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1.
J Neuroinflammation ; 19(1): 240, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36183107

RESUMO

BACKGROUND: Major depressive disorder (MDD) is a prevalent and devastating psychiatric illness. Unfortunately, the current therapeutic practice, generally depending on the serotonergic system for drug treatment is unsatisfactory and shows intractable side effects. Multiple evidence suggests that dopamine (DA) and dopaminergic signals associated with neuroinflammation are highly involved in the pathophysiology of depression as well as in the mechanism of antidepressant drugs, which is still in the early stage of study and well worthy of investigation. METHODS: We established two chronic stress models, including chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), to complementarily recapitulate depression-like behaviors. Then, hippocampal tissues were used to detect inflammation-related molecules and signaling pathways. Pathological changes in depressive mouse hippocampal astrocytes were examined by RNA sequencing. After confirming the dopamine receptor 2 (Drd2)/ß-arrestin2 signaling changes in the depressive mice brain, we then established the depressive mouse model using the ß-arrestin2 knockout mice or administrating the ß-arrestin2-biased Drd2 agonist to investigate the roles. Label-free mass spectrometry was used to identify the ß-arrestin2-binding proteins as the underlying mechanisms. We modeled neuroinflammation with interleukin-6 (IL-6) and corticosterone treatment and characterized astrocytes using multiple methods including cell viability assay, flow cytometry, and confocal immunofluorescence. RESULTS: Drd2-biased ß-arrestin2 pathway is significantly changed in the progression of depression, and genetic deletion of ß-arrestin2 aggravates neuroinflammation and depressive-like phenotypes. Mechanistically, astrocytic ß-arrestin2 retains STAT3 in the cytoplasm by structural combination with STAT3, therefore, inhibiting the JAK-STAT3 pathway-mediated inflammatory activation. Furtherly, pharmacological activation of Drd2/ß-arrestin2 pathway by UNC9995 abolishes the inflammation-induced loss of astrocytes and ameliorates depressive-like behaviors in mouse model for depression. CONCLUSIONS: Drd2/ß-arrestin2 pathway is a potential therapeutic target for depression and ß-arrestin2-biased Drd2 agonist UNC9995 is identified as a potential anti-depressant strategy for preventing astrocytic dysfunctions and relieving neuropathological manifestations in mouse model for depression, which provides insights for the therapy of depression.


Assuntos
Astrócitos , Transtorno Depressivo Maior , Animais , Astrócitos/metabolismo , Corticosterona/metabolismo , Depressão/tratamento farmacológico , Depressão/etiologia , Transtorno Depressivo Maior/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/uso terapêutico , Hipocampo/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Camundongos , Camundongos Knockout , Receptores de Dopamina D2/metabolismo , Estresse Psicológico/complicações , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/patologia , beta-Arrestina 1/metabolismo , beta-Arrestina 2/genética , beta-Arrestina 2/metabolismo
2.
Proc Natl Acad Sci U S A ; 119(41): e2204306119, 2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36191221

RESUMO

Recurrent seizure is a common comorbidity in early-stage Alzheimer's disease (AD) and may contribute to AD pathogenesis and cognitive decline. Similarly, many mouse models of Alzheimer's disease that overproduce amyloid beta are prone to epileptiform seizures that may result in early sudden death. We studied one such model, designated APP/PS1, and found that mutation of the TAM receptor tyrosine kinase (RTK) Mer or its ligand Gas6 greatly exacerbated early death. Lethality was tied to violent seizures that appeared to initiate in the dentate gyrus (DG) of the hippocampus, where Mer plays an essential role in the microglial phagocytosis of both apoptotic and newborn cells normally generated during adult neurogenesis. We found that newborn DG neurons and excitatory synapses between the DG and the cornu ammonis field 3 (CA3) field of the hippocampus were increased in TAM-deficient mice, and that premature death and adult neurogenesis in these mice were coincident. In contrast, the incidence of lethal seizures and the deposition of dense-core amyloid plaques were strongly anticorrelated. Together, these results argue that TAM-mediated phagocytosis sculpts synaptic connectivity in the hippocampus, and that seizure-inducing amyloid beta polymers are present prior to the formation of dense-core plaques.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Hipocampo/metabolismo , Ligantes , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Placa Amiloide/patologia , Polímeros , Proteínas Tirosina Quinases , Convulsões/genética , Convulsões/patologia
3.
Int J Mol Sci ; 23(17)2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-36076994

