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1.
Mol Psychiatry ; 27(6): 2787-2802, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35365810

RESUMO

The long lapse between the presumptive origin of schizophrenia (SCZ) during early development and its diagnosis in late adolescence has hindered the study of crucial neurodevelopmental processes directly in living patients. Dopamine, a neurotransmitter consistently associated with the pathophysiology of SCZ, participates in several aspects of brain development including pruning of neuronal extensions. Excessive pruning is considered the cause of the most consistent finding in SCZ, namely decreased brain volume. It is therefore possible that patients with SCZ carry an increased susceptibility to dopamine's pruning effects and that this susceptibility would be more obvious in the early stages of neuronal development when dopamine pruning effects appear to be more prominent. Obtaining developing neurons from living patients is not feasible. Instead, we used Monocyte-Derived-Neuronal-like Cells (MDNCs) as these cells can be generated in only 20 days and deliver reproducible results. In this study, we expanded the number of individuals in whom we tested the reproducibility of MDNCs. We also deepened the characterization of MDNCs by comparing its neurostructure to that of human developing neurons. Moreover, we studied MDNCs from 12 controls and 13 patients with SCZ. Patients' cells differentiate more efficiently, extend longer secondary neurites and grow more primary neurites. In addition, MDNCs from medicated patients expresses less D1R and prune more primary neurites when exposed to dopamine. Haloperidol did not influence our results but the role of other antipsychotics was not examined and thus, needs to be considered as a confounder.


Assuntos
Esquizofrenia , Adolescente , Dopamina/uso terapêutico , Humanos , Monócitos , Neurônios , Reprodutibilidade dos Testes
2.
Int J Neuropsychopharmacol ; 24(6): 519-531, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-33631001

RESUMO

BACKGROUND: Memantine, a noncompetitive N-methyl-D-aspartate receptor antagonist, has been approved for use in Alzheimer's disease, but an increasing number of studies have investigated its utility for neuropsychiatric disorders. Here, we characterized a novel compound, fluoroethylnormemtantine (FENM), which was derived from memantine with an extra Fluor in an optimized position for in vivo biomarker labeling. We sought to determine if FENM produced similar behavioral effects as memantine and/or if FENM has beneficial effects against fear, avoidance, and behavioral despair. METHODS: We administered saline, FENM, or memantine prior to a number of behavioral assays, including paired-pulse inhibition, open field, light dark test, forced swim test, and cued fear conditioning in male Wistar rats. RESULTS: Unlike memantine, FENM did not produce nonspecific side effects and did not alter sensorimotor gating or locomotion. FENM decreased immobility in the forced swim test. Moreover, FENM robustly facilitated fear extinction learning when administered prior to either cued fear conditioning training or tone reexposure. CONCLUSIONS: These results suggest that FENM is a promising, novel compound that robustly reduces fear behavior and may be useful for further preclinical testing.


Assuntos
Comportamento Animal/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Memantina/análogos & derivados , Memantina/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Masculino , Ratos Wistar
3.
J Neurosci ; 39(19): 3640-3650, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-30804096

RESUMO

Exposure to chronic stress leads to an array of anatomical, functional, and metabolic changes in the brain that play a key role in triggering psychiatric disorders such as depression. The hippocampus is particularly well known as a target of maladaptive responses to stress. To capture stress-induced changes in metabolic and functional connectivity in the hippocampus, stress-resistant (low-responders) or -susceptible (high-responders) rats exposed to a chronic unpredictable stress paradigm (categorized according to their hormonal and behavioral responses) were assessed by multimodal neuroimaging; the latter was achieved by using localized 1H MR spectroscopy and resting-state functional MRI (fMRI) at 11,7T data from stressed (n = 25) but also control (n = 15) male Wistar rats.Susceptible animals displayed increased GABA-glutamine (+19%) and glutamate-glutamine (+17%) ratios and decreased levels of macromolecules (-11%); these changes were positively correlated with plasma corticosterone levels. In addition, the neurotransmitter levels showed differential associations with functional connectivity between the hippocampus and the amygdala, the piriform cortex and thalamus between stress-resistant and -susceptible animals. Our observations are consistent with previously reported stress-induced metabolomic changes that suggest overall neurotransmitter dysfunction in the hippocampus. Their association with the fMRI data in this study reveals how local adjustments in neurochemistry relate to changes in the neurocircuitry of the hippocampus, with implications for its stress-associated dysfunctions.SIGNIFICANCE STATEMENT Chronic stress disrupts brain homeostasis, which may increase the vulnerability of susceptible individuals to neuropsychiatric disorders such as depression. Characterization of the differences between stress-resistant and -susceptible individuals on the basis of noninvasive imaging tools, such as magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI), contributes to improved understanding of the mechanisms underpinning individual differences in vulnerability and can facilitate the design of new diagnostic and intervention strategies. Using a combined functional MRI/MRS approach, our results demonstrate that susceptible- and non-susceptible subjects show differential alterations in hippocampal GABA and glutamate metabolism that, in turn, associate with changes in functional connectivity.


