RESUMO
Severe mental illnesses (SMI) collectively affect approximately 20% of the global population, as estimated by the World Health Organization (WHO). Despite having diverse etiologies, clinical symptoms, and pharmacotherapies, these diseases share a common pathophysiological characteristic: the misconnection of brain areas involved in reality perception, executive control, and cognition, including the corticolimbic system. Dendritic spines play a crucial role in excitatory neurotransmission within the central nervous system. These small structures exhibit remarkable plasticity, regulated by factors such as neurotransmitter tone, neurotrophic factors, and innate immunity-related molecules, and other mechanisms - all of which are associated with the pathophysiology of SMI. However, studying dendritic spine mechanisms in both healthy and pathological conditions in patients is fraught with technical limitations. This is where animal models related to these diseases become indispensable. They have played a pivotal role in elucidating the significance of dendritic spines in SMI. In this review, the information regarding the potential role of dendritic spines in SMI was summarized, drawing from clinical and animal model reports. Also, the implications of targeting dendritic spine-related molecules for SMI treatment were explored. Specifically, our focus is on major depressive disorder and the neurodevelopmental disorders schizophrenia and autism spectrum disorder. Abundant clinical and basic research has studied the functional and structural plasticity of dendritic spines in these diseases, along with potential pharmacological targets that modulate the dynamics of these structures. These targets may be associated with the clinical efficacy of the pharmacotherapy.
Assuntos
Transtorno do Espectro Autista , Transtorno Depressivo Maior , Animais , Humanos , Espinhas Dendríticas/patologia , Transtorno do Espectro Autista/patologia , Transtorno Depressivo Maior/patologia , Encéfalo/patologia , Transmissão Sináptica , Plasticidade Neuronal/fisiologia , Sinapses/patologiaRESUMO
BACKGROUND: Decreased affective flexibility is associated with depression symptoms, and it has been suggested that common interventions may target this mechanism. To explore this hypothesis, we evaluated whether real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) training to increase the amygdala responses during positive memory recall resulted in both symptom improvements, as has been observed previously, and flexibility to decrease amygdala reactivity in response to a cognitive task among patients with major depressive disorder (MDD). METHODS: In a double-blind, placebo-controlled, randomized clinical trial, adults with MDD received 2 sessions of rtfMRI-nf training to increase their amygdala (experimental group) or parietal (control group) responses during positive autobiographical memory recall. We evaluated signal changes in the amygdala during both the positive memory neurofeedback and a subsequent counting condition. RESULTS: We included 38 adults with MDD, including 16 in the experimental group and 22 in the control group. In the experimental group, amygdala activity increased (t > 2.01, df < 27, p < 0.05, d > 0.5) and depressive symptoms decreased (-8.57, 95 % confidence interval [CI] -15.12 to -2.59; t 13 = -3.06, p = 0.009, d = 1). Amygdala activity during the count condition decreased after rtfMRI-nf (-0.16, 95 % CI -0.23 to -0.09; t 396 = 4.73, p < 0.001, d = 0.48) and was correlated with decreased depression scores (r = 0.46, p = 0.01). We replicated previous results and extended them to show decreased amygdala reactivity to a cognitive task during which no neurofeedback was provided. LIMITATIONS: The count condition was reported by participants as negative, but emotionality or accuracy during this condition was not assessed. CONCLUSION: These results suggest that nominally targeting unidimensional change in neural mechanisms could have implications for bidirectional control, increasing the likely reach and explanatory framework for how common depression interventions work.Trial registration: ClinicalTrials.gov NCT02709161.
