Molecular pathways of major depressive disorder converge on the synapse

Molecular Psychiatry, Journal Year: 2022, Volume and Issue: 28(1), P. 284 - 297

Published: Oct. 6, 2022

Abstract Major depressive disorder (MDD) is a psychiatric disease of still poorly understood molecular etiology. Extensive studies at different levels point to high complexity numerous interrelated pathways as the underpinnings depression. systems under consideration include monoamines, stress, neurotrophins and neurogenesis, excitatory inhibitory neurotransmission, mitochondrial dysfunction, (epi)genetics, inflammation, opioid system, myelination, gut-brain axis, among others. This review aims illustrating how these multiple signaling may interact provide more comprehensive view MDD’s neurobiology. In particular, considering pattern synaptic activity closest physical representation mood, emotion, conscience we can conceptualize, each pathway or system will be scrutinized for links neurotransmission. Models neurobiology MDD discussed well future actions improve understanding treatment options.

Language: Английский

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Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics

Trends in Pharmacological Sciences, Journal Year: 2021, Volume and Issue: 42(11), P. 929 - 942

Published: Sept. 24, 2021

Language: Английский

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Microglial ERK-NRBP1-CREB-BDNF signaling in sustained antidepressant actions of (R)-ketamine

Molecular Psychiatry, Journal Year: 2021, Volume and Issue: 27(3), P. 1618 - 1629

Published: Nov. 24, 2021

Abstract ( R,S )-ketamine elicits rapid-acting and sustained antidepressant actions in treatment-resistant patients with depression. R produces longer-lasting effects than S rodents; however, the precise molecular mechanisms underlying of remain unknown. Using isobaric Tag for Relative Absolute Quantification, we identified nuclear receptor-binding protein 1 (NRBP1) that could contribute to different antidepressant-like two enantiomers chronic social defeat stress (CSDS) model. NRBP1 was localized microglia neuron, not astrocyte, mouse medial prefrontal cortex (mPFC). increased expression NRBP1, brain-derived neurotrophic factor (BDNF), phosphorylated cAMP response element binding (p-CREB)/CREB ratio primary cultures thorough extracellular signal-regulated kinase (ERK) activation. Furthermore, activate BDNF transcription through activation CREB as well MeCP2 (methyl-CpG 2) suppression microglia. Single intracerebroventricular (i.c.v.) injection CREB-DNA/RNA heteroduplex oligonucleotides (CREB-HDO) or exon IV-HDO blocked CSDS susceptible mice. Moreover, microglial depletion by colony-stimulating receptor (CSF1R) inhibitor PLX3397 In addition, inhibition single i.c.v. mannosylated clodronate liposomes (MCLs) significantly Finally, CREB-HDO, MCLs beneficial on reduced dendritic spine density mPFC These data suggest a novel ERK-NRBP1-CREB-BDNF pathways )-ketamine.

Language: Английский

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Sex hormone fluctuation and increased female risk for depression and anxiety disorders: From clinical evidence to molecular mechanisms

Frontiers in Neuroendocrinology, Journal Year: 2022, Volume and Issue: 66, P. 101010 - 101010

Published: June 15, 2022

Women are at twice the risk for anxiety and depression disorders as men are, although underlying biological factors mechanisms largely unknown. In this review, we address sex disparity both etiological mechanistic level. We dissect role of fluctuating hormones a critical factor contributing to increased in women. provide parallel evidence humans rodents that brain structure function vary with naturally-cycling ovarian hormones. This female-unique plasticity associated vulnerability primarily driven by estrogen level changes. For first time, hormone-driven molecular mechanism, namely chromatin organizational changes, regulates neuronal gene expression but may also prime (epi)genome psychopathology. Finally, map out future directions including experimental clinical studies will facilitate novel sex- gender-informed approaches treat disorders.

Language: Английский

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Psychedelics reopen the social reward learning critical period

Nature, Journal Year: 2023, Volume and Issue: 618(7966), P. 790 - 798

Published: June 14, 2023

Abstract Psychedelics are a broad class of drugs defined by their ability to induce an altered state consciousness 1,2 . These have been used for millennia in both spiritual and medicinal contexts, number recent clinical successes spurred renewed interest developing psychedelic therapies 3–9 Nevertheless, unifying mechanism that can account these shared phenomenological therapeutic properties remains unknown. Here we demonstrate mice the reopen social reward learning critical period is property across drugs. Notably, time course reopening proportional duration acute subjective effects reported humans. Furthermore, reinstate adulthood paralleled metaplastic restoration oxytocin-mediated long-term depression nucleus accumbens. Finally, identification differentially expressed genes ‘open state’ versus ‘closed provides evidence reorganization extracellular matrix common downstream underlying drug-mediated reopening. Together results important implications implementation psychedelics practice, as well design novel compounds treatment neuropsychiatric disease.

