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1.
J Neurosci ; 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32054675

RESUMO

The bed nucleus of the stria terminalis (BNST) is a forebrain region highly responsive to stress that expresses corticotropin-releasing hormone (CRH) and is implicated in mood disorders such as anxiety. However, the exact mechanism by which chronic stress induces CRH-mediated dysfunction in BNST and maladaptive behaviors remains unclear. Here, we first confirmed that selective acute optogenetic activation of the oval nucleus (ovBNST) increases maladaptive avoidance behavior in male mice. Next, we found that a 6-week chronic variable mild stress (CVMS) paradigm resulted in maladaptive behaviors and increased cellular excitability of ovBNST CRH neurons by potentiating mEPSC amplitude, altering the resting membrane potential, and diminishing M-currents (a voltage-gated K+ current that stabilizes membrane potential) in ex vivo slices. CVMS also increased c-fos+ cells in ovBNST following handling. We next investigated potential molecular mechanism underlying the electrophysiological effects and observed that CVMS increased CRH+ and pituitary adenylate cyclase-activating polypeptide+ (PACAP; a CRH upstream regulator) cells, but decreased striatal-enriched protein tyrosine phosphatase+ (STEP; a CRH inhibitor) cells in ovBNST. Interestingly, the electrophysiological effects of CVMS were reversed by CRHR1-selective antagonist R121919 application. CVMS also activated PKA in BNST, and chronic infusion of the PKA-selective antagonist H89 into ovBNST reversed the effects of CVMS. Co-administration of the PKA agonist forskolin prevented the beneficial effects of R121919. Finally, CVMS induced an increase in surface expression of phosphorylated GluR1 (S845) in BNST. Collectively, these findings highlight a novel and indispensable stress-induced role for PKA-dependent CRHR1 signaling in activating BNST CRH neurons and mediating maladaptive behaviors.Significance Statement:Chronic stress and acute activation of oval BNST (ovBNST) induces maladaptive behaviors in rodents. However, the precise molecular and electrophysiological mechanisms underlying these effects remain unclear. Here, we demonstrate that chronic variable mild stress (CVMS) activates CRH-associated stress signaling and CRH neurons in ovBNST by potentiating mEPSC amplitude and decreasing M-current in male mice. These electrophysiological alterations and maladaptive behaviors were mediated by BNST PKA-dependent CRHR1 signaling. Our results thus highlight the importance of BNST CRH dysfunction in chronic stress-induced disorders.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32070693

RESUMO

The retinoid family members, including vitamin A and derivatives like 13-cis-retinoic acid (ITT) and all-trans retinoic acid (ATRA), are essential for normal functioning of the developing and adult brain. When vitamin A intake is excessive, however, or after ITT treatment, increased risks have been reported for depression and suicidal ideation. Here, we review pre-clinical and clinical evidence supporting association between retinoids and depressive disorders and discuss possible underlying neurobiological mechanisms. Clinical evidence includes case reports and studies from healthcare databases and government agency sources. Preclinical studies further confirmed that RA treatment induces hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis and typical depressive-like behavior. Notably, the molecular components of the RA signaling are widely expressed throughout adult brain. We further discuss three most important brain systems, hippocampus, hypothalamus and orbitofrontal cortex, as major brain targets of RA. Finally, we highlight altered monoamine systems in the pathophysiology of RA-associated depression. A better understanding of the neurobiological mechanisms underlying RA-associated depression will provide new insights in its etiology and development of effective intervention strategies.

3.
Neurosci Lett ; 714: 134603, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31693931

RESUMO

The tree shrew is susceptible to stimuli. However, mapping of c-Fos expression in male tree shrew forebrain has not been explored. The present results provided the first detailed mapping of c-Fos expression in the forebrain of the tree shrew (Tupaia belangeri chinensis). Acute restraint stress rapidly increased the density of c-Fos-immunoreactive (-ir) neurons in the medial orbital cortex (MO), infralimbic cortex, intermediate part of the lateral septal nucleus (LSi), ventral part of the lateral septal nucleus (LSv), anterior part of the bed nucleus of the stria terminalis, posterior part of the bed nucleus of the stria terminalis (STP), paraventricular nucleus of the hypothalamus, supraoptic nucleus, lateral hypothalamic area, ventromedial hypothalamic nucleus (VMH), and medial amygdaloid nucleus (MeA). Furthermore, a significant increase in c-Fos expression was observed in the MO, LSi, LSv, STP, VMH, arcuate hypothalamic nucleus, anterior amygdaloid area, MeA, and cortical amygdaloid nucleus immediately after acute footshock stress. In addition, the distinct patterns of c-Fos expression in the forebrain were shown in context-, restraint-, or footshock-treated tree shrews. In general, the present study provides the first detailed maps of c-Fos expression in male tree shrew forebrain immediately after various stimuli.

