Biological Psychiatry最新文献

Stressful events are ubiquitous in everyday life. Exposure to these stressors initiates the temporally orchestrated release of a multitude of hormones, peptides, and neurotransmitters that target brain areas that have been critically implicated in learning and memory. This review summarizes recent insights on the profound impact of stress on 4 fundamental processes of memory: memory formation, memory contextualization, memory retrieval, and memory flexibility. Stress mediators instigate dynamic alterations in these processes, thereby facilitating efficient responding under stress and the creation of a decontextualized memory representation that can effectively aid coping with novel future threats. While they are generally adaptive, the same stress-related changes may contribute to the rigid behaviors, uncontrollable intrusions, and generalized fear responding seen in anxiety disorders and posttraumatic stress disorder. Drawing on recent discoveries in cognitive neuroscience and psychiatry, this review discusses how stress-induced alterations in memory processes can simultaneously foster adaptation to stressors and fuel psychopathology. The transition from adaptive to maladaptive changes in the impact of stress on memory hinges on the nuanced interplay of stressor characteristics and individual predispositions. Thus, taking individual differences in the cognitive response to stressors into account is essential for any successful treatment of stress-related mental disorders.

Exposure to stressful life events is associated with a high risk of developing psychiatric disorders with a wide variety of symptoms. Cognitive symptoms in stress-related psychiatric disorders can be particularly challenging to understand, both for those experiencing them and for health care providers. To gain insights, it is important to capture stress-induced structural, epigenomic, transcriptomic, and proteomic changes in relevant brain regions such as the amygdala, hippocampus, locus coeruleus, and prefrontal cortex that result in long-lasting alterations in brain function. In this review, we will emphasize a subset of stress molecular mechanisms that alter neuroplasticity, neurogenesis, and balance between excitatory and inhibitory neurons. Then, we discuss how to identify genetic risk factors that may accelerate stress-driven or stress-induced cognitive impairment. Despite the development of new technologies such as single-cell resolution sequencing, our understanding of the molecular effects of stress in the brain remains to be deepened. A better understanding of the diversity of stress effects in different brain regions and cell types is a prerequisite to open new avenues for mechanism-informed prevention and treatment of stress-related cognitive symptoms.

This brief review article will describe treatment approaches for posttraumatic stress disorder (PTSD) based on findings from basic research. The focus of this review will be fear conditioning and extinction models, which provide a translational model of PTSD that can help translate basic research in nonhuman animals through well-controlled trials confirming the efficacy of treatment approaches in humans with PTSD such as prolonged exposure therapy. Specific cognitive aspects of fear extinction processes, including consolidation and reconsolidation, are reviewed along with behavioral and pharmacological treatment strategies based on basic research in these areas including attempts to prevent the development of PTSD as well as the treatment of chronic PTSD. Pharmacological, behavioral, and device-based augmentation strategies of PTSD treatment based in basic science findings are reviewed, including those that disrupt noradrenergic receptor processes, medications that act on NMDA receptors, physical exercise, cannabinoids, estradiol, dexamethasone, yohimbine, losartan, dopamine, and MDMA, along with the evidence for their efficacy in human clinical samples. While fear extinction provides an exciting translational opportunity to improve PTSD based on basic science findings, we review limitations and challenges of the extant literature as well as future directions.

Most mental disorders involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), a recently evolved brain region that subserves working memory, abstraction, and the thoughtful regulation of attention, action, and emotion. For example, schizophrenia, depression, long COVID, and Alzheimer's disease are all associated with dlPFC dysfunction, with neuropathology often being focused in layer III. The dlPFC has extensive top-down projections, e.g., to the posterior association cortices to regulate attention and to the subgenual cingulate cortex via the rostral and medial PFC to regulate emotional responses. However, the dlPFC is particularly dependent on arousal state and is very vulnerable to stress and inflammation, which are etiological and/or exacerbating factors for most mental disorders. The cellular mechanisms by which stress and inflammation impact the dlPFC are a topic of current research and are summarized in this review. For example, the layer III dlPFC circuits that generate working memory-related neuronal firing have unusual neurotransmission, depending on NMDA receptor and nicotinic α7 receptor actions that are blocked under inflammatory conditions by kynurenic acid. These circuits also have unusual neuromodulation, with the molecular machinery to magnify calcium signaling in spines needed to support persistent firing, which must be tightly regulated to prevent toxic calcium actions. Stress rapidly weakens layer III connectivity by driving feedforward calcium-cAMP (cyclic adenosine monophosphate) opening of potassium channels on spines. This is regulated by postsynaptic noradrenergic α_2A adrenergic receptor and mGluR3 (metabotropic glutamate receptor 3) signaling but dysregulated by inflammation and/or chronic stress exposure, which contribute to spine loss. Treatments that strengthen the dlPFC via pharmacological (the α_2A adrenergic receptor agonist, guanfacine) or repetitive transcranial magnetic stimulation manipulation provide a rational basis for therapy.