RESUMO

(1) The neurotrophic protein S100B is a marker of brain injury and has been associated with neuroregeneration. In S100Btg mice rendering 12 copies of the murine S100B gene we evaluated whether S100B may serve as a treatment option. (2) In juvenile, adult, and one-year-old S100Btg mice (female and male; n = 8 per group), progenitor cell proliferation was quantified in the subgranular zone (SGZ) and the granular cell layer (GCL) of the dentate gyrus with the proliferative marker Ki67 and BrdU (50 mg/kg). Concomitant signaling was quantified utilizing glial fibrillary acidic protein (GFAP), apolipoprotein E (ApoE), brain-derived neurotrophic factor (BDNF), and the receptor for advanced glycation end products (RAGE) immunohistochemistry. (3) Progenitor cell proliferation in the SGZ and migration to the GCL was enhanced. Hippocampal GFAP was reduced in one-year-old S100Btg mice. ApoE in the hippocampus and frontal cortex of male and BDNF in the frontal cortex of female S100Btg mice was reduced. RAGE was not affected. (4) Enhanced hippocampal neurogenesis in S100Btg mice was not accompanied by reactive astrogliosis. Sex- and brain region-specific variations of ApoE and BDNF require further elucidations. Our data reinforce the importance of this S100Btg model in evaluating the role of S100B in neuroregenerative medicine.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Hipocampo , Animais , Apolipoproteínas E/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Neurogênese , Subunidade beta da Proteína Ligante de Cálcio S100/genética , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo
4.
Int J Mol Sci ; 23(17)2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36077281

RESUMO

The α2δ auxiliary subunits of voltage-gated calcium channels (VGCC) were traditionally regarded as modulators of biophysical channel properties. In recent years, channel-independent functions of these subunits, such as involvement in synapse formation, have been identified. In the central nervous system, α2δ isoforms 1, 2, and 3 are strongly expressed, regulating glutamatergic synapse formation by a presynaptic mechanism. Although the α2δ-4 isoform is predominantly found in the retina with very little expression in the brain, it was recently linked to brain functions. In contrast, Cachd1, a novel α2δ-like protein, shows strong expression in brain, but its function in neurons is not yet known. Therefore, we aimed to investigate the presynaptic functions of α2δ-4 and Cachd1 by expressing individual proteins in cultured hippocampal neurons. Both α2δ-4 and Cachd1 are expressed in the presynaptic membrane and could rescue a severe synaptic defect present in triple knockout/knockdown neurons that lacked the α2δ-1-3 isoforms (α2δ TKO/KD). This observation suggests that presynaptic localization and the regulation of synapse formation in glutamatergic neurons is a general feature of α2δ proteins. In contrast to this redundant presynaptic function, α2δ-4 and Cachd1 differentially regulate the abundance of presynaptic calcium channels and the amplitude of presynaptic calcium transients. These functional differences may be caused by subtle isoform-specific differences in α1-α2δ protein-protein interactions, as revealed by structural homology modelling. Taken together, our study identifies both α2δ-4 and Cachd1 as presynaptic regulators of synapse formation, differentiation, and calcium channel functions that can at least partially compensate for the loss of α2δ-1-3. Moreover, we show that regulating glutamatergic synapse formation and differentiation is a critical and surprisingly redundant function of α2δ and Cachd1.