Assuntos
Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Estresse Psicológico/diagnóstico por imagem , Estresse Psicológico/metabolismo , Animais , Doença Crônica , Modelos Animais de Doenças , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Descanso , Estresse Psicológico/psicologia
4.
Cancer Invest ; 38(10): 572-598, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32866046

RESUMO

The review states that antidepressants (ADs) increase brain-derived neurotrophic factor (BDNF) transmission concomitantly in the brain and the blood: ADs increasing BDNF synthesis in specific areas of the central nervous system (CNS) could presumably affect megakaryocyte's production of platelets. ADs increase BDNF levels in the CNS and improve mood. In the blood, ADs increase BDNF release from platelets. The hypothesis presented here is that the release of BDNF from platelets contributes to the ADs effects on neurogenesis and on tumor growth in the cancer disease. Oncological studies indicate that chemicals ADs exert an aggravating effect on the cancer disease, possibly by promoting proplatelets formation and enhancing BDNF release from platelets in the tumor.


Assuntos
Antidepressivos/administração & dosagem , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/tratamento farmacológico , Neoplasias/patologia , Neoplasias/prevenção & controle , Antidepressivos/efeitos adversos , Depressão/etiologia , Depressão/metabolismo , Humanos , Neoplasias/complicações , Neoplasias/metabolismo , Prognóstico
5.
Neurobiol Learn Mem ; 137: 163-170, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27916533

RESUMO

Noradrenaline (NA), released by the locus coeruleus (LC), plays a key role in mediating the effects of stress on memory functions. The LC provides diffuse projections to many forebrain nuclei including the hippocampus, the prefrontal cortex (PFC), and the basolateral amygdala (BLA). These three structures are intricately interlinked. The hippocampal-prefrontal (H-PFC) pathway is involved in various cognitive functions. The first aim of this study was to examine the role of BLA in H-PFC plasticity by infusion of drugs to activate and inactivate the BLA and studying the effects on H-PFC long-term potentiation (LTP) in the rat in vivo. Activation of the BLA with glutamate impaired, while inactivation with muscimol augmented, H-PFC LTP. This study also aimed to demonstrate how directly applying noradrenaline and other noradrenergic agents in the BLA can affect H-PFC LTP. Noradrenaline at 1µg/0.2µl enhanced H-PFC LTP. Stimulating alpha-2-adrenoceptors in the BLA with clonidine enhanced LTP while blocking alpha-2 adrenoceptors with idazoxan impaired it. Propranolol, a non-selective beta antagonist, enhanced H-PFC LTP while isoprenaline, a non-selective beta agonist, decreased H-PFC LTP. These results suggest that the BLA regulates H-PFC plasticity negatively and also provide a mechanism by which noradrenaline in the BLA can affect H-PFC plasticity via alpha-2 and beta adrenoceptors.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Clonidina/farmacologia , Idazoxano/farmacologia , Isoproterenol/farmacologia , Masculino , Norepinefrina/farmacologia , Propranolol/farmacologia , Ratos , Ratos Sprague-Dawley
6.
Learn Mem ; 23(12): 684-688, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27918272

RESUMO

Rodents are exquisitely sensitive to light and optogenetic behavioral experiments routinely introduce light-delivery materials into experimental situations, which raises the possibility that light could leak and influence behavioral performance. We examined whether rats respond to a faint diffusion of light, termed caplight, which emanated through the translucent dental acrylic resin used to affix deep-brain optical cannulas in place. Although rats did not display significant changes in locomotion or rearing to caplight in a darkened open field, they did acquire conditional fear via caplight-footshock pairings. These findings highlight the potential confounding influence of extraneous light emanating from light-delivery materials during optogenetic analyses.