Posttraumatic stress disorder (PTSD) is widely recognized as involving disruption of core neurocircuitry that underlies processing, regulation, and response to threat. In particular, the prefrontal cortex-hippocampal-amygdala circuit is a major contributor to posttraumatic dysfunction. However, the functioning of core threat neurocircuitry is partially dependent on sensorial inputs, and previous research has demonstrated that dense, reciprocal connections exist between threat circuits and the ventral visual stream. Furthermore, emergent evidence suggests that trauma exposure and resultant PTSD symptoms are associated with altered structure and function of the ventral visual stream. In the current review, we discuss evidence that both threat and visual circuitry together are an integral part of PTSD pathogenesis. An overview of the relevance of visual processing to PTSD is discussed in the context of both basic and translational research, highlighting the impact of stress on affective visual circuitry. This review further synthesizes emergent literature to suggest potential timing-dependent effects of traumatic stress on threat and visual circuits that may contribute to PTSD development. We conclude with recommendations for future research to move the field toward a more complete understanding of PTSD neurobiology.

Alzheimer's disease (AD) is a progressive, age-related neurodegenerative disorder to which genetic mutations and risk factors contribute. Evidence is increasing that environmental and lifestyle-related factors, such as exercise, nutrition, education, and exposure to (early-life) stress modify the onset, incidence, and progression of AD. Here, we discuss recent preclinical findings on putative substrates that can explain or contribute to the effects of stress early in life on the risk of developing AD. We focus in particular on stress hormones, neural networks, synapses, mitochondria, nutrient and lipid metabolism, adult neurogenesis, engram cell ensembles, and neuroinflammation. We discuss the idea that stress exposure early in life can alter these processes, either combined or in isolation, thereby reducing the capacity of the brain to resist deleterious consequences of, for example, amyloid-β accumulation, thereby accelerating cognitive decline and progression of Alzheimer-related changes in model systems of the disease. A better understanding of whether experiences early in life also modify trajectories of cognitive decline and pathology in AD and how the substrates discussed translate to humans may help develop novel preventive and/or therapeutic strategies to mitigate the consequences of stressors early in life and increase resilience to developing dementia.

Extinction of traumatic memory, a primary treatment approach (termed exposure therapy) in posttraumatic stress disorder (PTSD), occurs through relearning and may be subserved at the molecular level by long-term potentiation of relevant circuits. In parallel, repetitive transcranial magnetic stimulation (TMS) is thought to work through long-term potentiation-like mechanisms and may provide a novel, safe, and effective treatment for PTSD. In a recent failed randomized controlled trial we emphasized the necessity of correctly identifying cortical targets, the directionality of TMS protocols, and the role of memory activation. Here, we provide a systematic review of TMS for PTSD to further identify how, where, and when TMS treatment should be delivered to alleviate PTSD symptoms. We conducted a systematic review of the literature by searching for repetitive TMS clinical trials involving patients with PTSD and outcomes. We searched MEDLINE through October 25, 2023, for "TMS and PTSD" and "transcranial magnetic stimulation and posttraumatic stress disorder." Thirty-one publications met our inclusion criteria (k = 17 randomized controlled trials, k = 14 open label). Randomized controlled trial protocols were varied in terms of TMS protocols, cortical TMS targets, and memory activation protocols. There was no clear superiority of low-frequency (k = 5) versus high-frequency (k = 6) protocols or by stimulation location. Memory provocation or exposure protocols (k = 7) appear to enhance response. Overall, TMS appears to be effective in treating PTSD symptoms across a variety of TMS frequencies, hemispheric target differences, and exposure protocols. Disparate protocols may be conceptually harmonized when viewed as potentiating proposed anxiolytic networks or suppressing anxiogenic networks.

