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1.
Mol Psychiatry ; 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34799691

RESUMO

Child abuse (CA) is a strong predictor of psychopathologies and suicide, altering normal trajectories of brain development in areas closely linked to emotional responses such as the prefrontal cortex (PFC). Yet, the cellular underpinnings of these enduring effects are unclear. Childhood and adolescence are marked by the protracted formation of perineuronal nets (PNNs), which orchestrate the closure of developmental windows of cortical plasticity by regulating the functional integration of parvalbumin interneurons into neuronal circuits. Using well-characterized post-mortem brain samples, we show that a history of CA is specifically associated with increased densities and morphological complexity of WFL-labeled PNNs in the ventromedial PFC (BA11/12), possibly suggesting increased recruitment and maturation of PNNs. Through single-nucleus sequencing and fluorescent in situ hybridization, we found that the expression of canonical components of PNNs is enriched in oligodendrocyte progenitor cells (OPCs), and that they are upregulated in CA victims. These correlational findings suggest that early-life adversity may lead to persistent patterns of maladaptive behaviors by reducing the neuroplasticity of cortical circuits through the enhancement of developmental OPC-mediated PNN formation.

2.
Cells ; 10(5)2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33919292

RESUMO

Many studies evaluated the functional role of adult hippocampal neurogenesis (AHN) and its key role in cognitive functions and mood regulation. The effects of promoting AHN on the recovery of stress-induced symptoms have been well studied, but its involvement in stress resilience remains elusive. We used a mouse model enabling us to foster AHN before the exposure to unpredictable chronic mild stress (UCMS) to evaluate the potential protective effects of AHN on stress, assessing the depressive-like phenotype and executive functions. For this purpose, an inducible transgenic mouse model was used to delete the pro-apoptotic gene Bax from neural progenitors four weeks before UCMS, whereby increasing the survival of adult-generated neurons. Our results showed that UCMS elicited a depressive-like phenotype, highlighted by a deteriorated coat state, a higher immobility duration in the tail suspension test (TST), and a delayed reversal learning in a water maze procedure. Promoting AHN before UCMS was sufficient to prevent the development of stressed-induced behavioral changes in the TST and the water maze, reflecting an effect of AHN on stress resilience. Taken together, our data suggest that increasing AHN promotes stress resilience on some depressive-like symptoms but also in cognitive symptoms, which are often observed in MD.


Assuntos
Depressão , Hipocampo , Neurogênese , Estresse Psicológico , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Transgênicos
3.
Brain Behav Immun ; 94: 159-174, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33609652

RESUMO

BACKGROUND: Several lines of evidence suggest that neuroinflammation might be a key neurobiological mechanism of depression. In particular, the P2X7 receptor (P2X7R), an ATP-gated ion channel involved in activation of the pro-inflammatory interleukin IL-1ß, has been shown to be a potential new pharmacological target in depression. The aim of this study was to explore the impact of unpredictable chronic mild stress (UCMS) on behavioural changes, hippocampal neurogenesis, and cellular characterisation of brain immune cells, in P2X7R Knock-Out (KO) mice. METHODS: P2X7R KO and wild-type (WT) mice were subjected to a 6-week UCMS protocol and received a conventional oral antidepressant (15 mg.kg-1 fluoxetine) or water per os. The mice then underwent behavioural tests consisting of the tail suspension test (TST), the elevated plus maze (EPM) test, the open field test, the splash test and the nest building test (week 7). Doublecortin immunostaining (DCX) of brain slices was used to assess neurogenesis in the dentate gyrus. Iba1 and TMEM119 immunostaining was used to characterise brain immune cells, Iba1 as a macrophage marker (including microglial cells) and TMEM119 as a potential specific resident microglial cells marker. RESULTS: After a 6-week UCMS exposure, P2X7R KO mice exhibited less deterioration of their coat state, spent a significantly smaller amount of time immobile in the TST and spent a larger amount of time in the open arms of the EPM. As expected, adult ventral hippocampal neurogenesis was significantly decreased by UCMS in WT mice, while P2X7R KO mice maintained ventral hippocampal neurogenesis at similar levels in both control and UCMS conditions. In stress-related brain regions, P2X7R KO mice also exhibited less recruitment of Iba1+/TMEM119+ and Iba1+/TMEM119- cells in the brain. The ratio between these two staining patterns revealed that brain immune cells were mostly composed of Iba1+/TMEM119+ cells (87 to 99%), and this ratio was affected neither by P2X7R genetic depletion nor by antidepressant treatment. DISCUSSION: Behavioural patterns, neurogenesis levels and density of brain immune cells in P2X7R KO mice after exposure to UCMS significantly differed from control conditions. Brain immune cells were mostly increased in brain regions known to be sensitive to UCMS exposure in WT but not in P2X7R KO mice. Considering Iba1+/TMEM119- staining might characterize peripheral immune cells, the ratio between Iba1+/TMEM119+ cells and IBA1+/TMEM119- cells, suggests that the rate of peripheral immune cells recruitment may not be modified neither by P2X7R gene expression nor by antidepressant treatment.