Assuntos
Canais de Cálcio , Neurônios , Canais de Cálcio/metabolismo , Hipocampo/metabolismo , Neurogênese , Neurônios/metabolismo , Sinapses/metabolismo
5.
Int J Mol Sci ; 23(17)2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36077346

RESUMO

We performed RNA sequencing of the dorsal and ventral parts of the hippocampus and compared it with previously published data to determine the differences in the dorsoventral gradients of gene expression that may result from biological or technical variability. Our data suggest that the dorsal and ventral parts of the hippocampus differ in the expression of genes related to signaling pathways mediated by classical neurotransmitters (glutamate, GABA, monoamines, etc.) as well as peptide and Wnt ligands. These hippocampal parts also diverge in the expression of axon-guiding molecules (both receptors and ligands) and splice isoforms of genes associated with intercellular signaling and cell adhesion. Furthermore, analysis of differential expressions of genes specific for astrocytes, microglia, oligodendrocytes, and vascular cells suggests that non-neuronal cells may also differ in the characteristics between hippocampal parts. Analysis of expression of transposable elements showed that depletion of ribosomal RNA strongly increased the representation of transposable elements in the RNA libraries and helped to detect a weak predominance of expression of these elements in the ventral hippocampus. Our data revealed new molecular dimensions of functional differences between the dorsal and ventral hippocampus and points to possible cascades that may be involved in the longitudinal organization of the hippocampus.


Assuntos
Elementos de DNA Transponíveis , Hipocampo , Animais , Expressão Gênica , Hipocampo/metabolismo , Ratos
6.
Cells ; 11(17)2022 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-36078069

RESUMO

Early-life metabolic stress has been demonstrated to affect brain development, persistently influence brain plasticity and to exert multigenerational effects on cognitive functions. However, the impact of an ancestor's diet on the adult neurogenesis of their descendants has not yet been investigated. Here, we studied the effects of maternal high fat diet (HFD) on hippocampal adult neurogenesis and the proliferation of neural stem and progenitor cells (NSPCs) derived from the hippocampus of both the second and the third generations of progeny (F2HFD and F3HFD). Maternal HFD caused a multigenerational depletion of neurogenic niche in F2HFD and F3HFD mice. Moreover, NSPCs derived from HFD descendants showed altered expression of genes regulating stem cell proliferation and neurodifferentiation (i.e., Hes1, NeuroD1, Bdnf). Finally, ancestor HFD-related hyper-activation of both STAT3 and STAT5 induced enhancement of their binding on the regulatory sequences of Gfap gene and an epigenetic switch from permissive to repressive chromatin on the promoter of the NeuroD1 gene. Collectively, our data indicate that maternal HFD multigenerationally affects hippocampal adult neurogenesis via an epigenetic derangement of pro-neurogenic gene expression in NSPCs.


Assuntos
Dieta Hiperlipídica , Hipocampo , Animais , Proliferação de Células , Dieta Hiperlipídica/efeitos adversos , Epigênese Genética , Hipocampo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
7.
Molecules ; 27(17)2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36080418

RESUMO

Melatonin (MEL), an indolamine with diverse functions in the brain, has been shown to produce antidepressant-like effects, presumably through stimulating neurogenesis. We recently showed that the combination of MEL with ketamine (KET), an NMDA receptor antagonist, has robust antidepressant-like effects in mice, at doses that, by themselves, are non-effective and have no adverse effects. Here, we show that the KET/MEL combination increases neurogenesis in a clone derived from human olfactory neuronal precursors, a translational pre-clinical model for effects in the human CNS. Neurogenesis was assessed by the formation of cell clusters > 50 µm in diameter, positively stained for nestin, doublecortin, BrdU and Ki67, markers of progenitor cells, neurogenesis, and proliferation. FGF, EGF and BDNF growth factors increased the number of cell clusters in cultured, cloned ONPs. Similarly, KET or MEL increased the number of clusters in a dose-dependent manner. The KET/MEL combination further increased the formation of clusters, with a maximal effect obtained after a triple administration schedule. Our results show that the combination of KET/MEL, at subeffective doses that do not produce adverse effects, stimulate neurogenesis in human neuronal precursors. Moreover, the mechanism by which the combination elicits neurogenesis is meditated by melatonin receptors, CaM Kinase II and CaM antagonism. This could have clinical advantages for the fast treatment of depression.