4.
J Comp Neurol ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31674014

RESUMO

The tree shrew (Tupaia belangeri chinensis) is the closest living relative of primates. Yet, little is known about the anatomical distribution of tyrosine hydroxylase (TH)-immunoreactive (ir) structures in the hypothalamus of the tree shrew. Here, we provide the first detailed description of the distribution of TH-ir neurons in the hypothalamus of tree shrews via immunohistochemical techniques. TH-ir neurons were widely distributed throughout the hypothalamus of tree shrew. The majority of hypothalamic TH-ir neurons were found in the paraventricular hypothalamic nucleus (PVN) and supraoptic nucleus (SON), as was also observed in the human hypothalamus. In contrast, rare TH-ir neurons were localized in the PVN and SON of rats. Vasopressin (AVP) colocalized with TH-ir neurons in the PVN and SON in a large number of neurons, but oxytocin and corticotropin-releasing hormone did not colocalize with TH. In addition, colocalization of TH with AVP was also observed in the other hypothalamic regions. Moreover, TH-ir neurons in the PVN and SON of tree shrews expressed other dopaminergic markers (aromatic l-amino acid decarboxylase and vesicular monoamine transporter, Type 2), further supporting that TH-ir neurons in the PVN and SON were catecholaminergic. These findings provide a detailed description of TH-ir neurons in the hypothalamus of tree shrews and demonstrate species differences in the distribution of this enzyme, providing a neurobiological basis for the participation of TH-ir neurons in the regulation of various hypothalamic functions.

6.
Nat Neurosci ; 22(10): 1649-1658, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31451801

RESUMO

Comorbid depressive symptoms (CDS) in chronic pain are a common health problem, but the neural circuit mechanisms underlying these symptoms remain unclear. Here we identify a novel pathway involving 5-hydroxytryptamine (5-HT) projections from the dorsal raphe nucleus (5-HTDRN) to somatostatin (SOM)-expressing and non-SOM interneurons in the central nucleus of the amygdala (CeA). The SOMCeA neurons project directly to the lateral habenula, an area known involved in depression. Inhibition of the 5-HTDRN→SOMCeA pathway produced depression-like behavior in a male mouse model of chronic pain. Activation of this pathway using pharmacological or optogenetic approaches reduced depression-like behavior in these mice. Human functional magnetic resonance imaging data showed that compared to healthy controls, functional connectivity between the CeA-containing centromedial amygdala and the DRN was reduced in patients with CDS but not in patients in chronic pain without depression. These findings indicate that a novel 5-HTDRN→SOMCeA→lateral habenula pathway may mediate at least some aspects of CDS.


Assuntos
Dor Crônica/patologia , Depressão/patologia , Vias Neurais/patologia , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/patologia , Animais , Comportamento Animal , Dor Crônica/complicações , Dor Crônica/diagnóstico por imagem , Depressão/complicações , Depressão/diagnóstico por imagem , Núcleo Dorsal da Rafe/diagnóstico por imagem , Núcleo Dorsal da Rafe/patologia , Feminino , Habenula/diagnóstico por imagem , Habenula/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/diagnóstico por imagem , Neuralgia/diagnóstico por imagem , Neuralgia/patologia , Optogenética , Serotonina/metabolismo , Somatostatina/metabolismo
7.
PLoS Biol ; 17(8): e3000417, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31469831

RESUMO

Threatening sounds can elicit a series of defensive behavioral reactions in animals for survival, but the underlying neural substrates are not fully understood. Here, we demonstrate a previously unexplored neural pathway in mice that projects directly from the auditory cortex (ACx) to the lateral periaqueductal gray (lPAG) and controls noise-evoked defensive behaviors. Electrophysiological recordings showed that the lPAG could be excited by a loud noise that induced an escape-like behavior. Trans-synaptic viral tracing showed that a great number of glutamatergic neurons, rather than GABAergic neurons, in the lPAG were directly innervated by those in layer V of the ACx. Activation of this pathway by optogenetic manipulations produced a behavior in mice that mimicked the noise-evoked escape, whereas inhibition of the pathway reduced this behavior. Therefore, our newly identified descending pathway is a novel neural substrate for noise-evoked escape and is involved in controlling the threat-related behavior.

