Circulating myeloid-derived MMP8 in stress susceptibility and depression

Nature, Journal Year: 2024, Volume and Issue: 626(8001), P. 1108 - 1115

Published: Feb. 7, 2024

Abstract Psychosocial stress has profound effects on the body, including immune system and brain 1,2 . Although a large number of pre-clinical clinical studies have linked peripheral alterations to stress-related disorders such as major depressive disorder (MDD) 3 , underlying mechanisms are not well understood. Here we show that expression circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in serum humans with MDD stress-susceptible mice following chronic social defeat (CSDS). In mice, this increase leads extracellular space neurophysiological changes nucleus accumbens (NAc), altered behaviour. Using combination mass cytometry single-cell RNA sequencing, performed high-dimensional phenotyping cells circulation demonstrate monocytes strongly affected by stress. both traffic showed Mmp8 We further MMP8 directly infiltrates NAc parenchyma controls ultrastructure space. Depleting prevented stress-induced avoidance behaviour neurophysiology Collectively, these data establish mechanism which factors can affect central nervous function context Targeting specific cell-derived metalloproteinases could constitute novel therapeutic targets for neuropsychiatric disorders.

Language: Английский

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Neurocognitive effects of stress: a metaparadigm perspective

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(7), P. 2750 - 2763

Published: Feb. 9, 2023

Abstract Stressful experiences, both physical and psychological, that are overwhelming (i.e., inescapable unpredictable), can measurably affect subsequent neuronal properties cognitive functioning of the hippocampus. At cellular level, stress has been shown to alter hippocampal synaptic plasticity, spike local field potential activity, dendritic morphology, neurogenesis, neurodegeneration. behavioral found impair learning memory for declarative (or explicit) tasks based on cognition, such as verbal recall in humans spatial rodents, while facilitating those emotion, differential fear conditioning contextual rodents. These vertically related alterations hippocampus, procedurally observed after subjects have undergone stress, generally believed be mediated by recurrently elevated circulating hypothalamic-pituitary-adrenal (HPA) axis effector hormones, glucocorticoids, directly acting neurons densely populated with corticosteroid receptors. The main purposes this review (i) provide a synopsis neurocognitive effects historical context led contemporary HPA dogma basic translational research, (ii) critically reappraise necessity sufficiency glucocorticoid hypothesis (iii) suggest an alternative metaparadigm approach monitor manipulate progression at neural coding level. Real-time analyses reveal activity markers hippocampus used extrapolate across range paradigms resolve scaling dichotomous issues) understand individual differences, thereby providing novel neurophysiological scaffold advancing future research.

Language: Английский

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Psychoneuroimmunology: An Introduction to Immune-to-Brain Communication and Its Implications for Clinical Psychology

Annual Review of Clinical Psychology, Journal Year: 2023, Volume and Issue: 19(1), P. 331 - 359

Published: Feb. 15, 2023

Research conducted over the past several decades has revolutionized our understanding of role immune system in neural and psychological development function across life span. Our goal this review is to introduce dynamic area research a audience highlight its relevance for clinical psychology. We begin by introducing basic physiology immune-to-brain signaling neuroimmune network, focusing on inflammation. Drawing from preclinical research, we then examine effects activation key domains, including positive negative valence systems, social processes, cognition, arousal (fatigue, sleep), as well links with disorders (depression, posttraumatic stress disorder, anxiety, schizophrenia). also consider psychosocial critical modulator activity focus early adversity. Finally, mind–body interventions that influence may promote resilience.

Language: Английский

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Neurobiology and systems biology of stress resilience

Physiological Reviews, Journal Year: 2024, Volume and Issue: 104(3), P. 1205 - 1263

Published: March 14, 2024

Stress resilience is the phenomenon that some people maintain their mental health despite exposure to adversity or show only temporary impairments followed by quick recovery. Resilience research attempts unravel factors and mechanisms make possible harness its insights for development of preventative interventions in individuals at risk acquiring stress-related dysfunctions. Biological has been lagging behind psychological social sciences but seen a massive surge recent years. At same time, progress this field hampered methodological challenges related finding suitable operationalizations study designs, replicating findings, modeling animals. We embed review behavioral, neuroimaging, neurobiological, systems biological findings adults critical methods discussion. find preliminary evidence hippocampus-based pattern separation prefrontal-based cognitive control functions protect against pathological fears aftermath singular, event-type stressors [as found fear-related disorders, including simpler forms posttraumatic stress disorder (PTSD)] facilitating perception safety. Reward system-based pursuit savoring positive reinforcers appear more generalized dysfunctions anxious-depressive spectrum resulting from severe longer-lasting (as depression, comorbid anxiety, PTSD). Links between preserved functioning these neural under neuroplasticity, immunoregulation, gut microbiome composition, integrity barrier blood-brain are beginning emerge. On basis, avenues pointed out.