Assuntos
Ketamina , Melatonina , Animais , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Hipocampo/metabolismo , Humanos , Ketamina/metabolismo , Ketamina/farmacologia , Melatonina/metabolismo , Melatonina/farmacologia , Camundongos , Neurogênese , Neurônios
8.
Neuroreport ; 33(14): 597-603, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-36062510

RESUMO

BACKGROUND: Stress is not scarce in peoples' daily life that may result in mental diseases and cognitive impairments. Chronic restraint stress (CRS) is a well-validated animal model used to investigate the mechanism of stress-associated depression and cognitive impairments. Dl-3-n-butylphthalide (NBP) possesses anti-oxidant, anti-inflammatory and anti-apoptotic, promoting neurogenesis and neuroplasticity that exerts neuroprotective effects. However, the effects of NBP on CRS-induced depression and cognitive impairments remain unclear. METHODS: C57BL/6 male mice were randomly divided into the control group, stress group and stress+NBP group. Mice were exposed to CRS for three consecutive weeks and mice in the NBP treatment group were administered with NBP before the CRS procedure. After that, depression and cognition behaviors were evaluated followed by phosphorylation of Ca2+/calmodulin-dependent protein kinase II (p-CaMKII), phosphorylation of cAMP-response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF) proteins expression, immunohistochemistry of hippocampal postsynaptic density 95 (PSD95) and synaptophysin, and hippocampal morphology. RESULTS: Our results showed that mice exhibited depression-like behaviors and cognitive deficits after 3 weeks exposure to CRS. Additionally, CRS downregulated CaMKII/CREB/BDNF signaling pathway, reduced PSD95 and synaptophysin expression and induced hippocampal CA1 and dentate gyrus ment significantly reversed the hippocampal pathological and molecular changes induced by CRS. CONCLUSION: In conclusion, these results reveal that NBP exerts a neuroprotective effect on depression and cognitive deficit through activating CaMKII/CREB/BDNF pathway, enhancing PSD95 and synaptophysin expression and protecting hippocampal morphology.


Assuntos
Disfunção Cognitiva , Fármacos Neuroprotetores , Animais , Benzofuranos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/prevenção & controle , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Depressão/etiologia , Depressão/metabolismo , Depressão/prevenção & controle , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais , Sinaptofisina/metabolismo
9.
BMC Psychiatry ; 22(1): 590, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064335

RESUMO

Depression is a mental disease involving complex pathophysiological mechanisms, and there are many ways to establish depressive mouse models. The purpose of this study is to comprehensively compare the behavioral changes and its mechanism induced by two different models. This study established two depressive mouse models by maternal separation (MS) or lipopolysaccharide (LPS) administration, and added fluoxetine treatment group respectively for comparison. MS induced more apparent anxiety-like behavior while LPS induced more apparent depressive-like behavior. LPS increased peripheral inflammatory factors more apparent, which were mitigated by fluoxetine. MS inhibited the 5-HT system more obviously and was relieved by fluoxetine. LPS triggered stronger immune response in the hippocampus and prefrontal cortex (PFC). MS significantly reduced the expression of neurotrophic proteins and was alleviated by fluoxetine. Overall, LPS induced stronger system inflammation, while MS impaired the function of HPA axis and 5-HT system. Our results will contribute to a deeper understanding of the pathophysiology of different stress-induced depression and will also help researchers select appropriate models of depression for their own needs.


Assuntos
Fluoxetina , Lipopolissacarídeos , Animais , Depressão/metabolismo , Modelos Animais de Doenças , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Hipocampo/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Inflamação/metabolismo , Privação Materna , Camundongos , Sistema Hipófise-Suprarrenal/metabolismo , Serotonina/metabolismo
10.
Cell Rep ; 40(10): 111271, 2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36070700

RESUMO

Healthy aging is an ambitious aspiration for humans, but neurodegenerative disorders, such as Alzheimer's disease (AD), strongly affect quality of life. Using an integrated omics approach, we investigate alterations in the molecular composition of postmortem hippocampus samples of healthy persons and individuals with AD. Profound differences are apparent between control and AD male and female cohorts in terms of up- and downregulated metabolic pathways. A decrease in the insulin response is evident in AD when comparing the female with the male group. The serine metabolism (linked to the glycolytic pathway and generating the N-methyl-D-aspartate [NMDA] receptor coagonist D-serine) is also significantly modulated: the D-Ser/total serine ratio represents a way to counteract age-related cognitive decline in healthy men and during AD onset in women. These results show how AD changes and, in certain respects, almost reverses sex-specific proteomic and metabolomic profiles, highlighting how different pathophysiological mechanisms are active in men and women.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/metabolismo , Feminino , Hipocampo/metabolismo , Humanos , Insulina/metabolismo , Masculino , Proteômica , Qualidade de Vida , Receptores de N-Metil-D-Aspartato/metabolismo , Serina/metabolismo
11.
Neuroreport ; 33(14): 623-628, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-36062512