Language: Английский

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Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity

Biochemistry, Journal Year: 2022, Volume and Issue: 61(3), P. 127 - 136

Published: Jan. 21, 2022

In addition to producing profound subjective effects following acute administration, psychedelic compounds can induce beneficial behavioral changes relevant the treatment of neuropsychiatric disorders that last long after have been cleared from body. One hypothesis with potential explain remarkable enduring psychedelics is related their abilities promote structural and functional neuroplasticity in prefrontal cortex (PFC). A hallmark many stress-related diseases, including depression, post-traumatic stress disorder (PTSD), addiction, atrophy neurons PFC. Psychedelics appear be particularly effective catalysts for growth these key neurons, ultimately leading restoration synaptic connectivity this critical brain region. Furthermore, evidence suggests hallucinogenic are not directly linked ability neuroplasticity. If we develop improved alternatives treating must fully characterize molecular mechanisms give rise psychedelic-induced Here, I review our current understanding biochemical signaling pathways activated by neuroplasticity-promoting molecules, an emphasis on unanswered questions.

Language: Английский

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The role of BDNF in major depressive disorder, related clinical features, and antidepressant treatment: Insight from meta-analyses

Neuroscience & Biobehavioral Reviews, Journal Year: 2023, Volume and Issue: 149, P. 105159 - 105159

Published: April 4, 2023

The brain-derived neurotrophic factor (BDNF) has received considerable attention as a potential biomarker of major depressive disorder (MDD) and antidepressant response. We conducted an overview meta-analyses investigating the relationship BDNF with MDD, related clinical features, treatment. Based on systematic screening main electronic databases, 11 reviews were included. Available evidence suggests that people MDD have peripheral central levels lower than non-depressed individuals. A negative correlation between blood symptom severity emerged, while no association suicidality was detected. Moreover, increase in after treatment, proportional to improvement, reported. seem be increased both treatment responders remitters, remaining stable non-responders. Conversely, variations concentrations non-pharmacological interventions (electroconvulsive therapy, repetitive transcranial magnetic stimulation, physical activity) found. findings this appear consistent hypothesis depression, suggesting may play role pathophysiology pharmacological

Language: Английский

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5-HT2ARs Mediate Therapeutic Behavioral Effects of Psychedelic Tryptamines

ACS Chemical Neuroscience, Journal Year: 2023, Volume and Issue: 14(3), P. 351 - 358

Published: Jan. 11, 2023

Psychedelic compounds have displayed antidepressant potential in both humans and rodents. Despite their promise, psychedelics can induce undesired effects that pose safety concerns limit clinical scalability. The rational development of optimized psychedelic-related medicines will require a full mechanistic understanding how these molecules produce therapeutic effects. While the hallucinogenic properties are generally attributed to activation serotonin 2A receptors (5-HT2ARs), it is currently unclear if also mediate as several nonhallucinogenic analogues with antidepressant-like been developed. Moreover, many exhibit promiscuous pharmacology, making challenging identify primary target(s). Here, we use combination pharmacological genetic tools demonstrate 5-HT2A essential for tryptamine-based Our results suggest psychedelic tryptamines through same receptor.

Language: Английский

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BDNF Unveiled: Exploring Its Role in Major Depression Disorder Serotonergic Imbalance and Associated Stress Conditions

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(8), P. 2081 - 2081

Published: Aug. 3, 2023

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays significant role in the survival and development of neurons, being involved several diseases such as Alzheimer’s disease major depression disorder. The association between BDNF depressive disorder subject extensive research. Indeed, numerous studies indicate decreased levels are linked to an increased occurrence symptoms, neuronal loss, cortical atrophy. Moreover, it has been observed antidepressive therapy can help restore levels. In this review, we will focus on serotonergic imbalance associated stress conditions, particularly hypothalamic–pituitary–adrenal (HPA) axis dysregulation oxidative stress. All these features highly connected signaling pathways context disease, exploring topic aim advance our understanding disorder, improve diagnostic treatment approaches, potentially identify new therapeutic targets alleviate heavy burden society.

Language: Английский

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TrkB transmembrane domain: bridging structural understanding with therapeutic strategy

Trends in Biochemical Sciences, Journal Year: 2024, Volume and Issue: 49(5), P. 445 - 456

Published: March 2, 2024

TrkB (neuronal receptor tyrosine kinase-2, NTRK2) is the for brain-derived neurotrophic factor (BDNF) and a critical regulator of activity-dependent neuronal plasticity. The past few years have witnessed an increasing understanding structure function TrkB, including its transmembrane domain (TMD). interacts with membrane cholesterol, which bidirectionally regulates signaling. Additionally, has recently been recognized as binding target antidepressant drugs. A variety different antidepressants, typical rapid-acting well psychedelic compounds, act allosteric potentiators BDNF signaling through TrkB. This suggests that common compounds. Although more research needed, current knowledge promising further drug development.

Language: Английский

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