Assuntos
Depressão , Estresse Psicológico , Animais , Antidepressivos , Modelos Animais de Doenças , Hipocampo , Camundongos , Camundongos Knockout , Receptores Purinérgicos P2X7/genética
4.
Pharmacol Res ; 163: 105215, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33007421

RESUMO

Cholesterol homeostasis is a highly regulated process in human body because of its several functions underlying the biology of cell membranes, the synthesis of all steroid hormones and bile acids and the need of trafficking lipids destined to cell metabolism. In particular, it has been recognized that peripheral and central nervous system cholesterol metabolism are separated by the blood brain barrier and are regulated independently; indeed, peripherally, it depends on the balance between dietary intake and hepatic synthesis on one hand and its degradation on the other, whereas in central nervous system it is synthetized de novo to ensure brain physiology. In view of this complex metabolism and its relevant functions in mammalian, impaired levels of cholesterol can induce severe cellular dysfunction leading to metabolic, cardiovascular and neurodegenerative diseases. The aim of this review is to clarify the role of cholesterol homeostasis in health and disease highlighting new intriguing aspects of the cross talk between its central and peripheral metabolism.

5.
Brain Imaging Behav ; 15(3): 1499-1507, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32761564

RESUMO

Brain changes associated with the personality trait of neuroticism have been partly elucidated. While subcortical brain volume changes, especially a larger amygdala, appear consistent in high neuroticism, functional changes, such as cerebral blood flow (CBF) differences, have shown conflicting results, possibly because of the limitations in methods of CBF measurement. In our study, we investigated changes in amygdala volume and CBF-related function associated with neuroticism in healthy and depressed subjects using both conventional magnetic resonance imaging (MRI) measures of brain volume and the innovative technique of ultrasound Tissue Pulsatility Imaging (TPI), which has a high level of detection in measuring brain tissue pulsatility (BTP). Middle-aged females with depression (n = 25) and without depression (n = 25) underwent clinical examination, magnetic resonance imaging (MRI) and ultrasound assessment (TPI). Neuroticism was positively associated with left amygdala volume and mean BTP in individuals without depression, in both simple and multiple regressions that included potential confounding factors such as age and body mass index. No association was found in the depressed group. We confirmed the role of the left amygdala in the brain physiology of neuroticism in nondepressed individuals. Moreover, we identified a novel mechanism associated with high neuroticism, namely BTP, that may reflect greater CBF and account for the increased risk of cerebrovascular disease in individuals with high neuroticism. Because neuroticism is considered a risk factor for depression, our paper provides potential objective biomarkers for the identification of subjects at risk for depression.