RESUMO

N-methyl-D-aspartate (NMDA) receptor antagonists mediate adult neurogenic effects. Here, the neurogenic effect of a new NMDA receptor antagonist endowed with neuroprotective effects in Alzheimer's disease mice model. Nine-month-old senescence-accelerated mouse prone 8 (SAMP8) with UB-ALT-EV were orally treated. 5-Bromo-2-deoxyuridine (BrdU) (50 mg/kg) was 3× injected I.P. every 2 h. After 28 days of treatment, SAMP8-treated group improved working memory. Moreover, the number of BrdU+ cells and DCX+ cells in the SAMP8 dentate gyrus (DG) was significantly increased. GFAP+ cells were not affected by treatment. Together, these results provided evidence that UB-ALT-EV promotes the survival and proliferation of neural progenitor cells in the aged SAMP8 hippocampus.


Assuntos
Células-Tronco Neurais , Receptores de N-Metil-D-Aspartato , Envelhecimento , Animais , Bromodesoxiuridina , Hipocampo/metabolismo , Camundongos , Células-Tronco Neurais/metabolismo , Neurogênese , Receptores de N-Metil-D-Aspartato/metabolismo
12.
Open Biol ; 12(9): 220188, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36067793

RESUMO

Zinc is an essential trace element that stabilizes protein structures and allosterically modulates a plethora of enzymes, ion channels and neurotransmitter receptors. Labile zinc (Zn2+) acts as an intracellular and intercellular signalling molecule in response to various stimuli, which is especially important in the central nervous system. Zincergic neurons, characterized by Zn2+ deposits in synaptic vesicles and presynaptic Zn2+ release, are found in the cortex, hippocampus, amygdala, olfactory bulb and spinal cord. To provide an overview of synaptic Zn2+ and intracellular Zn2+ signalling in neurons, the present paper summarizes the fluorescent sensors used to detect Zn2+ signals, the cellular mechanisms regulating the generation and buffering of Zn2+ signals, as well as the current perspectives on their pleiotropic effects on phosphorylation signalling, synapse formation, synaptic plasticity, as well as sensory and cognitive function.


Assuntos
Transdução de Sinais , Zinco , Hipocampo/metabolismo , Neurônios/metabolismo , Bulbo Olfatório/fisiologia , Transdução de Sinais/fisiologia , Zinco/metabolismo
13.
Behav Pharmacol ; 33(7): 492-504, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36148837

RESUMO

The intrinsic pain inhibitory mechanisms can be activated by fear, anxiety, and stress. Stressful experiences produce analgesia, referred to as stress-induced analgesia (SIA). Major components of the limbic system, including the ventral tegmental area, nucleus accumbens, amygdala, and hippocampus, are involved in the SIA. In this study, we tried to understand the role of dopamine receptors in the cornu ammonis area 1 (CA1) of the hippocampus in the forced swim stress (FSS)-induced analgesia. Stereotaxic surgery was unilaterally performed on 129 adult male Wistar rats weighing 220-280 g. SCH23390 (0.25, 1, and 4 µg/0.5 µl saline) or sulpiride (0.25, 1, and 4 µg/0.5 µl DMSO), as D1- and D2-like dopamine receptor antagonists, respectively, were microinjected into the CA1 area, 5 min before exposure to FSS for a 6-min period. The vehicle groups received saline or DMSO instead of SCH23390 or sulpiride, respectively. The formalin test was done using formalin injection (50 µl; 2.5%) into the plantar surface of the rat's hind paw immediately after exposure to FSS. The results demonstrated that FSS produces analgesia during the early and late phases of the formalin test. However, intra-CA1 microinjection of SCH23390 or sulpiride attenuated the FSS-induced analgesia in both phases of the formalin test. This study provides new insight into the role of D1- and D2-like dopamine receptors in the CA1 area in the FSS-induced analgesia during persistent inflammatory pain.