8.
ACS Chem Neurosci ; 10(8): 3859-3867, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31343167

RESUMO

A reliable and reproducible detection of Aß deposits would be beneficial for the early diagnosis of Alzheimer's disease (AD). In the present study, the feasibility of applying chemical exchange saturation transfer (CEST) for Aß deposit detection using angiopep-2 as a probe was evaluated, and it was demonstrated that CEST could detect angiopep-2 and Aß-angiopep-2 aggregates in vitro. Furthermore, APP/PS1 mice injected with angiopep-2 exhibited a significantly higher in vivo CEST effect when compared with controls. The distribution of Aß deposits detected by CEST imaging was consistent with the histological staining results. The present study is the first to report a reliable exogenous CEST probe to noninvasively evaluate Aß deposits in APP/PS1 mice. Furthermore, these results demonstrate the potential for clinical AD diagnosis and Aß-targeted drug therapy assessment using CEST imaging with the angiopep-2 probe.

9.
Neurosci Bull ; 35(2): 244-252, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30604279

RESUMO

Investigating the pathophysiological mechanisms underlying brain disorders is a priority if novel therapeutic strategies are to be developed. In vivo studies of animal models and in vitro studies of cell lines/primary cell cultures may provide useful tools to study certain aspects of brain disorders. However, discrepancies among these studies or unsuccessful translation from animal/cell studies to human/clinical studies often occur, because these models generally represent only some symptoms of a neuropsychiatric disorder rather than the complete disorder. Human brain slice cultures from postmortem tissue or resected tissue from operations have shown that, in vitro, neurons and glia can stay alive for long periods of time, while their morphological and physiological characteristics, and their ability to respond to experimental manipulations are maintained. Human brain slices can thus provide a close representation of neuronal networks in vivo, be a valuable tool for investigation of the basis of neuropsychiatric disorders, and provide a platform for the evaluation of novel pharmacological treatments of human brain diseases. A brain bank needs to provide the necessary infrastructure to bring together donors, hospitals, and researchers who want to investigate human brain slices in cultures of clinically and neuropathologically well-documented material.


Assuntos
Encéfalo , Técnicas de Cultura de Tecidos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Encefalopatias/tratamento farmacológico , Encefalopatias/fisiopatologia , Humanos
10.
IBRO Rep ; 5: 137-146, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30591954

RESUMO

As a central player of the hypothalamic-pituitary-adrenal (HPA) axis, the corticotropin -releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) determine the state of HPA axis and play a key role in stress response. Evidence supports that during stress response the transcription and expression of CRH was finely tuned, which involved cis-element-transcriptional factor (TF) interactions and epigenetic mechanisms. Here we reviewed recent progress in CRH transcription regulation from DNA methylation to classic TFs regulation, in which a number of paired receptors were involved. The imbalance of multiple paired receptors in regulating the activity of CRH neurons indicates a possible molecular network mechanisms underlying depression etiology and directs novel therapeutic strategies of depression in the future.

11.
J Comp Neurol ; 526(17): 2744-2775, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30155886

RESUMO

The cerebellum is involved in the control of movement, emotional responses, and reward processing. The tree shrew is the closest living relative of primates. However, little is known not only about the systematic nomenclature for the tree shrew cerebellum but also about the detailed neurochemical characterization and afferent projections. In this study, Nissl staining and acetylcholinesterase histochemistry were used to reveal anatomical features of the cerebellum of tree shrews (Tupaia belangeri chinensis). The cerebellar cortex presented a laminar structure. The morphological characteristics of the cerebellum were comprehensively described in the coronal, sagittal, and horizontal sections. Moreover, distributive maps of calbindin-immunoreactive (-ir) cells in the Purkinje cell layer of the cerebellum of tree shrews were depicted using coronal, sagittal, and horizontal schematics. In addition, 5th cerebellar lobule (5Cb)-projecting neurons were present in the pontine nuclei, reticular nucleus, spinal vestibular nucleus, ventral spinocerebellar tract, and inferior olive of the tree shrew brain. The anterior part of the paramedian lobule of the cerebellum (PMa) received mainly strong innervation from the lateral reticular nucleus, inferior olive, pontine reticular nucleus, spinal trigeminal nucleus, pontine nuclei, and reticulotegmental nucleus of the pons. The present results provide the first systematic nomenclature, detailed atlas of the whole cerebellum, and whole-brain mapping of afferent projections to the 5Cb and PMa in tree shrews. Our findings provide morphological support for tree shrews as an alternative model for studies of human cerebellar pathologies.