Assuntos
Transtorno Depressivo Maior , Memória Episódica , Adulto , Humanos , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/terapia , Transtorno Depressivo Maior/patologia , Regulação para Cima , Depressão , Imageamento por Ressonância Magnética/métodos , Processamento de Imagem Assistida por Computador/métodos , Tonsila do CerebeloRESUMO
Growing evidence has associated major depressive disorder (MDD) as a risk factor or prodromal syndrome for the occurrence of Alzheimer's disease (AD). Although this dilemma remains open, it is widely shown that a lifetime history of MDD is correlated with faster progression of AD pathology. Therefore, antidepressant drugs with neuroprotective effects could be an interesting therapeutic conception to target this issue simultaneously. In this sense, 1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4- carboxamide (QTC-4-MeOBnE) was initially conceived as a multi-target ligand with affinity to ß-secretase (BACE), glycogen synthase kinase 3ß (GSK3ß), and acetylcholinesterase but has also shown secondary effects on pathways involved in neuroinflammation and neurogenesis in preclinical models of AD. Herein, we investigated the effect of QTC-4-MeOBnE (1 mg/kg) administration for 45 days on depressive-like behavior and memory impairment in 3xTg mice, before the pathology is completely established. The treatment with QTC-4-MeOBnE prevented memory impairment and depressive-like behavior assessed by the Y-Maze task and forced swimming test. This effect was associated with the modulation of plural pathways involved in the onset and progression of AD, in cerebral structures of the cortex and hippocampus. Among them, the reduction of amyloid beta (Aß) production mediated by changes in amyloid precursor protein metabolism and hippocampal tau phosphorylation through the inhibition of kinases. Additionally, QTC-4-MeOBnE also exerted beneficial effects on neuroinflammation and synaptic integrity. Overall, our studies suggest that QTC-4-MeOBnE has a moderate effect in a transgenic model of AD, indicating that perhaps studies regarding the neuropsychiatric effects as a neuroprotective molecule are more prone to be feasible.
Assuntos
Doença de Alzheimer , Transtorno Depressivo Maior , Camundongos , Animais , Peptídeos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Camundongos Transgênicos , Transtorno Depressivo Maior/patologia , Doenças Neuroinflamatórias , Acetilcolinesterase/metabolismo , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Triazóis/farmacologia , Transtornos da Memória/complicações , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Hipocampo/metabolismo , Modelos Animais de Doenças , Precursor de Proteína beta-Amiloide/metabolismoRESUMO
It is possible to consider the stimulation of the cingulate gyrus in its portion below the corpus callosum (SCC, or subcallosal cingulate cortex) as an effective, promising, and safe alternative intervention for treatment-resistant depression. In studies with deep brain stimulation - DBS, when follow-on with functional magnetic resonance imaging and/or PET-CT (Positron emission tomography-computed tomography) is performed, it is observed an increase in the blood supply and glucose metabolism in this region, which is the anterior part of the limbic system. This same location has good experimental results also for the treatment of anorexia nervosa. The hypotheses suggest a greater activation of the reward system, a greater sense of well-being, and a consequent reduction in depressive symptoms, the objective of the treatment. Over the last 20 years, multicenter studies have shown symptomatic improvement in 50-60% of patients, and about a third even reach criteria for remission of the depressive disorder.
Assuntos
Estimulação Encefálica Profunda , Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Estimulação Encefálica Profunda/métodos , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/patologia , Transtorno Depressivo Maior/terapia , Transtorno Depressivo Resistente a Tratamento/diagnóstico por imagem , Transtorno Depressivo Resistente a Tratamento/patologia , Transtorno Depressivo Resistente a Tratamento/terapia , Giro do Cíngulo/fisiologia , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia ComputadorizadaRESUMO
Many studies have suggested that imbalance of the gut microbial composition leads to an increase in pro-inflammatory cytokines and promotes oxidative stress, and this are directly associated with neuropsychiatric disorders, including major depressive disorder (MDD). Clinical data indicated that the probiotics have positive impacts on the central nervous system and thus may have a key role to treatment of MDD. This study examined the benefits of administration of Komagataella pastoris KM71H (8 log UFC·g-1/animal, intragastric route) in attenuating behavioral, neurochemical, and neuroendocrine changes in animal models of depressive-like behavior induced by repeated restraint stress and lipopolysaccharide (0.83 mg/kg). We demonstrated that pretreatment of mice with this yeast prevented depression-like behavior induced by stress and an inflammatory challenge in mice. We believe that this effect is due to modulation of the permeability of the blood-brain barrier, restoration in the mRNA levels of the Nuclear factor kappa B, Interleukin 1ß, Interferon γ, and Indoleamine 2 3-dioxygenase, and prevention of oxidative stress in the prefrontal cortices, hippocampi, and intestine of mice and of the decrease the plasma corticosterone levels. Thus, we conclude that K. pastoris KM71H has properties for a new proposal of probiotic with antidepressant-like effect, arising as a promising therapeutic strategy for MDD.