Assuntos
Analgesia , Sulpirida , Animais , Benzazepinas/farmacologia , Dimetil Sulfóxido , Modelos Animais de Doenças , Antagonistas de Dopamina/farmacologia , Formaldeído , Hipocampo/metabolismo , Masculino , Dor/tratamento farmacológico , Ratos , Ratos Wistar , Receptores Dopaminérgicos , Receptores de Dopamina D1/metabolismo , Sulpirida/farmacologia
14.
Neuropharmacology ; 219: 109237, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36049536

RESUMO

The transcription factor cAMP response element-binding protein (CREB) is widely regarded as orchestrating the genomic response that underpins a range of physiological functions in the central nervous system, including learning and memory. Of the means by which CREB can be regulated, emphasis has been placed on the phosphorylation of a key serine residue, S133, in the CREB protein, which is required for CREB-mediated transcriptional activation in response to a variety of activity-dependent stimuli. Understanding the role of CREB S133 has been complicated by molecular genetic techniques relying on over-expression of either dominant negative or activating transgenes that may distort the physiological role of endogenous CREB. A more elegant recent approach targeting S133 in the endogenous CREB gene has yielded a mouse with constitutive replacement of this residue with alanine (S133A), but has generated results (no behavioural phenotype and no effect on gene transcription) at odds with contemporary views as to the role of CREB S133, and which may reflect compensatory changes associated with the constitutive mutation. To avoid this potential complication, we generated a post-natal and forebrain-specific CREB S133A mutant in which the expression of the mutation was under the control of CaMKIIα promoter. Using male and female mice we show that CREB S133 is necessary for spatial cognitive flexibility, the regulation of basal synaptic transmission, and for the expression of long-term potentiation (LTP) in hippocampal area CA1. These data point to the importance of CREB S133 in neuronal function, synaptic plasticity and cognition in the mammalian brain.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Potenciação de Longa Duração , Alanina , Animais , Cognição , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Feminino , Hipocampo/metabolismo , Potenciação de Longa Duração/fisiologia , Masculino , Mamíferos/metabolismo , Camundongos , Fosforilação , Serina/genética , Serina/metabolismo
15.
Neuropharmacology ; 219: 109238, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36055413

RESUMO

Dopamine and cAMP-regulated phosphoprotein, 32 kDa (DARPP-32)-mediated protein phosphatase 1 (PP1) inhibition leads to the increase in phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR), which potentiates channel activity and current and thereby may facilitate seizure activity. In the present study, we found that pyridoxal-5'-phosphate phosphatase/chronophin (PLPP/CIN) transiently dephosphorylated DARPP-32 serine (S) 97 site in the early time window, and casein kinase 2 (CK2) subsequently phosphorylated this site in the later time points after kainic acid (KA) injection, which increased the latency of seizure onset in response to KA, but exacerbated the intensity (severity), duration and progression of seizures. TMCB (a CK2 inhibitor) delayed the seizure onset in response to KA, concomitant with the reduced DARPP-32 S97 phosphorylation. Therefore, our findings suggest that PLPP/CIN may play an important role in the latency of seizure onset via DARPP-32-PP1-AMPAR signaling pathway, and may be one of the potential therapeutic targets for medication of seizure or epilepsy.


Assuntos
Ácido Caínico , Serina , Animais , Caseína Quinase II/metabolismo , Dopamina/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Hipocampo/metabolismo , Ácido Caínico/farmacologia , Camundongos , Fosfatos/metabolismo , Fosfoproteínas/metabolismo , Fosforilação , Proteína Fosfatase 1/metabolismo , Piridoxal , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/metabolismo , Serina/metabolismo , Serina/farmacologia
16.
Mol Neurobiol ; 59(11): 6874-6895, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36048340