Assuntos
Cerebelo/anatomia & histologia , Neuroquímica , Neurônios Aferentes/fisiologia , Tupaiidae/fisiologia , Acetilcolinesterase/análise , Acetilcolinesterase/metabolismo , Animais , Mapeamento Encefálico , Calbindinas/metabolismo , Córtex Cerebelar/anatomia & histologia , Córtex Cerebelar/química , Córtex Cerebelar/citologia , Cerebelo/química , Cerebelo/citologia , Imuno-Histoquímica , Masculino , Ponte/anatomia & histologia , Ponte/química , Ponte/citologia , Células de Purkinje/fisiologia , Terminologia como Assunto
12.
Neurosci Bull ; 34(3): 405-418, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29508249

RESUMO

The striatum and globus pallidus are principal nuclei of the basal ganglia. Nissl- and acetylcholinesterase-stained sections of the tree shrew brain showed the neuroanatomical features of the caudate nucleus (Cd), internal capsule (ic), putamen (Pu), accumbens, internal globus pallidus, and external globus pallidus. The ic separated the dorsal striatum into the Cd and Pu in the tree shrew, but not in rats and mice. In addition, computer-based 3D images allowed a better understanding of the position and orientation of these structures. These data provided a large-scale atlas of the striatum and globus pallidus in the coronal, sagittal, and horizontal planes, the first detailed distribution of parvalbumin-immunoreactive cells in the tree shrew, and the differences in morphological characteristics and density of parvalbumin-immunoreactive neurons between tree shrew and rat. Our findings support the tree shrew as a potential model for human striatal disorders.


Assuntos
Corpo Estriado/anatomia & histologia , Globo Pálido/anatomia & histologia , Tupaiidae/anatomia & histologia , Acetilcolinesterase/metabolismo , Animais , Mapeamento Encefálico , Corpo Estriado/citologia , Corpo Estriado/metabolismo , Globo Pálido/citologia , Globo Pálido/metabolismo , Imagem Tridimensional , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Neurônios/metabolismo , Parvalbuminas/metabolismo , Ratos , Ratos Sprague-Dawley , Estatísticas não Paramétricas
13.
Brain Pathol ; 28(4): 536-547, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-28752602

RESUMO

Altered levels of steroids have been reported in the brain, cerebral spinal fluid and plasma of patients with mood disorders. Neuroimaging studies have reported both functional and structural alterations in mood disorders, for instance in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC). In order to determine whether the endogenous production of steroids is altered in the ACC and DLPFC of patients with major depressive disorder (MDD) or bipolar disorder (BPD), quantitative real-time PCR was performed to detect mRNA expression level of key enzymes in the steroid biosynthetic pathways. In MDD, a significant decrease in mRNA level of cytochrome P450 17A1 (CYP17A1, synthesizing C19 ketosteroids) in the ACC and a significant increase in mRNA levels of hydroxysteroid sulfotransferase 2A1 [SULT2A1, catalyzing the sulfate conjugation of dehydroepiandrosterone (DHEA)] were observed in the DLPFC, suggesting alterations in DHEA and its sulfate metabolite DHEAS levels. Decreased intensity and distribution of CYP17A1 immunohistochemical staining was found in the ACC of MDD patients. Interestingly, there was a significant positive correlation between the mRNA levels of CYP17A1 and tyrosine-related kinase B (TrkB) full length isoform. In a unique post-mortem human brain slice culture paradigm, BDNF mRNA expression was found to be significantly increased following incubation with DHEA. Together, these data indicate a close relationship between DHEA and BDNF-TrkB pathways in depression. Furthermore, in the DLPFC, higher mRNA levels of 11ß-hydroxysteroid dehydrogenase-1 (HSD11B1, reducing cortisone to the active hormone cortisol) and steroidogenic acute regulatory protein (STAR, facilitating the shuttle of cholesterol through the intermembrane space) were found in the MDD patients and BPD patients, respectively. In conclusion, this study suggests the presence of a disturbance in the endogenous synthesis of DHEA and DHEAS in mood disorders, which has a close relationship with BDNF-TrkB signaling.