Assuntos
Resinas Acrílicas , Cateteres de Demora , Medo , Luz , Fibras Ópticas , Optogenética/instrumentação , Animais , Condicionamento Clássico , Eletrochoque , Reação de Congelamento Cataléptica , Luz/efeitos adversos , Masculino , Atividade Motora , Ratos Long-Evans , Detecção de Sinal Psicológico
7.
Cell Mol Neurobiol ; 36(8): 1331-1342, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26814839

RESUMO

The tuning of glutamatergic transmission is an essential mechanism for neuronal communication. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are ionotropic glutamate receptors that mediate fast synaptic transmission. The phosphorylation states of specific serine residues on the GluA1 and GluA2 AMPAR subunits are considered critical post-translational modifications that regulate AMPAR activity and subcellular trafficking. While behavioral stress, via stress hormones, exerts specific alterations on such glutamatergic processes, there have been conflicting data concerning the influence of stress on AMPAR phosphorylation in different brain regions, and the post-stress signaling mechanisms mediating these processes are not well delineated. Here, we examined the dynamics of phosphorylation at three AMPAR serine residues (ser831-GluA1, ser845-GluA1, and ser880-GluA2) in four brain regions [amygdala, medial prefrontal cortex (mPFC), dorsal hippocampus, and ventral hippocampus] of the rat during the hour following behavioral stress. We also tested the impact of post-stress corticosteroid receptor blockade on AMPAR phosphorylation. Both GluA1 subunit residues exhibited elevated phosphorylation after stress, yet post-stress administration of corticosteroid receptor antagonists curtailed these effects only at ser831-GluA1. In contrast, ser880-GluA2 displayed a time-dependent tendency for early decreased phosphorylation (that was selectively augmented by mifepristone treatment in the amygdala and mPFC of stressed animals) followed by increased phosphorylation later on. These findings show that the in vivo regulation of AMPAR phosphorylation after stress is a dynamic and subunit-specific process, and they provide support for the hypothesis that corticosteroid receptors have an ongoing role in the regulation of ser831-GluA1 phosphorylation during the post-stress interval.


Assuntos
Receptores de AMPA/metabolismo , Estresse Psicológico/metabolismo , Animais , Encéfalo/metabolismo , Corticosterona/sangue , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Fosforilação , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/antagonistas & inibidores , Serina/metabolismo
8.
Curr Biol ; 32(14): 3180-3188.e4, 2022 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-35705096

RESUMO

Current treatments for trauma-related disorders remain ineffective for many patients.1,2 Fear extinction deficiency is a prominent feature of these diseases,3 and many behavioral treatments rely on extinction training.4,5 However, in many patients, therapy is followed by a relapse of symptoms, and the underpinnings of such interindividual variations in vulnerability to relapse remain unknown.6-8 Here, we modeled interindividual differences in post-therapy fear relapse with an ethologically relevant trauma recovery paradigm. After fear conditioning, male rats underwent fear extinction while foraging in a large enriched arena, permitting the expression of a wide spectrum of behaviors. An automated multidimensional behavioral assessment revealed that post-conditioning fear response profiles clustered into two groups: some animals expressed fear by freezing more, whereas others darted more, as if fleeing from danger. Remarkably, the tendency of an animal to dart or to freeze after CS presentation during the first extinction session was, respectively, associated with stronger or weaker fear renewal. Moreover, genome-wide transcriptional profiling revealed that these groups differentially regulated specific sets of genes, some of which were previously implicated in anxiety and trauma-related disorders. Our results suggest that post-trauma behavioral phenotypes and the associated gene expression landscapes can serve as markers of fear relapse susceptibility and thus may be instrumental for future development of more effective treatments for psychiatric patients.