RESUMO

Stress-induced neuroinflammation is a hallmark of modern society and has been linked to various emotional disorders, including anxiety. However, how microglia-associated neuroinflammation under chronic unpredictable mild stress (CUMS) alters mitochondrial function and subsequent medial prefrontal cortex-hippocampus (mPFC-HIPP) connectivity remains obscure. We speculated that CUMS might induce neuroinflammation, which involves altered mitochondrial protein levels, blockade of neuroinflammation by a microglial modulator, minocycline, protects against CUMS-induced alterations. Mice were exposed to CUMS for 3 weeks and received minocycline (50 mg/kg) intraperitoneally for 7 consecutive days during the 3rd week of CUMS. Novelty-suppressed feeding test and contextual anxiety test assessed anxiety-like behavior. Western blotting and immunofluorescent staining were employed to evaluate levels of proteins involved in neuroinflammation and mitochondrial function. In vivo dual-site extracellular recordings of local field potential (LFP) were conducted to evaluate the oscillatory activity and brain connectivity in mPFC-HIPP circuitry. We show that CUMS results in excessive microglial activation accompanied by aberrant levels of mitochondrial proteins, such as ATP-5A and the fission protein, Drp-1, increased oxidative stress indicated by elevated levels of nitrotyrosine, and decreased Nrf-2 levels. Furthermore, CUMS causes downregulation of α1 subunit of GABAAR, vesicular GABA transporter (Vgat), and glutamine synthetase (GS), leading to impaired LFP and connectivity of the mPFC-HIPP circuitry. Strikingly, blockage of microglial activation by minocycline ameliorates CUMS-induced aberrant levels of mitochondrial and GABAergic signaling proteins and prevents CUMS-induced anxiety-like behavior in mice. To the end, the study revealed that microglia is critically involved in stress-induced neuroinflammation, which may underlie the molecular mechanism of CUMS-induced anxiety behavior.


Assuntos
Depressão , Minociclina , Trifosfato de Adenosina/metabolismo , Animais , Depressão/metabolismo , Modelos Animais de Doenças , Glutamato-Amônia Ligase/metabolismo , Hipocampo/metabolismo , Camundongos , Minociclina/farmacologia , Minociclina/uso terapêutico , Proteínas Mitocondriais/metabolismo , Doenças Neuroinflamatórias , Córtex Pré-Frontal/metabolismo , Estresse Psicológico/complicações , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Ácido gama-Aminobutírico/metabolismo
17.
Toxicol Pathol ; 50(6): 754-762, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36125102

RESUMO

As regulators of homeostasis, astrocytes undergo morphological changes after injury to limit the insult in central nervous system (CNS). Trimethyltin (TMT) is a known neurotoxicant that induces reactive astrogliosis in rat CNS. To evaluate the degree of reactive astrogliosis, the assessment relies on manual counting or semiquantitative scoring. We hypothesized that deep learning algorithm could be used to identify the grade of reactive astrogliosis in immunoperoxidase-stained sections in a quantitative manner. The astrocyte algorithm was created using a commercial supervised deep learning platform and the used training set consisted of 940 astrocytes manually annotated from hippocampus and cortex. Glial fibrillary acidic protein-labeled brain sections of rat TMT model were analyzed for astrocytes with the trained algorithm. Algorithm was able to count the number of individual cells, cell areas, and circumferences. The astrocyte algorithm identified astrocytes with varying sizes from immunostained sections with high confidence. Algorithm analysis data revealed a novel morphometric marker based on cell area and circumference. This marker correlated with the time-dependent progression of the neurotoxic profile of TMT. This study highlights the potential of using novel deep learning-based image analysis tools in neurotoxicity and pharmacology studies.


Assuntos
Aprendizado Profundo , Compostos de Trimetilestanho , Animais , Astrócitos/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Gliose , Hipocampo/metabolismo , Ratos , Compostos de Trimetilestanho/toxicidade
18.
Epilepsy Res ; 186: 107018, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36126608

RESUMO

Epilepsy is a chronic neurological disorder and there is increasing evidence about the role of inflammation in epileptogenesis. These findings have spurred the search for new immunomodulatory approaches that can improve prognosis. Using an animal model of chemically-induced epileptic seizures, we tested exercise alone as non-pharmacological therapy, and exercise combined with an anti-inflammatory drug. Five groups were used: sedentary, diazepam, aerobic exercise alone, aerobic exercise combined with an anti-inflammatory drug, and naive control. Our goal was to compare the severity of the epileptic seizures between groups as well as seizure latency in a pentylenetetrazole-induced paradigm. Cytokine levels (IL-1ß, TNF-α, and IL-10) were measured. Both exercise groups showed a reduction in seizure severity and lower levels of pro-inflammatory cytokines in the cortex, while the levels of cytokines in the hippocampus remained unaffected.