Assuntos
Transtorno Bipolar/metabolismo , Transtorno Depressivo Maior/metabolismo , Transtornos do Humor/metabolismo , Córtex Pré-Frontal/metabolismo , Esteroides/biossíntese , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Feminino , Giro do Cíngulo/metabolismo , Humanos , Masculino , Glicoproteínas de Membrana/biossíntese , RNA Mensageiro/metabolismo , Receptor trkB/biossíntese , Transdução de Sinais , Esteroide 17-alfa-Hidroxilase/biossíntese , Sulfotransferases/biossíntese
14.
Mol Neurodegener ; 12(1): 38, 2017 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-28499404

RESUMO

BACKGROUND: Herpes simplex virus type 1 strain 129 (H129) has represented a promising anterograde neuronal circuit tracing tool, which complements the existing retrograde tracers. However, the current H129 derived tracers are multisynaptic, neither bright enough to label the details of neurons nor capable of determining direct projection targets as monosynaptic tracer. METHODS: Based on the bacterial artificial chromosome of H129, we have generated a serial of recombinant viruses for neuronal circuit tracing. Among them, H129-G4 was obtained by inserting binary tandemly connected GFP cassettes into the H129 genome, and H129-ΔTK-tdT was obtained by deleting the thymidine kinase (TK) gene and adding tdTomato coding gene to the H129 genome. Then the obtained viral tracers were tested in vitro and in vivo for the tracing capacity. RESULTS: H129-G4 is capable of transmitting through multiple synapses, labeling the neurons by green florescent protein, and visualizing the morphological details of the labeled neurons. H129-ΔTK-tdT neither replicates nor spreads in neurons alone, but transmits to and labels the postsynaptic neurons with tdTomato in the presence of complementary expressed TK from a helper virus. H129-ΔTK-tdT is also capable to map the direct projectome of the specific neuron type in the given brain regions in Cre transgenic mice. In the tested brain regions where circuits are well known, the H129-ΔTK-tdT tracing patterns are consistent with the previous results. CONCLUSIONS: With the assistance of the helper virus complimentarily expressing TK, H129-ΔTK-tdT replicates in the initially infected neuron, transmits anterogradely through one synapse, and labeled the postsynaptic neurons with tdTomato. The H129-ΔTK-tdT anterograde monosynaptic tracing system offers a useful tool for mapping the direct output in neuronal circuitry. H129-G4 is an anterograde multisynaptic tracer with a labeling signal strong enough to display the details of neuron morphology.


Assuntos
Corantes Fluorescentes , Proteínas de Fluorescência Verde , Vias Neurais/citologia , Neurônios/citologia , Coloração e Rotulagem/métodos , Animais , Herpesvirus Humano 1 , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
15.
Eur J Med Chem ; 124: 117-128, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27565554

RESUMO

A series of 6-methoxy indanone derivatives was synthesized and evaluated as potential probes for ß-amyloid plaque imaging in Alzheimer's disease (AD). Two derivatives (5d and 5k) displayed significant binding abilities in fluorescent staining experiments using the brain sections of AD patients. Two derivatives showed high binding affinities to ß-amyloid aggregates (5j, Ki = 5.82 ± 0.19 nM) and brain homogenates of AD patients (5j, Ki = 18.96 ± 0.28 nM) in in vitro binding assay. With a log P value of 3.45, [125I]5k exhibited an excellent initial brain uptake (5.29%ID g-1, 2 min after i.v.) and a fast clearance from the brain in biodistribution experiments in normal mice. In autoradiography, [125I]5k exhibited an obvious binding ability to ß-amyloid plaques and a relatively low nonspecific binding in the brain sections of AD patients (in vitro) and APP/PS1 transgenic mice (in vitro and ex vivo). Results suggest that 5k is a potential probe for detecting ß-amyloid plaques in vivo.