Assuntos
Encéfalo , Imageamento por Ressonância Magnética , Tonsila do Cerebelo/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Circulação Cerebrovascular , Feminino , Humanos , Pessoa de Meia-Idade , Neuroticismo
6.
Eur J Neurosci ; 53(1): 151-171, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32150310

RESUMO

Some recent clinical and preclinical evidence suggests that neuroinflammation is a key factor that interacts with the three neurobiological correlates of major depressive disorder: depletion of brain serotonin, dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis and alteration of the continuous production of adult-generated neurons in the dentate gyrus of the hippocampus. This review discusses the main players in brain immunity as well as how inflammation interacts with the above three mechanisms. It is reported that kynurenine (KYN) pathway alteration in favour of its excitotoxic component and HPA axis dysregulation have the common effect of increasing extracellular glutamate levels and glutamate neurotransmission, which can impact hippocampal neurogenesis. This pathophysiological cascade appears to be triggered or sustained and reinforced by any chronic inflammatory condition involving increased circulating markers of inflammation that are able to cross the blood-brain barrier and activate microglia; it can also be the consequence of primary brain neuroinflammation, such as in neurodegenerative disorders with early manifestations that are frequently depressive symptoms. Further recent data indicate that primary microglial activation may also result from a direct impact of chronic stress on vascular function. The intricated dynamic crosstalk between neuroinflammation and other relevant neurobiological correlates of depression add to evidence that neuroinflammation may be a key therapeutic target for future therapeutic strategies in major depressive disorder.


Assuntos
Transtorno Depressivo Maior , Sistema Hipotálamo-Hipofisário , Depressão , Hipocampo , Humanos , Neurogênese , Sistema Hipófise-Suprarrenal
7.
Psychoneuroendocrinology ; 124: 105097, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33302237

RESUMO

Major depressive disorder is a common debilitating mental health problem that represents one of the leading causes of disability. Up to date, the therapeutic targets and approaches are still limited. Adult hippocampal neurogenesis (AHN) has been proposed as a critical contributor to the pathophysiology and treatment of depression, altering the hippocampal control over stress response at network, neuroendocrine and behavioral levels. These findings together have suggested that manipulating AHN may be a promising therapeutic strategy for depression. To investigate this question, we assessed whether increasing adult neurogenesis would be sufficient to produce antidepressant-like effects at behavioral and neuroendocrine levels in a mouse model of depression; the unpredictable chronic mild stress (UCMS). For this purpose, we used a bi-transgenic mouse line (iBax) in which AHN increase was induced by deletion of the pro-apoptotic gene Bax from the neural progenitors following the tamoxifen-dependent action of CreERT2 recombinases. UCMS induced a syndrome that is reminiscent of depression-like states, including anhedonia (cookie test), physical changes (coat deterioration, reduced weight gain), anxiety-like behaviors (higher latency in the novelty-supressed feeding -NSF- test), passive stress-coping behaviors (immobility in the forced swim test -FST-) and a blunted hypothalamo-pituitary-adrenal (HPA) axis reactivity to acute stress in addition to AHN decrease. Tamoxifen injection reversed the AHN decrease as well as partly counteracted UCMS effects on the cookie test and HPA axis but not for the coat state, weight gain, NSF test and FST. Taken together, our results suggest that a strategy directing at increasing AHN may be able to alleviate some depression-related behavioral and neuroendocrine dimensions of UCMS, such as anhedonia and HPA axis reactivity deficits, but may be hardly sufficient to produce a complete recovery.

8.
Mol Psychiatry ; 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33219358

RESUMO

Major depressive disorder (MDD) is a complex and debilitating illness whose etiology remains unclear. Small RNA molecules, such as micro RNAs (miRNAs) have been implicated in MDD, where they display differential expression in the brain and the periphery. In this study, we quantified miRNA expression by small RNA sequencing in the anterior cingulate cortex and habenula of individuals with MDD and psychiatrically-healthy controls. Thirty-two miRNAs showed significantly correlated expression between the two regions (False Discovery Rate < 0.05), of which four, miR-204-5p, miR-320b, miR-323a-3p, and miR-331-3p, displayed upregulated expression in MDD. We assessed the expression of predicted target genes of differentially expressed miRNAs in the brain, and found that the expression of erb-b2 receptor tyrosine kinase 4 (ERBB4), a gene encoding a neuregulin receptor, was downregulated in both regions, and was influenced by miR-323a-3p in vitro. Finally, we assessed the effects of manipulating miRNA expression in the mouse ACC on anxiety- and depressive-like behaviors. Mice in which miR-323-3p was overexpressed or knocked-down displayed increased and decreased emotionality, respectively. Additionally, these mice displayed significantly downregulated and upregulated expression of Erbb4, respectively. Overall, our findings indicate the importance of brain miRNAs in the pathology of MDD, and emphasize the involvement of miR-323a-3p and ERBB4 in this phenotype. Future studies further characterizing miR-323a-3p and neuregulin signaling in depression are warranted.