Assuntos
Antidepressivos/uso terapêutico , Depressão/terapia , Transtorno Depressivo Maior/terapia , Probióticos/uso terapêutico , Saccharomycetales , Estresse Psicológico/terapia , Animais , Antidepressivos/farmacologia , Comportamento Animal , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Corticosterona/sangue , Depressão/metabolismo , Depressão/patologia , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/patologia , Modelos Animais de Doenças , Expressão Gênica , Intestino Delgado/anatomia & histologia , Intestino Delgado/metabolismo , Lipopolissacarídeos , Masculino , Camundongos , Estresse Oxidativo , Probióticos/farmacologia , Baço/patologia , Estresse Psicológico/metabolismo , Estresse Psicológico/patologiaRESUMO
The endocannabinoid 2-arachidonoylglycerol (2-AG) is an atypical neurotransmitter synthesized on demand in response to a wide range of stimuli, including exposure to stress. Through the activation of cannabinoid receptors, 2-AG can interfere with excitatory and inhibitory neurotransmission in different brain regions and modulate behavioural, endocrine and emotional components of the stress response. Exposure to chronic or intense unpredictable stress predisposes to maladaptive behaviour and is one of the main risk factors involved in developing mood disorders, such as major depressive disorder (MDD). In this review, we describe the molecular mechanisms involved in 2-AG signalling in the brain of healthy and stressed animals and discuss how such mechanisms could modulate stress adaptation and susceptibility to depression. Furthermore, we review preclinical evidence indicating that the pharmacological modulation of 2-AG signalling stands as a potential new therapeutic target in treating MDD. Particular emphasis is given to the pharmacological augmentation of 2-AG levels by monoacylglycerol lipase (MAGL) inhibitors and the modulation of CB2 receptors.
Assuntos
Antidepressivos/farmacologia , Ácidos Araquidônicos/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Animais , Antidepressivos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/patologia , Transtorno Depressivo Maior/psicologia , Modelos Animais de Doenças , Humanos , Monoacilglicerol Lipases/antagonistas & inibidores , Monoacilglicerol Lipases/metabolismo , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/metabolismo , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Transmissão Sináptica/efeitos dos fármacosRESUMO
BACKGROUND: Mood disorders are the most frequent psychiatric disorders in patients with temporal lobe epilepsy caused by hippocampal sclerosis (TLE-HS). The pathophysiological mechanisms in common between TLE and mood disorders include abnormalities in the serotonergic pathway. We aimed to evaluate the association between serotonin transporter genetic polymorphisms - 5-HTTLPR and 5-HTTVNTR - and the presence of mood disorders in patients with TLE-HS. METHODS: We evaluated 119 patients with TLE-HS, with and without psychiatric disorder; 146 patients diagnosed with major depressive disorder (MDD), and 113 healthy volunteers. Individuals were genotyped for the 5-HTTLPR and 5-HTTVNTR polymorphisms. RESULTS: No difference was observed between the TLE-HS groups, healthy controls, and MDD without epilepsy. There was a correlation between the 12-allele of the 5-HTTVNTR and the family history of patients with epilepsy with TLE-HS (pâ¯=â¯0.013). CONCLUSIONS: In this study conducted in two Brazilian centers, the serotonin transporter polymorphisms evaluated cannot be associated with depressive disorder in patients with TLE-HS. Still, they do have some influence over some clinical characteristics of epilepsy in TLE-HS. These data may not be reproduced in other populations with distinct ethnic characteristics.
Assuntos
Transtorno Depressivo Maior , Epilepsia do Lobo Temporal , Brasil , Depressão , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/patologia , Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/genética , Epilepsia do Lobo Temporal/patologia , Hipocampo/patologia , Humanos , Polimorfismo Genético/genética , Esclerose/genética , Esclerose/patologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/genéticaRESUMO
A role for microglia in neuropsychiatric diseases, including major depressive disorder (MDD), has been postulated. Regulation of microglial phenotype by immune receptors has become a central topic in many neurological conditions. We explored preclinical and clinical evidence for the role of the CD300f immune receptor in the fine regulation of microglial phenotype and its contribution to MDD. We found that a prevalent nonsynonymous single-nucleotide polymorphism (C/T, rs2034310) of the human CD300f receptor cytoplasmic tail inhibits the protein kinase C phosphorylation of a threonine and is associated with protection against MDD, mainly in women. Interestingly, CD300f-/- mice displayed several characteristic MDD traits such as augmented microglial numbers, increased interleukin 6 and interleukin 1 receptor antagonist messenger RNA, alterations in synaptic strength, and noradrenaline-dependent and persistent depressive-like and anhedonic behaviors in females. This behavioral phenotype could be potentiated inducing the lipopolysaccharide depression model. RNA sequencing and biochemical studies revealed an association with impaired microglial metabolic fitness. In conclusion, we report a clear association that links the function of the CD300f immune receptor with MDD in humans, depressive-like and anhedonic behaviors in female mice, and altered microglial metabolic reprogramming.