Assuntos
Doença de Alzheimer/complicações , Indanos/química , Sondas Moleculares/química , Placa Amiloide/complicações , Placa Amiloide/diagnóstico por imagem , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Estabilidade de Medicamentos , Indanos/metabolismo , Indanos/farmacocinética , Masculino , Camundongos , Sondas Moleculares/metabolismo , Sondas Moleculares/farmacocinética , Placa Amiloide/metabolismo , Distribuição Tecidual
16.
Neuroscience ; 333: 162-80, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27436534

RESUMO

The bed nucleus of the stria terminalis (BST) plays an important role in integrating and relaying input information to other brain regions in response to stress. The cytoarchitecture of the BST in tree shrews (Tupaia belangeri chinensis) has been comprehensively described in our previous publications. However, the inputs to the BST have not been described in previous reports. The aim of the present study was to investigate the sources of afferent projections to the BST throughout the brain of tree shrews using the retrograde tracer Fluoro-Gold (FG). The present results provide the first detailed whole-brain mapping of BST-projecting neurons in the tree shrew brain. The BST was densely innervated by the prefrontal cortex, entorhinal cortex, ventral subiculum, amygdala, ventral tegmental area, and parabrachial nucleus. Moreover, moderate projections to the BST originated from the medial preoptic area, supramammillary nucleus, paraventricular thalamic nucleus, pedunculopontine tegmental nucleus, dorsal raphe nucleus, locus coeruleus, and nucleus of the solitary tract. Afferent projections to the BST are identified in the ventral pallidum, nucleus of the diagonal band, ventral posteromedial thalamic nucleus, posterior complex of the thalamus, interfascicular nucleus, retrorubral field, rhabdoid nucleus, intermediate reticular nucleus, and parvicellular reticular nucleus. In addition, the different densities of BST-projecting neurons in various regions were analyzed in the tree shrew brains. In summary, whole-brain mapping of direct inputs to the BST is delineated in tree shrews. These brain circuits are implicated in the regulation of numerous physiological and behavioral processes including stress, reward, food intake, and arousal.


Assuntos
Núcleos Septais/anatomia & histologia , Tupaiidae/anatomia & histologia , Vias Aferentes/anatomia & histologia , Animais , Imuno-Histoquímica , Masculino , Técnicas de Rastreamento Neuroanatômico , Marcadores do Trato Nervoso , Fotomicrografia , Estilbamidinas
17.
Sci Rep ; 6: 24905, 2016 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-27125313

RESUMO

Stress is increasingly present in everyday life in our fast-paced society and involved in the pathogenesis of many psychiatric diseases. Corticotrophin-releasing-hormone (CRH) plays a pivotal role in regulating the stress responses. The tree shrews are highly vulnerable to stress which makes them the promising animal models for studying stress responses. However, the mechanisms underlying their high stress-susceptibility remained unknown. Here we confirmed that cortisol was the dominate corticosteroid in tree shrew and was significantly increased after acute stress. Our study showed that the function of tree shrew CRH - hypothalamic-pituitary-adrenal (HPA) axis was nearly identical to human that contributed little to their hyper-responsiveness to stress. Using CRH transcriptional regulation analysis we discovered a peculiar active glucocorticoid receptor response element (aGRE) site within the tree shrew CRH promoter, which continued to recruit co-activators including SRC-1 (steroid receptor co-activator-1) to promote CRH transcription under basal or forskolin/dexamethasone treatment conditions. Basal CRH mRNA increased when the aGRE was knocked into the CRH promoter in human HeLa cells using CAS9/CRISPR. The aGRE functioned critically to form the "Stress promoter" that contributed to the higher CRH expression and susceptibility to stress. These findings implicated novel molecular bases of the stress-related diseases in specific populations.


Assuntos
Hidrocortisona/metabolismo , Regiões Promotoras Genéticas , Elementos de Resposta , Estresse Fisiológico , Tupaiidae/fisiologia , Animais , Hormônio Liberador da Corticotropina/biossíntese , Perfilação da Expressão Gênica , Técnicas de Introdução de Genes , Células HeLa , Humanos , Transcrição Genética
18.
Hippocampus ; 26(7): 911-23, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26860546