Assuntos
Extinção Psicológica , Medo , Animais , Condicionamento Clássico/fisiologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Masculino , Fenótipo , Ratos , Recidiva
9.
Cells ; 11(7)2022 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-35406745

RESUMO

Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this circuit revealed EGIS 11150 (S 36549). EGIS 11150 induced theta rhythm in hippocampal slice preparations in the stratum lacunosum molecular area of CA1, which was resistant to atropine and prazosin. EGIS 11150 enhanced H-PFC coherence, and increased the 8−9 Hz theta band of the EEG power spectrum (from 0.002 mg/kg i.p, at >30× lower doses than clozapine, and >100× for olanzapine, risperidone, or haloperidol). EGIS 11150 fully blocked the effects of phencyclidine (PCP) or ketamine on EEG. Inhibition of long-term potentiation (LTP) in H-PFC was blocked by platform stress, but was fully restored by EGIS 11150 (0.01 mg/kg i.p.), whereas clozapine (0.3 mg/kg ip) only partially restored LTP. EGIS 11150 has a unique electrophysiological profile, so phenotypical screening on H-PFC connectivity can reveal novel antipsychotics.


Assuntos
Antipsicóticos , Clozapina , Animais , Antipsicóticos/farmacologia , Clozapina/farmacologia , Hipocampo , Plasticidade Neuronal , Córtex Pré-Frontal , Ratos , Ratos Wistar , Risperidona/farmacologia
10.
Therapie ; 76(2): 75-86, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33358639

RESUMO

The multiple brain circuits involved in psychiatric diseases may appear daunting, but we prefer to concentrate on a select few, with a particular sensitivity to stress and neurodevelopmental issues, with a clear pharmacotherapy. This review is structured around 1. the key circuits, their role in health and disease, and the neurotransmitters maintaining them, 2. The influence of upbringing, stress, chronobiology, inflammation and infection, 3. The genetic and epigenetic influence on these circuits, particularly regarding copy number variants and neuronal plasticity, 4. The use and abuse of pharmacological agents with the particular risks of stress and chronobiology at critical periods. A major emphasis is placed on the links between hippocampus, prefrontal cortex and amygdala/periaqueductal grey which control specific aspects of cognition, mood, pain and even violence. Some of the research findings were from the innovative medicine initiative (IMI) NEWMEDS, a 22M€ academic/industrial consortium on the brain circuits critical for psychiatric disease.


Assuntos
Transtornos Mentais , Tonsila do Cerebelo , Hipocampo , Humanos , Córtex Pré-Frontal
11.
Int J Neuropsychopharmacol ; 13(9): 1219-31, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20128952

RESUMO

Stimulation of the subiculum/CA1 of the hippocampal formation evokes monosynaptic field potentials in the prefrontal cortex (PFC). High-frequency stimulation of the hippocampus (HPC) can induce long-term potentiation (LTP) in this hippocampo-prefrontal cortical (hippo-PFC) pathway. Previous studies have shown that dopamine and serotonin modulate hippo-PFC LTP. Here, we investigated whether the locus coeruleus (LC) and noradrenaline (NA) can modulate LTP in the rat hippo-PFC pathway. Stimulation of the LC in combination with stimulation of the HPC increased hippo-PFC LTP. Infusion of lidocaine into the LC reduced hippo-PFC LTP. Administration of the noradrenaline reuptake inhibitor, nisoxetine or the alpha2 adrenoceptor antagonist, idazoxan prior to high-frequency stimulation of the HPC enhanced hippo-LTP. In contrast, administration of clonidine, an alpha2 adrenoceptor agonist, impaired hippo-PFC LTP. Partial noradrenergic (NAergic) lesioning with DSP-4 also impaired hippo-PFC LTP. In conclusion, the LC and NAergic mechanisms modulate hippo-PFC LTP.