Language: Английский

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The neuroimmune connectome in health and disease

Nature, Journal Year: 2025, Volume and Issue: 638(8050), P. 333 - 342

Published: Feb. 12, 2025

Language: Английский

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Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging

The EMBO Journal, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 4, 2024

Abstract Mitophagy neutralizes mitochondrial damage, thereby preventing cellular dysfunction and apoptosis. Defects in mitophagy have been strongly implicated age-related neurodegenerative disorders such as Parkinson’s Alzheimer’s disease. While decreases throughout the lifespan of short-lived model organisms, it remains unknown whether a decline occurs aging mammalian brain—a question fundamental importance for understanding cell type- region-specific susceptibility to neurodegeneration. Here, we define longitudinal dynamics basal macroautophagy across neuronal non-neuronal types within intact mouse brain vivo. Quantitative profiling reporter cohorts from young geriatric ages reveals cell- tissue-specific alterations between distinct subregions populations, including dopaminergic neurons, cerebellar Purkinje cells, astrocytes, microglia interneurons. We also find that healthy is hallmarked by dynamic accumulation differentially acidified lysosomes several neural subsets. Our findings argue against any widespread mitophagic activity, instead demonstrating fluctuations trajectory, with strong implications ongoing theragnostic development.

Language: Английский

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Psychedelic control of neuroimmune interactions governing fear

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: April 23, 2025

Language: Английский

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Reversal of hyperactive higher-order thalamus attenuates defensiveness in a mouse model of PTSD

Science Advances, Journal Year: 2023, Volume and Issue: 9(5)

Published: Feb. 3, 2023

Posttraumatic stress disorder (PTSD) is a highly prevalent and debilitating psychiatric disease often accompanied by severe defensive behaviors, preventing individuals from integrating into society. However, the neural mechanisms of defensiveness in PTSD remain largely unknown. Here, we identified that higher-order thalamus, posteromedial complex thalamus (PoM), was overactivated mouse model PTSD, suppressing PoM activity alleviated excessive behaviors. Moreover, found diminished thalamic inhibition derived reticular nucleus major cause hyperactivity mice. Overloaded innervation to downstream cortical area, frontal association cortex, drove abnormal defensiveness. Overall, our study revealed malfunction mediates behaviors highlighted thalamocortical circuit as potential target for treating PTSD-related overreactivity symptoms.

Language: Английский

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The missing hallmark of health: psychosocial adaptation

Cell Stress, Journal Year: 2024, Volume and Issue: 8, P. 21 - 50

Published: Jan. 1, 2024

The eight biological hallmarks of health that we initially postulated (Cell. 2021 Jan 7;184(1):33-63) include features spatial compartmentalization (integrity barriers, containment local perturbations), maintenance homeostasis over time (recycling & turnover, integration circuitries, rhythmic oscillations) and an array adequate responses to stress (homeostatic resilience, hormetic regulation, repair regeneration). These affect all somatic strata the human body (molecules, organelles, cells, supracellular units, organs, organ systems, systemic circuitries meta-organism). Here postulate mental socioeconomic factors must be added this 8×8 matrix as additional hallmark (“psychosocial adaptation”) stratum interactions”), hence building a 9×9 matrix. Potentially, perturbation each affects psychosocial vice versa. Finally, discuss (patho)physiological bases these interactions their implications for improvement.

Language: Английский

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Adolescent neurodevelopment and psychopathology: The interplay between adversity exposure and genetic risk for accelerated brain ageing

Developmental Cognitive Neuroscience, Journal Year: 2023, Volume and Issue: 60, P. 101229 - 101229

Published: March 15, 2023

In adulthood, stress exposure and genetic risk heighten psychological vulnerability by accelerating neurobiological senescence. To investigate whether molecular brain network maturation processes play a similar role in adolescence, we analysed genetic, as well longitudinal task neuroimaging (inhibitory control, incentive processing) early life adversity (i.e., material deprivation, violence) data from the Adolescent Brain Cognitive Development study (N = 980, age range: 9–13 years). Genetic was estimated separately for Major Depressive Disorder (MDD) Alzheimer's Disease (AD), two pathologies linked to allegedly sharing causal connection (MDD-to-AD). Adversity MDD/AD jointly predicted functional segregation patterns suggestive of accelerated (GABA-linked) visual/attentional, but delayed (dopamine [D2]/glutamate [GLU5R]-linked) somatomotor/association system development. A positive relationship between psychopathology emerged only among less vulnerable adolescents, thereby implying that normatively maladaptive neurodevelopmental alterations could foster adjustment more exposed genetically susceptible youths. Transcriptomic analyses suggested sensitivity may underpin joint effect MDD/AD, line with proposed negative emotionality precursor AD, likely account alleged impact MDD on dementia onset.

Language: Английский

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