9.
Curr Opin Pharmacol ; 50: R1, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32800111

RESUMO

This article has been withdrawn: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been withdrawn at the request of the editor and publisher. The publisher regrets that an error occurred which led to the premature publication of this paper. This error bears no reflection on the article or its authors. The publisher apologizes to the authors and the readers for this unfortunate error.

10.
Artigo em Inglês | MEDLINE | ID: mdl-32169563

RESUMO

BACKGROUND: Increasing evidence suggests that ultrasound (US) imaging may provide biomarkers and therapeutic options in mental disorders. We systematically reviewed the literature to provide a global overview of the possibilities of US for psychiatry. METHODS: Original English language articles published between January 2000 and September 2019 were identified through databases searching and analyzed to summarize existing evidence according to PRISMA methodology. RESULTS: A total of 81 articles were included. Various US techniques and markers have been used in mental disorders, including Transcranial Doppler and Intima-Media Thickness. Most of the studies have focused on characterizing the pathophysiology of mental disorders, especially vascular physiology. Studies on therapeutic applications are still scarce. DISCUSSION: US imaging has proved to be useful in characterizing vascular impairment and structural and functional brain changes in mental disorders. Preliminary findings also suggest potential interests for therapeutic applications. Growing evidence suggests that US imaging could provide a non-invasive, portable and low-cost tool for pathophysiological characterization, prognostic assessment and therapeutic applications in mental disorders.


Assuntos
Encéfalo/diagnóstico por imagem , Transtornos Mentais/diagnóstico por imagem , Transtornos Mentais/terapia , Ultrassonografia Doppler Transcraniana/métodos , Estudos Transversais , Humanos , Estudos Longitudinais , Transtornos Mentais/psicologia
11.
Neurosci Biobehav Rev ; 111: 199-228, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32001274

RESUMO

Sadness is typically characterized by raised inner eyebrows, lowered corners of the mouth, reduced walking speed, and slumped posture. Ancient subcortical circuitry provides a neuroanatomical foundation, extending from dorsal periaqueductal grey to subgenual anterior cingulate, the latter of which is now a treatment target in disorders of sadness. Electrophysiological studies further emphasize a role for reduced left relative to right frontal asymmetry in sadness, underpinning interest in the transcranial stimulation of left dorsolateral prefrontal cortex as an antidepressant target. Neuroimaging studies - including meta-analyses - indicate that sadness is associated with reduced cortical activation, which may contribute to reduced parasympathetic inhibitory control over medullary cardioacceleratory circuits. Reduced cardiac control may - in part - contribute to epidemiological reports of reduced life expectancy in affective disorders, effects equivalent to heavy smoking. We suggest that the field may be moving toward a theoretical consensus, in which different models relating to basic emotion theory and psychological constructionism may be considered as complementary, working at different levels of the phylogenetic hierarchy.


Assuntos
Sistema Nervoso Autônomo , Córtex Cerebral , Epigênese Genética/fisiologia , Interocepção , Transtornos do Humor , Rede Nervosa , Neurociências , Teoria Psicológica , Tristeza/fisiologia , Sistema Nervoso Autônomo/metabolismo , Sistema Nervoso Autônomo/fisiopatologia , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Humanos , Interocepção/fisiologia , Transtornos do Humor/genética , Transtornos do Humor/metabolismo , Transtornos do Humor/fisiopatologia , Rede Nervosa/metabolismo , Rede Nervosa/fisiopatologia
12.
Curr Opin Pharmacol ; 50: 88-95, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32007727

RESUMO

The hippocampus is particularly involved in cognitive processes and is a key regulator of stress responses and emotions. Therefore, the role of adult-born neurons in this region has become a crucial field of research in order to understand mood and stress disorders, such as major depression. Many studies have characterized the role of these neurons in cognition, mood regulation and antidepressant actions. Nevertheless, the precise mechanisms underpinning these antidepressant effects remain unclear. In this review, we first discuss the effects of stress and antidepressant treatments on adult-born neurons, and subsequently, the role and mechanisms of neurogenesis in antidepressant action. Some studies have shown that adult-born neurons could affect overall hippocampal activity, thus normalizing the latter which could restore neuronal pathways underlying antidepressant effects.