Assuntos
Anedonia , Transtorno Depressivo Maior/patologia , Inflamação/etiologia , Microglia/patologia , Polimorfismo de Nucleotídeo Único , Receptores Imunológicos/genética , Receptores Imunológicos/fisiologia , Animais , Comportamento Animal , Estudos de Coortes , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/psicologia , Feminino , Perfilação da Expressão Gênica , Humanos , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , SinapsesRESUMO
Despite the strong genetic component of psychiatric disorders, traditional genetic studies have failed to find individual genes of large effect size. Thus, alternative methods, using bioinformatics, have been proposed to solve these biological puzzles. Of these, here we employ systems biology-based approaches to identify potential master regulators (MRs) of bipolar disorder (BD), schizophrenia (SZ), and major depressive disorder (MDD), their association with biological processes and their capacity to differentiate disorders' phenotypes. High-throughput gene expression data was used to reconstruct standard human dorsolateral prefrontal cortex regulatory transcriptional network, which was then queried for regulatory units and MRs associated with the psychiatric disorders of interest. Furthermore, the activity status (active or repressed) of MR candidates was obtained and used in cluster analysis to characterize disease phenotypes. Finally, we explored the biological processes modulated by the MRs using functional enrichment analysis. Thirty-one, thirty-four, and fifteen MR candidates were identified in BD, SZ, and MDD, respectively. The activity state of these MRs grouped the illnesses in three clusters: MDD only, mostly BD, and a third one with BD and SZ. While BD and SZ share several biological processes related to ion transport and homeostasis, synapse, and immune function, SZ showed peculiar enrichment of processes related to cytoskeleton and neuronal structure. Meanwhile, MDD presented mostly processes related to glial development and fatty acid metabolism. Our findings suggest notable differences in functional enrichment between MDD and BD/SZ. Furthermore, similarities between BD and SZ may impose particular challenges in attempts to discriminate these pathologies based solely on their transcriptional profiles. Nevertheless, we believe that systems-oriented approaches are promising strategies to unravel the pathophysiology peculiarities underlying mental illnesses and reveal therapeutic targets.
Assuntos
Transtorno Bipolar/genética , Transtorno Depressivo Maior/genética , Redes Reguladoras de Genes/genética , Córtex Pré-Frontal/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Transtorno Depressivo Maior/patologia , Humanos , Esquizofrenia/genéticaRESUMO
Major depressive disorder (MDD) is a prevalent psychiatric disorder associated with varied prognosis, chronic course, and duration of illness with reduced quality of life. One factor that significantly contributes to the relevant disease burden of MDD is the heterogeneous treatment response patients experience with current treatment options. A variety of experimental protocols in humans and animals have highlighted that inflammation and neuroinflammation are relevant biological factors that interact with external stimuli and neurophysiological mechanisms, and can trigger MDD. It is well established that exercise is efficacious in treating mild to moderate depression with response rates comparable to mainstream therapies such as antidepressant medication and cognitive behavioral therapy. Several studies have shown that physical exercise is beneficial for a range of chronic diseases. Indeed, physical exercise can promote molecular changes that swerve a chronic pro-inflammatory state to an anti-inflammatory state in both periphery and central nervous system. The changes caused by physical exercise include an increase in PGC1α gene expression, a transcriptional co-activator involved in reducing the synthesis and releasing of pro-inflammatory cytokines, and an increase in anti-inflammatory cytokines. PGC1α changes the metabolism of kynurenine towards, and, in turn, it reduces glutamatergic neurotoxicity. Moreover, some studies have shown that physical exercise promotes alterations in the circuitry of monoaminergic neurotransmission, at least in some aspects, through the effects on the release of proinflammatory cytokines. This review will highlight the effects of physical exercise as therapy and its relation with the biological mechanisms involved in the pathophysiology of MDD, with particular emphasis in the interactions among physical exercise, hypothalamic-pituitary-adrenal (HPA) axis, neuroinflammation, and with the neurotransmitters underlying the main brain circuits involved in the MDD.