Assuntos
Hipocampo/efeitos dos fármacos , Locus Cerúleo/efeitos dos fármacos , Potenciação de Longa Duração , Norepinefrina/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Adrenérgicos/metabolismo , Adrenérgicos/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Agonistas alfa-Adrenérgicos/metabolismo , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Benzilaminas/metabolismo , Benzilaminas/farmacologia , Clonidina/metabolismo , Clonidina/farmacologia , Dopamina/metabolismo , Dopamina/fisiologia , Hipocampo/metabolismo , Hipocampo/fisiologia , Idazoxano/metabolismo , Idazoxano/farmacologia , Locus Cerúleo/fisiologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Córtex Pré-Frontal/fisiologia , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Serotonina/fisiologia
12.
J Psychopharmacol ; 34(12): 1443-1448, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33256509

RESUMO

BACKGROUND: Major depressive disorder is a common illness that severely decreases psychosocial functioning. Due to the major limitations of current treatments including response failure, it is crucial to develop better therapy strategies. Evidence suggests that dopamine dysregulation might play a major role in major depressive disorder physiopathology. AIMS: This study investigates whether the dopamine D1 receptor agonist A77636 modulates antidepressant-like activity in rats. METHODS: Rats were injected with an acute single dose of A77636 (0.75, 1.5 or 3 mg/kg), a potent and selective dopamine D1-like receptor agonist. Their locomotor activity, social interactions and behavioural response to the forced swim test were analysed 30 min after the injection. RESULTS: During the forced swim test, the D1 agonist dose dependently reduced the immobility while the time of bursting was increased. Social interactions were significantly increased in the animals exposed to 3 mg/kg of A77636 whereas no significant changes were measured in general motor activity. CONCLUSIONS: The present results provide evidence that pharmacological modulation of D1 receptor by the selective agonist A77636 induces antidepressant-like effects in rats, which encourages further studies regarding D1-specific modulation in major depressive disorder treatment.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Locomoção/efeitos dos fármacos , Receptores de Dopamina D1/agonistas , Interação Social , Adamantano/análogos & derivados , Adamantano/farmacologia , Animais , Antidepressivos/administração & dosagem , Benzopiranos/farmacologia , Agonistas de Dopamina/administração & dosagem , Masculino , Ratos , Ratos Sprague-Dawley
13.
Transl Psychiatry ; 10(1): 41, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-32066701

RESUMO

Genetic microdeletion at the 22q11 locus is associated with very high risk for schizophrenia. The 22q11.2 microdeletion (Df(h22q11)/+) mouse model shows cognitive deficits observed in this disorder, some of which can be linked to dysfunction of the prefrontal cortex (PFC). We used behavioral (n = 10 per genotype), electrophysiological (n = 7 per genotype per group), and neuroanatomical (n = 5 per genotype) techniques to investigate schizophrenia-related pathology of Df(h22q11)/+ mice, which showed a significant decrease in the total number of parvalbumin positive interneurons in the medial PFC. The Df(h22q11)/+ mice when tested on PFC-dependent behavioral tasks, including gambling tasks, perform significantly worse than control animals while exhibiting normal behavior on hippocampus-dependent tasks. They also show a significant decrease in hippocampus-medial Prefrontal cortex (H-PFC) synaptic plasticity (long-term potentiation, LTP). Acute platform stress almost abolished H-PFC LTP in both wild-type and Df(h22q11)/+ mice. H-PFC LTP was restored to prestress levels by clozapine (3 mg/kg i.p.) in stressed Df(h22q11)/+ mice, but the restoration of stress-induced LTP, while significant, was similar between wild-type and Df(h22q11)/+ mice. A medial PFC dysfunction may underlie the negative and cognitive symptoms in human 22q11 deletion carriers, and these results are relevant to the current debate on the utility of clozapine in such subjects.