Assuntos
Depressão/fisiopatologia , Hipocampo/fisiologia , Neurogênese , Animais , Humanos , Estresse Psicológico
13.
Pharmacol Ther ; 210: 107515, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32109488

RESUMO

The neurogenic hypothesis of depression states that adult hippocampal neurogenesis is disrupted by stress and depression and is recovered by chronic treatments with antidepressants. Indeed, chronic antidepressant treatments increased newborn neurons in the adult dentate gyrus in many early studies. However, conflicting findings appeared over time. Thus, our motivation to write this unbiased systematic review and meta-analysis was to answer the following question: can antidepressants reliably promote neurogenesis in adult hippocampus? A meta-analysis was performed on studies in naive rodents. Results indicated that increased neurogenesis is a more nuanced, compound-dependent action of antidepressants than a yes-or-no event. This nuanced notion can lead to a new understanding of the concepts of neurogenic-dependent and neurogenic-independent effects of antidepressants, which would be better described as effects "more-dependent" or "less-dependent" on hippocampal neurogenesis. Further studies are on the way to investigate the strength of the causal relationship between adult hippocampal neurogenesis and behavioural effects of antidepressants.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Fatores Etários , Animais , Depressão/fisiopatologia , Depressão/psicologia , Modelos Animais de Doenças , Hipocampo/fisiopatologia , Camundongos , Ratos
14.
Int J Psychophysiol ; 150: 29-36, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31987868

RESUMO

INTRODUCTION: Recent evidence suggests that biomechanical parameters of the brain, such as Brain Tissue Pulsatility (BTP), could be involved in emotional reactivity. However, no study has investigated the impact of an emotional task on BTP. We used the ultrasound method of Tissue Pulsatility Imaging (TPI) to assess changes in BTP to exciting and relaxing classical music, in a musical perception task, as a validated paradigm to assess emotional reactivity. METHODS: 25 healthy volunteers were exposed via earphones to four 5-minute musical excerpts (two exciting and two relaxing musical excerpts) presented in a randomized order and intersected by 5 silence periods. Measures of BTP, Heart Rate (HR) and Skin Conductance (SC) were collected during the entire task. RESULTS: The BTP significantly decreased with relaxing music compared to silence, and especially with the excerpt 'Entrance of the Shades' by Minkus. The HR and SC, but not Heart Rate Variability, were also decreased with relaxing music. We found no significant effect of exciting music. DISCUSSION: We report, for the first time, that classical relaxing music decreases the amplitude of the brain pulsatile movements related to cerebral blood flow and mechanical properties of the brain parenchyma, which provides further evidence of the involvement of BTP in emotional reactivity. In addition, we validate the use of TPI as a non-invasive, portable and low cost tool for studies in psychophysiology, with the potential to be implemented as a biomarker in musicotherapy trials notably.


Assuntos
Encéfalo/fisiologia , Ecoencefalografia/métodos , Emoções/fisiologia , Neuroimagem Funcional/métodos , Música/psicologia , Relaxamento/fisiologia , Adolescente , Adulto , Circulação Cerebrovascular/fisiologia , Feminino , Resposta Galvânica da Pele/fisiologia , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição Aleatória , Adulto Jovem
15.
Curr Opin Pharmacol ; 50: 17-24, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31785488

RESUMO

The Publisher regrets that this article is an accidental duplication of an article that has already been published in Current Opinion in Pharmacology, 50 (2020), 88-95, https://doi.org/10.1016/j.coph.2019.11.009. The duplicate article has therefore been withdrawn.

