthermore, abuse of psychotomimetic drugs, which exacerbate reality distortion, contributes to poor long-term outcome in schizophrenia. Neural circuits involved in modulating volitional acts are well understood to be implicated in addiction. Plastic changes in these circuits may account for the association between psychotomimetic drug abuse and poor outcomes in schizophrenia. We propose a mechanistic model according to which unbalanced inputs to the corpus striatum disturb the precision of subcortical modulation of cortical activity supporting volitional action. This model accounts for the evidence that early classical symptoms predict poor outcome, while in some circumstances, persistent reality distortion also predicts poor outcome. This model has implications for the development of novel treatments that address the risk of persisting symptoms and disabilities in schizophrenia.