Assuntos
Cognição , Córtex Pré-Frontal , Animais , Modelos Animais de Doenças , Hipocampo , Camundongos , Camundongos Endogâmicos C57BL
14.
Front Psychiatry ; 11: 680, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754072

RESUMO

INTRODUCTION: The emergence of psychosis in at-risk individuals results from interactions between genetic vulnerability and environmental factors, possibly involving dysregulation of the hypothalamic-pituitary-adrenal axis. Hypercorticism was indeed described in schizophrenia and ultra-high-risk states, but its association with clinical outcome has yet to be demonstrated. The impact of stress through cortisol may vary depending on the expression level of genes related to the stress pathway. METHODS: To test this hypothesis, we selected NR3C1, the gene encoding the glucocorticoid receptor, and modeled through logistic regression how its peripheral expression could explain some of the risk of psychosis, independently of peripheral cortisol levels, in a French longitudinal prospective cohort of 133 at-risk individuals, adjusted for sex, age, cannabis, and antipsychotic medication intake. We then performed a genome-wide association analysis, stratified by sex (55 females and 78 males), to identify NR3C1 expression quantitative trait loci to be used as instrumental variables in a Mendelian randomization framework. RESULTS: NR3C1 expression was significantly associated with a higher risk of conversion to psychosis (OR = 2.03, p = 0.03), independently of any other factor. Cortisol was not associated with outcome nor correlated with NR3C1. In the female subgroup, rs6849528 was associated both with NR3C1 mRNA levels (p = 0.015, Effect-Size = 2.7) and conversion (OR = 8.24, p = 0.03). CONCLUSIONS: For the same level of cortisol, NR3C1 expression increases psychotic risk, independently of sex, age, cannabis, and antipsychotic intake. In females, Mendelian randomization confirmed NR3C1's effect on outcome to be unbiased by any environmental confounder.

15.
Neuropharmacology ; 56(1): 37-46, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18657555

RESUMO

Exposure to stress causes dysfunctions in circuits connecting hippocampus and prefrontal cortex (H-PFC). Long term potentiation (LTP) induced in vivo in rats at H-PFC synapses is impaired by acute elevated platform stress in a manner that can be restored by treatment with certain antidepressants. To identify biochemical pathways in rat frontal cortex underlying this stress-mediated impairment of synaptic plasticity, we examined the phosphorylation state of receptors, signaling proteins and transcription factors implicated in neuronal plasticity. Transient changes in the phosphorylation states of Ser217/221-MEK, Thr183/Tyr185-p42MAPK, Thr202/Tyr204-p44MAPK, Thr180/Tyr182-p38MAPK, Thr218/Tyr220-ERK5, Thr308-Akt, Ser63-ATF-1, Ser1303-GluN2B, Tyr490/515-TrkA/B were found. BDNF was down-regulated after elevated platform stress suggesting that it could regulate the MEK/MAPK signaling cascade. Acute treatment with the antidepressants tianeptine and imipramine reversed the stress-induced down-regulation of P-Ser217/221-MEK. However, stress-induced impairment of H-PFC LTP was only restored by acute treatment with tianeptine and not by imipramine. Tianeptine, but not imipramine, increased the phosphorylation of Ser831-GluA1. Altogether, these results indicate that acute elevated platform stress down-regulates a putative BDNF/MEK/MAPK signaling cascade in the frontal cortex in a manner that is reversible by the antidepressants tianeptine and imipramine. Moreover, changes in LTP may be associated with phosphorylation of AMPA receptors and with some specificity for certain antidepressants. Indeed, stress-induced impairment of H-PFC LTP was only restored by acute treatment with tianeptine and not by imipramine. Tianeptine, but not imipramine, increased the phosphorylation of Ser831-GluA1, indicating a potential effect on AMPA receptor phosphorylation being involved in the reversal of LTP.


Assuntos
Antidepressivos/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de AMPA/metabolismo , Estresse Psicológico/patologia , Estresse Psicológico/fisiopatologia , Animais , Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Estimulação Elétrica/métodos , Ensaio de Imunoadsorção Enzimática/métodos , Potenciação de Longa Duração/fisiologia , Masculino , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Serina/metabolismo , Estresse Psicológico/tratamento farmacológico , Fatores de Tempo
16.
Eur J Pain ; 23(7): 1225-1233, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30793421