16.
J Neural Transm (Vienna) ; 126(11): 1383-1408, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31584111

RESUMO

Major depression is a leading contributor to the global burden of disease. This situation is mainly related to the chronicity and/or recurrence of the disorder, and to poor response to antidepressant therapy. Progress in this area requires valid animal models. Current models are based either on manipulating the environment to which rodents are exposed (during the developmental period or adulthood) or biological underpinnings (i.e. gene deletion or overexpression of candidate genes, targeted lesions of brain areas, optogenetic control of specific neuronal populations, etc.). These manipulations can alter specific behavioural and biological outcomes that can be related to different symptomatic and pathophysiological dimensions of major depression. However, animal models of major depression display substantial shortcomings that contribute to the lack of innovative pharmacological approaches in recent decades and which hamper our capabilities to investigate treatment-resistant depression. Here, we discuss the validity of these models, review putative models of treatment-resistant depression, major depression subtypes and recurrent depression. Furthermore, we identify future challenges regarding new paradigms such as those proposing dimensional rather than categorical approaches to depression.


Assuntos
Comportamento Animal , Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Modelos Animais de Doenças , Animais
17.
Neurobiol Aging ; 84: 61-69, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31514054

RESUMO

It remains unclear whether benzodiazepines (BZDs) constitute a risk factor for Alzheimer's disease (AD). In this study, we investigated associations between chronic use of BZDs and brain amyloid load, a hallmark of AD, in 268 nondemented older individuals. F18-florbetapir positron emission tomography scans were performed to assess amyloid load as measured by standardized uptake value ratios, which were compared between chronic BZD users and nonusers using adjusted multiple linear regressions. Short- versus long-acting BZDs were also considered in the analyses. Standardized uptake value ratios were significantly lower in BZD users (n = 47) than in nonusers (n = 221), independent of multiple adjustments. The effect was stronger for short-acting BZDs than for long-acting BZDs. This is the first large clinical study showing a reduced brain amyloid load in chronic BZD users, especially with short-acting BZDs. Our results do not support the view of BZD use as a risk factor for AD and instead support the involvement of pharmacological mechanisms related to neuronal hyperactivity, neuroinflammation, and sleep quality as potential targets for blocking amyloid accumulation.


Assuntos
Doença de Alzheimer/prevenção & controle , Proteínas Amiloidogênicas/metabolismo , Benzodiazepinas/administração & dosagem , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Doença de Alzheimer/metabolismo , Estudos de Coortes , Humanos , Tomografia por Emissão de Pósitrons
18.
Neurobiol Stress ; 10: 100161, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31309134

RESUMO

Exposure to prolonged, unpredictable stress leads to glucocorticoids-mediated long-lasting neuroendocrine abnormalities associated with emotional and cognitive impairments. Excessive levels of serum glucocorticoids (cortisol in humans, corticosterone in rodents) contribute notably to deficits in working memory (WM), a task which heavily relies on functional interactions between the medial prefrontal cortex (PFC) and the dorsal hippocampus (dHPC). However, it is unknown whether stress-induced increases in plasma corticosterone mirror corticosterone levels in specific brain regions critical for WM. After a 6 week-UCMS exposure, C57BL/6 J male mice exhibited increased anxiety- and depressive-like behaviors when measured one week later and displayed WM impairments timely associated with increased plasma corticosterone response. In chronically stressed mice, basal phosphorylated/activated CREB (pCREB) was markedly increased in the PFC and the CA1 area of the dHPC and WM testing did not elicit any further increase in pCREB in the two regions. Using microdialysis samples from freely-moving mice, we found that WM testing co-occurred with a rapid and sustained increase in corticosterone response in the PFC while there was a late, non-significant rise of corticosterone in the dHPC. The results also show that non-stressed mice injected with corticosterone (2 mg/kg i.p.) before WM testing displayed behavioral and molecular alterations similar to those observed in stressed animals while a pre-WM testing metyrapone injection (35 mg/kg i.p.), a corticosterone synthesis inhibitor, prevented the effects of UCMS exposure. Overall, the abnormal regional increase of corticosterone concentrations mainly in the PFC emerges as a key factor of enduring WM dysfunctions in UCMS-treated animals.