People exhibit an extraordinary capacity to adjust to stressful situations. Here, we argue that the acute stress response is a major driving force behind this adaptive process. In addition to immediately freeing energy reserves, facilitating a rapid and robust neurocognitive response, and helping to reinstate homeostasis, the stress response also critically regulates neuroplasticity. Therefore, understanding the healthy acute stress response is crucial for understanding stress resilience-the maintenance or rapid recovery of mental health during and after times of adversity. Contemporary resilience research differentiates between resilience factors and resilience mechanisms. Resilience factors refer to a broad array of social, psychological, or biological variables that are stable but potentially malleable and predict resilient outcomes. In contrast, resilience mechanisms refer to proximate mechanisms activated during acute stress that enable individuals to effectively navigate immediate challenges. In this article, we review literature related to how neurotransmitter and hormonal changes during acute stress regulate the activation of resilience mechanisms. We integrate literature on the timing-dependent and neuromodulator-specific regulation of neurocognition, episodic memory, and behavioral and motivational control, highlighting the distinct and often synergistic roles of catecholamines (dopamine and norepinephrine) and glucocorticoids. We conclude that stress resilience is bolstered by improved future predictions and the success-based reinforcement of effective coping strategies during acute stress. The resulting generalized memories of success, controllability, and safety constitute beneficial plasticity that lastingly improves self-control under stress. Insight into such mechanisms of resilience is critical for the development of novel interventions focused on prevention rather than treatment of stress-related disorders.

Background: Diverse antidepressants were recently described to bind to TrkB (tyrosine kinase B) and drive a positive allosteric modulation of endogenous BDNF (brain-derived neurotrophic factor). Although neurotrophins such as BDNF can bind to p75NTR (p75 neurotrophin receptor), their precursors are the high-affinity p75NTR ligands. While part of an unrelated receptor family capable of inducing completely opposite physiological changes, TrkB and p75NTR feature a crosslike conformation dimer and carry a cholesterol-recognition amino acid consensus in the transmembrane domain. As such qualities were found to be crucial for antidepressants to bind to TrkB and drive behavioral and neuroplasticity effects, we hypothesized that their effects might also depend on p75NTR.

Methods: Enzyme-linked immunosorbent assay-based binding and nuclear magnetic resonance spectroscopy were performed to assess whether antidepressants would bind to p75NTR. HEK293T cells and a variety of in vitro assays were used to investigate whether fluoxetine (FLX) or ketamine (KET) would trigger any α- and γ-secretase-dependent p75NTR proteolysis and lead to p75NTR nuclear localization. Ocular dominance shift was performed with male and female p75NTR knockout mice to study the effects of KET and FLX on brain plasticity, in addition to pharmacological interventions to verify how p75NTR signaling is important for the effects of KET and FLX in enhancing extinction memory in male wild-type mice and rats.

Results: Antidepressants were found to bind to p75NTR. FLX and KET triggered the p75NTR proteolytic pathway and induced p75NTR-dependent behavioral/neuroplasticity changes.

Conclusions: We hypothesize that antidepressants co-opt both BDNF/TrkB and proBDNF/p75NTR systems to induce a more efficient activity-dependent synaptic competition, thereby boosting the brain's ability for remodeling.

Background: Bipolar disorder (BD), a severe neuropsychiatric condition, often appears during adolescence. Traditional diagnostic methods, which primarily rely on clinical interviews and single-modal magnetic resonance imaging (MRI) techniques, may have limitations in accuracy. This study aimed to improve adolescent BD diagnosis by integrating behavioral assessments with multimodal MRI. We hypothesized that this combination would enhance diagnostic accuracy for at-risk adolescents.

Methods: A retrospective cohort of 309 participants, including patients with BD, offspring of patients with BD (with and without subthreshold symptoms), non-BD offspring with subthreshold symptoms, and healthy control participants, was analyzed. Behavioral attributes were integrated with MRI features from T1-weighted, resting-state functional MRI, and diffusion tensor imaging. Three diagnostic models were developed using GLMNET multinomial regression: a clinical diagnosis model based on behavioral attributes, an MRI-based model, and a comprehensive model integrating both datasets.

Results: The comprehensive model achieved a prediction accuracy of 0.83 (95% CI, 0.72-0.92), significantly higher than the clinical (0.75) and MRI-based (0.65) models. Validation with an external cohort showed high accuracy (0.89, area under the curve = 0.95). Structural equation modeling revealed that clinical diagnosis (β = 0.487, p < .0001), parental BD history (β = -0.380, p < .0001), and global function (β = 0.578, p < .0001) significantly affected brain health, while psychiatric symptoms showed only a marginal influence (β = -0.112, p = .056).

Conclusions: This study highlights the value of integrating multimodal MRI with behavioral assessments for early diagnosis in at-risk adolescents. Combining neuroimaging enables more accurate patient subgroup distinctions, facilitating timely interventions and improving health outcomes. Our findings suggest a paradigm shift in BD diagnostics, advocating for incorporating advanced imaging techniques in routine evaluations.