RESUMO

BACKGROUND: Cannabinoids are proposed in a wide array of medical indications. Yet, the evaluation of adverse effects in controlled clinical studies, following the evidence-based model, has partly been bypassed. On the other hand, studies on the consequences of recreational use of cannabis and experimental studies bring some insights on the potential long-term consequences of cannabinoids use. RESULTS: Epidemiological studies have consistently demonstrated that cannabis use is associated with a risk of persistent cognitive deficits and increased risk of schizophrenia-like psychoses. These risks are modulated by the dose and duration of use, on top of age of use and genetic factors, including partially shared genetic predisposition with schizophrenia. Experimental studies in healthy humans showed that cannabis and its principal psychoactive component, the delta-9-tetrahydrocannabinol (THC), could produce transient, dose-dependent, psychotic symptoms as well as cognitive effects, which can be attenuated by cannabidiol (CBD). Studies in rodents have confirmed these effects and shown that adolescent exposure results in structural changes and impaired synaptic plasticity, impacting fronto-limbic systems that are critically involved in higher brain functions. The endocannabinoid system plays an important role in brain maturation. Its over-activation by cannabinoid receptor type 1 agonists (e.g., THC) during adolescence and the resulting changes in neuroplasticity could alter brain maturation and cause long-lasting changes that persist in the adult brain. CONCLUSIONS: Exposure to cannabinoids can have long-term impact on the brain, with an inter-individual variability that could be conveyed by personal and family history of psychiatric disorders and genetic background. Adolescence and early adulthood are critical periods of vulnerability. SIGNIFICANCE: The assessment of benefice-risk balance of medical use of cannabis and cannabinoids needs to carefully explore populations that could be more at-risk of psychiatric and cognitive complications.


Assuntos
Canabinoides/efeitos adversos , Transtornos Cognitivos/induzido quimicamente , Transtornos Mentais/induzido quimicamente , Adolescente , Adulto , Encéfalo/efeitos dos fármacos , Canabidiol/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Canabinoides/farmacologia , Cannabis/efeitos adversos , Disfunção Cognitiva , Dronabinol/farmacologia , Humanos
17.
J Neurosci ; 27(11): 2781-7, 2007 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-17360899

RESUMO

Research on the detrimental effects of stress in the brain has mainly focused on the hippocampus. Because prefrontal cortex (PFC) dysfunction characterizes many stress-related disorders, we here analyzed the impact of chronic stress in rats on the integrity of the hippocampal-PFC pathway, monitored by behavioral and electrophysiological function and morphological assessment. We show that chronic stress impairs synaptic plasticity by reducing LTP induction in the hippocampal-PFC connection; in addition, it induces selective atrophy within the PFC and severely disrupts working memory and behavioral flexibility, two functions that depend on PFC integrity. We also demonstrate that short periods of stress exposure induce spatial reference memory deficits before affecting PFC-dependent tasks, thus suggesting that the impairment of synaptic plasticity within the hippocampus-to-PFC connection is of relevance to the stress-induced PFC dysfunction. These findings evidence a fundamental role of the PFC in maladaptive responses to stress and identify this area as a target for intervention in stress-related disorders.


Assuntos
Transtornos da Memória/fisiopatologia , Córtex Pré-Frontal/fisiologia , Estresse Fisiológico/fisiopatologia , Animais , Hipocampo/fisiologia , Masculino , Memória/fisiologia , Transtornos da Memória/psicologia , Vias Neurais/fisiologia , Plasticidade Neuronal/fisiologia , Ratos , Ratos Wistar , Estresse Fisiológico/psicologia
18.
Neuroscience ; 385: 11-24, 2018 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-29902504

RESUMO

During mobile phone conversations, the temporal lobe neural networks involved in processing auditory information are exposed to electromagnetic fields (EMF) such as pulse-modulated GSM-1800 MHz radiofrequencies that convey wireless communications. The effects of these EMF on the brain affected by a pathological condition remain little investigated. In this study, rats injected with lipopolysaccharide (LPS) to induce neuroinflammation were exposed "head-only" to GSM-1800 MHz signals for two hours at a specific absorption rate (SAR) that reached an average value of 1.55 W/kg in the auditory cortex (ACx). Immunodetection of Iba1, a microglial marker, and electrophysiological recordings in the ACx three to six hours after global system for communication (GSM) exposure, or sham-exposure, showed that exposure to GSM-1800 MHz resulted in a growth of microglial processes and a reduction in spontaneous firing rate. More importantly, there was a significant reduction in evoked responses to artificial and natural stimuli and an increase in response duration. The response latency and the bandwidth of the frequency tuning were unchanged, but the GSM exposure led to a higher proportion of cortical sites exhibiting abnormally high acoustic thresholds. These modifications were not observed in rats exposed to GSM-1800 MHz without pretreatment with LPS. Together our data provide evidence that in neuroinflammatory conditions, acute exposure to GSM-1800 MHz can significantly affect microglia and neuronal activity underling auditory perception.