Assuntos
Epilepsia , Pentilenotetrazol , Animais , Anti-Inflamatórios/efeitos adversos , Citocinas/metabolismo , Diazepam/uso terapêutico , Modelos Animais de Doenças , Epilepsia/tratamento farmacológico , Exercício Físico , Hipocampo/metabolismo , Interleucina-10 , Pentilenotetrazol/toxicidade , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismo
19.
Clinics (Sao Paulo) ; 77: 100104, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36137346

RESUMO

BACKGROUND: Postoperative cognitive dysfunction is widely recognized as severe postoperative central nervous dysfunction and has a significant impact on the 'patient's physical and mental health. METHODS: Postoperative models of tibial fracture in aged rats were established, including the control group, model group, CCL11 protein injection group, and saline injection group. Morris water maze test was used to detect the behavioral characteristics of rats. Enzyme-Linked Immunosorbent Assay was used or determine the content of CCL11 and CXCL10. Immunofluorescence staining was used to detect the distribution of CD14+CD163+macrophages in colon tissues and CD11b+CCR3+microglia cells in hippocampal tissues. Western blot analyzed NOX1 and STAT3 expression in hippocampus tissues. RESULTS: Water maze test results confirmed severe cognitive impairment in CCL11 rats. The content of CCL11 and CXCL10 in the CCL11 group was much higher than that of the model group. The distribution of macrophage and microglia cells in the CCL11 model group was greater than that in the model group and the saline group. The expression of NOX1 and STAT3 in the CCL11 group was higher compared with the model group. CONCLUSION: Abnormal macrophage function and excessive CCL11 secretion were observed in the rats with lower limb fractures after surgery. Postoperative central inflammation in rats with lower limb fracture induced postoperative cognitive dysfunction through the gut-brain axis molecular mechanism.


Assuntos
Disfunção Cognitiva , Complicações Cognitivas Pós-Operatórias , Animais , Eixo Encéfalo-Intestino , Disfunção Cognitiva/etiologia , Hipocampo/metabolismo , Inflamação/metabolismo , Complicações Cognitivas Pós-Operatórias/etiologia , Ratos
20.
BMC Neurosci ; 23(1): 54, 2022 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-36163017

RESUMO

BACKGROUND: Exercise boosts the health of some brain parts, such as the hippocampus and hypothalamus. Several studies show that long-term exercise improves spatial learning and memory, enhances hypothalamic leptin sensitivity, and regulates energy balance. However, the effect of exercise on the hippocampus and hypothalamus is not fully understood. The study aimed to find epigenetic modifications or changes in gene expression of the hippocampus and hypothalamus due to exercise. METHODS: Male C57BL/6 mice were randomly divided into sedentary and exercise groups. All mice in the exercise group were subjected to treadmill exercise 5 days per week for 1 h each day. After the 12-week exercise intervention, the hippocampus and hypothalamus tissue were used for RNA-sequencing or molecular biology experiments. RESULTS: In both groups, numerous differentially expressed genes of the hippocampus (up-regulated: 53, down-regulated: 49) and hypothalamus (up-regulated: 24, down-regulated: 40) were observed. In the exercise group, increased level of N6-methyladenosine (m6A) was observed in the hippocampus and hypothalamus (p < 0.05). Furthermore, the fat mass and obesity-associated gene (FTO) of the hippocampus and hypothalamus were down-regulated in the exercise group (p < 0.001). In addition, the Fto co-expression genes of the mouse brain were studied and analyzed using database to determine the potential roles of exercise-downregulated FTO in the brain. CONCLUSION: The findings demonstrate that long-term exercise might elevates the levels of m6A-tagged transcripts in the hippocampus and hypothalamus via down-regulation of FTO. Hence, exercise might be an effective intervention for epigenetic modification.


Assuntos
Leptina , Animais , Epigênese Genética , Hipocampo/metabolismo , Hipotálamo/metabolismo , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA/metabolismo
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