19.
Brain Stimul ; 12(1): 87-95, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30228049

RESUMO

BACKGROUND: Post-traumatic stress disorder (PTSD) is a severe mental illness correlated with alterations in fear extinction neurocircuits that involve prefrontal, amygdala and hippocampal structures. Current treatments indirectly restore prefrontal control of fear responses, but still cannot achieve full remission in all patients. OBJECTIVE/HYPOTHESIS: Repetitive TMS (rTMS) can directly and chronically act on subparts of the prefrontal cortex (PFC) as a potential alternative treatment. However, preclinical studies are needed to further the comprehension of its mechanisms and thus enhance its efficacy. METHODS: A 40-mm coil is used on a stereotaxic frame to apply 12-Hz high-intensity rTMS of the ventromedial PFC (vmPFC) in a foot-shock mouse model of PTSD. Chronic rTMS treatment was applied 7 days after the shocks every day up to day 12 (5 sessions, 3750 pulses). RESULTS: One session of rTMS (750 pulses) was able to precisely evoke immediate c-Fos activity in an area of the vmPFC (0.5 mm2) in preliminary control mice. When used in the foot-shock model, chronic rTMS treatment (n = 19) counteracted short-term episodic memory deficits at day 18, and enhanced extinction dynamics when reexposed to the shocking chamber at day 22. Associated c-Fos activity was found increased in the rodent's vmPFC (infralimbic cortex), the basolateral amygdala and the ventral CA1 (hippocampal output). CONCLUSIONS: This study is the first to use prefrontal cortex rTMS in a mouse model of PTSD. Chronic rTMS of the vmPFC reversed stress-induced behavioral impairments and acted on distributed networks of fear extinction up to 10 days after treatment.


Assuntos
Modelos Animais de Doenças , Medo/fisiologia , Córtex Pré-Frontal/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Estimulação Transcraniana por Corrente Contínua/métodos , Animais , Medo/psicologia , Masculino , Camundongos , Transtornos de Estresse Pós-Traumáticos/psicologia , Transtornos de Estresse Pós-Traumáticos/terapia
20.
Psychoneuroendocrinology ; 97: 120-130, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30015007

RESUMO

A polymorphism in the P2RX7 gene that encodes for the P2X7 ionotropic ATP-gated receptor (P2X7R) protein has been shown to be associated with an increased risk for developing depressive illnesses. However, the role of P2X7R in depression is still unclear. To better understand the role of P2X7R and its subsequent impact on microglial activation, we compared the effect of the P2X7R antagonist Brilliant Blue G (BBG) with that of fluoxetine in an unpredictable chronic mild stress (UCMS) model of depression in mice. Our results indicate that BBG (50 mg/kg body weight in 0.9% NaCl, 10 ml/kg/day) successfully reversed the degradation of coat states and nest-building scores induced by exposure to UCMS, similar to the conventional antidepressant fluoxetine (15 mg/kg body weight in 0.9% NaCl, 10 ml/kg/day). BBG also reversed the UCMS-induced microglial activation in cortical and hippocampal regions and the basal nuclei of mouse brains and corrected the UCMS-induced hypothalamo-pituitary-adrenal (HPA) axis dysregulation. In contrast to fluoxetine, however, BBG treatment did not increase the density of doublecortin-positive cells in the dentate gyrus, indicating that BBG had no impact on hippocampal neurogenesis. These results suggest that P2X7R is involved in recovery from depressive-like states caused by exposure to UCMS in a mechanism that involves restoration of the HPA axis but not hippocampal neurogenesis. These results add to the evidence that P2X7R antagonist agents may have potential value in the pharmacological management of depression.


Assuntos
Depressão/metabolismo , Antagonistas do Receptor Purinérgico P2X/farmacologia , Corantes de Rosanilina/farmacologia , Animais , Antidepressivos , Comportamento Animal/efeitos dos fármacos , Doença Crônica , Giro Denteado/efeitos dos fármacos , Transtorno Depressivo , Modelos Animais de Doenças , Fluoxetina , Hipocampo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microglia/efeitos dos fármacos , Neurogênese , Sistemas Neurossecretores/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2X/metabolismo , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Estresse Psicológico
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