Assuntos
Córtex Auditivo/efeitos da radiação , Inflamação/patologia , Microglia/efeitos da radiação , Neurônios/efeitos da radiação , Animais , Córtex Auditivo/patologia , Forma Celular/efeitos da radiação , Campos Eletromagnéticos , Inflamação/induzido quimicamente , Lipopolissacarídeos , Masculino , Microglia/patologia , Neurônios/patologia , Ratos , Ratos Wistar
19.
Front Mol Neurosci ; 11: 323, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30760979

RESUMO

Despite progress, our understanding of psychiatric and neurological illnesses remains poor, at least in part due to the inability to access neurons directly from patients. Currently, there are in vitro models available but significant work remains, including the search for a less invasive, inexpensive and rapid method to obtain neuronal-like cells with the capacity to deliver reproducible results. Here, we present a new protocol to transdifferentiate human circulating monocytes into neuronal-like cells in 20 days and without the need for viral insertion or reprograming. We have thoroughly characterized these monocyte-derived-neuronal-like cells (MDNCs) through various approaches including immunofluorescence (IF), flow cytometry, qRT-PCR, single cell mRNA sequencing, electrophysiology and pharmacological techniques. These MDNCs resembled human neurons early in development, expressed a variety of neuroprogenitor and neuronal genes as well as several neuroprogenitor and neuronal proteins and also presented electrical activity. In addition, when these neuronal-like cells were exposed to either dopamine or colchicine, they responded similarly to neurons by retracting their neuronal arborizations. More importantly, MDNCs exhibited reproducible differentiation rates, arborizations and expression of dopamine 1 receptors (DR1) on separate sequential samples from the same individual. Differentiation efficiency measured by cell morphology was on average 11.9 ± 1.4% (mean, SEM, n = 38,819 cells from 15 donors). To provide context and help researchers decide which in vitro model of neuronal development is best suited to address their scientific question,we compared our results with those of other in vitro models currently available and exposed advantages and disadvantages of each paradigm.

20.
Biol Psychiatry ; 62(4): 359-62, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17210139

RESUMO

BACKGROUND: Understanding of the molecular mechanisms of prefrontal cortex (PFC) plasticity is important for developing new treatment strategies for mental disorders such as depression and schizophrenia. Long-term potentiation (LTP) is a valid model for synaptic plasticity. The extracellular proteolytic system composed of matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) has recently been shown to play major role in the hippocampal plasticity. METHODS: We tested whether induction of hippocampal-prefrontal LTP results in accumulation of tissue inhibitor of MMP-1, TIMP-1 mRNA, in the PFC of rats and whether adenovirally driven overexpression of TIMP-1 affects LTP. Additional study of slices was done with a specific MMP-9 inhibitor. RESULTS: The TIMP-1 is induced in the rat medial PFC by stimuli evoking late LTP; its overexpression blocks the gelatinolytic activity of the MMP family; its overexpression before tetanization blocks late LTP in vivo; and MMP-9 inhibitor prevents late LTP in vitro. CONCLUSIONS: We suggest a novel extracellular mechanism of late LTP in the PFC, engaging TIMP-1-controlled proteolysis as an element of information integration. Our results may also be meaningful to an understanding of mental diseases and development of new treatment strategies that are based on extracellular mechanisms of synaptic plasticity.


Assuntos
Potenciação de Longa Duração/fisiologia , Metaloproteinase 9 da Matriz/metabolismo , Vias Neurais/enzimologia , Córtex Pré-Frontal/enzimologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Animais , Hipocampo/enzimologia , Imuno-Histoquímica , Masculino , Inibidores de Proteases/metabolismo , Ratos , Ratos Sprague-Dawley
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