RESUMO

Clinical studies have highlighted an association between retinoid treatment and depressive symptoms. As we had shown before that chronic application of all-trans retinoic acid (RA) potently activated the hypothalamus-pituitary-adrenal (HPA) stress axis, we here questioned whether RA also induced changes in adult hippocampal neurogenesis, a form of structural plasticity sensitive to stress and implicated in aspects of depression and hippocampal function. RA was applied intracerebroventricularly (i.c.v.) to adult rats for 19 days after which animals were subjected to tests for depressive-like behavior (sucrose preference) and spatial learning and memory (water maze) performance. On day 27, adult hippocampal neurogenesis and astrogliosis was quantified using BrdU (newborn cell survival), PCNA (proliferation), doublecortin (DCX; neuronal differentiation), and GFAP (astrocytes) as markers. RA was found to increase retinoic acid receptor-α (RAR-α) protein expression in the hippocampus, suggesting an activation of RA-induced signaling mechanisms. RA further potently suppressed cell proliferation, newborn cell survival as well as neurogenesis, but not astrogliosis. These structural plasticity changes were significantly correlated with scores for anhedonia, a core symptom of depression, but not with water maze performance. Our results suggest that RA-induced impairments in hippocampal neurogenesis correlate with depression-like symptoms but not with spatial learning and memory in this design. Thus, manipulations aimed to enhance neurogenesis may help ameliorate emotional aspects of RA-associated mood disorders. © 2016 Wiley Periodicals, Inc.


Assuntos
Depressão/induzido quimicamente , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Tretinoína/toxicidade , Anedonia/efeitos dos fármacos , Anedonia/fisiologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Astrócitos/fisiologia , Western Blotting , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Depressão/patologia , Depressão/fisiopatologia , Sacarose na Dieta , Gliose/patologia , Gliose/fisiopatologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Imuno-Histoquímica , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Neurogênese/fisiologia , Neurônios/patologia , Neurônios/fisiologia , Distribuição Aleatória , Ratos Sprague-Dawley , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia , Percepção Gustatória/efeitos dos fármacos , Percepção Gustatória/fisiologia
19.
Curr Neuropharmacol ; 14(4): 307-13, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26644152

RESUMO

Dementia, which can be induced by diverse factors, is a clinical syndrome characterized by the decline of cognitive function. Behavioral and psychological symptoms of dementia (BPSD) include depression, agitation, and aggression. Dementia causes a heavy burden on patients and their caregivers. Patients with BPSD should be assessed comprehensively by practitioners and offered appropriate non-pharmacologic and pharmacologic therapy. Nonpharmacologic therapy has been recommended as the basal treatment for BPSD; however, pharmacologic therapy is required under many situations. Medications, including antipsychotic agents, antidepressants, sedative and hypnotic agents, mood stabilizers, cholinesterase inhibitors, and amantadine, are extensively used in clinical practice. We have reviewed the progression of pharmacologic therapy for BPSD.


Assuntos
Demência/tratamento farmacológico , Amantadina/uso terapêutico , Antidepressivos/uso terapêutico , Antipsicóticos/uso terapêutico , Sintomas Comportamentais/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Feminino , Humanos , Hipnóticos e Sedativos/uso terapêutico , Masculino , Resultado do Tratamento
20.
Behav Brain Res ; 300: 106-13, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26698394

RESUMO

Abscisic acid (ABA), a crucial phytohormone, is distributed in the brains of mammals and has been shown to have antidepressant effects in the chronic unpredictable mild stress test. The forced swim test (FST) is another animal model that can be used to assess antidepressant-like behavior in rodents. Here, we report that the antidepressant effects of ABA are associated with sensitivities to the FST in mice. Based on mean immobility in the 5-min forced swim pre-test, ICR mice were divided into short immobility mice (SIM) and long immobility mice (LIM) substrains. FST was carried out 8 days after drug administration. Learned helplessness, as shown by increased immobility, was only observed in SIM substrain and could be prevented by an 8-day ABA treatment. Our results show that ABA has antidepressant effects in SIM substrain and suggest that mice with learned helplessness might be more suitable for screening potential antidepressant drugs.


Assuntos
Ácido Abscísico/farmacologia , Antidepressivos/farmacologia , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Testes Neuropsicológicos , Animais , Peso Corporal , Transtorno Depressivo/metabolismo , Modelos Animais de Doenças , Predisposição Genética para Doença , Desamparo Aprendido , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , RNA Mensageiro/metabolismo , Distribuição Aleatória , Natação , Sinapsinas/metabolismo
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