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Ulcerative colitis (UC) is a refractory inflammatory bowel disease, which is known to cause psychiatric disorders such as anxiety and depression at a high rate in addition to peripheral inflammatory symptoms. However, the pathogenesis of these psychiatric disorders remains mostly unknown. While prior research revealed that the Enterococcus faecalis 2001 (EF-2001) suppressed UC-like symptoms and accompanying depressive-like behaviors, observed in a UC model using dextran sulfate sodium (DSS), whether it has an anxiolytic effect remains unclear. Therefore, we examined whether EF-2001 attenuates DSS-induced anxiety-like behaviors. Treatment with 2% DSS for seven days induced UC-like symptoms and anxiety-like behavior through the hole-board test, increased serum lipopolysaccharide (LPS) and corticosterone concentration, and p-glucocorticoid receptor (GR) in the prefrontal cortex (PFC), and decreased N-methyl-D-aspartate receptor subunit (NR) 2A and NR2B expression levels in the PFC. Interestingly, these changes were reversed by EF-2001 administration. Further, EF-2001 administration enhanced CAMKII/CREB/BDNF-Drebrin pathways in the PFC of DSS-treated mice, and labeling of p-GR, p-CAMKII, and p-CREB showed colocalization with neurons. EF-2001 attenuated anxiety-like behavior by reducing serum LPS and corticosterone levels linked to the improvement of UC symptoms and by facilitating the CAMKII/CREB/BDNF-Drebrin pathways in the PFC. Our findings suggest a close relationship between UC and anxiety.
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Ansiolíticos , Sulfato de Dextran , Modelos Animales de Enfermedad , Enterococcus faecalis , Animales , Ratones , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Sulfato de Dextran/toxicidad , Masculino , Ansiedad/tratamiento farmacológico , Lipopolisacáridos , Corticosterona/sangre , Corteza Prefrontal/metabolismo , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/microbiología , Ratones Endogámicos C57BLRESUMEN
The gut microbiota is associated with memory; however, the relationship between dysbiosis-induced memory deficits and hippocampal glutamatergic neurons remains unclear. In our study, a mouse dysbiosis model showed impaired memory-related behavior in the passive avoidance test; decreased expression levels of glutaminase, excitatory amino acid transporter (EAAT)1, EAAT2, vesicular glutamate transporter 2, synaptophysin, brain-derived neurotrophic factor, doublecortin, neuronal nuclear protein, glial fibrillary acidic protein, and S100ß; and decreased phosphorylation of N-methyl-D-aspartate receptor subunit 1, calmodulin-dependent protein kinase II, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit 1, and cAMP response element-binding protein in the hippocampus. This suggests that dysbiosis-induced memory dysfunction is associated with the hippocampal glutamatergic nervous system.
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Antibacterianos , Disbiosis , Ratones , Animales , Disbiosis/metabolismo , Hipocampo/metabolismo , Neuronas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transportador 1 de Aminoácidos Excitadores/metabolismoRESUMEN
Impaired olfactory function may be associated with the development of psychiatric disorders such as depression and anxiety; however, knowledge on the mechanisms underlying psychiatric disorders is incomplete. A reversible model of olfactory dysfunction, zinc sulfate (ZnSO4) nasal-treated mice, exhibit depression-like behavior accompanying olfactory dysfunction. Therefore, we investigated olfactory function and depression-like behaviors in ZnSO4-treated mice using the buried food finding test and tail suspension test, respectively; investigated the changes in the hippocampal microglial activity and neurogenesis in the dentate gyrus by immunohistochemistry; and evaluated the inflammation and microglial polarity related-proteins in the hippocampus using western blot study. On day 14 after treatment, ZnSO4-treated mice showed depression-like behavior in the tail suspension test and recovery of the olfactory function in the buried food finding test. In the hippocampus of ZnSO4-treated mice, expression levels of ionized calcium-binding adapter molecule 1 (Iba1), cluster of differentiation 40, inducible nitric oxide synthase, interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, cleaved caspase-3, as well as the number of Iba1-positive cells and cell body size increased, and arginase-1 expression and neurogenesis decreased. Except for the increased IL-6, these changes were prevented by a microglia activation inhibitor, minocycline. The findings suggest that neuroinflammation due to polarization of M1-type hippocampal microglia is involved in depression accompanied with olfactory dysfunction.
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Depresión , Trastornos del Olfato , Humanos , Ratones , Animales , Depresión/metabolismo , Microglía/metabolismo , Interleucina-6/metabolismo , Hipocampo/metabolismoRESUMEN
Clinicians are unable to detect glaucoma until substantial loss or dysfunction of retinal ganglion cells occurs. To this end, novel measures are needed. We have developed an optical imaging solution based on adaptive optics optical coherence tomography (AO-OCT) to discern key clinical features of glaucoma and other neurodegenerative diseases at the cellular scale in the living eye. Here, we test the feasibility of measuring AO-OCT-based reflectance, retardance, optic axis orientation, and angiogram at specifically targeted locations in the living human retina and optic nerve head. Multifunctional imaging, combined with focus stacking and global image registration algorithms, allows us to visualize cellular details of retinal nerve fiber bundles, ganglion cell layer somas, glial septa, superior vascular complex capillaries, and connective tissues. These are key histologic features of neurodegenerative diseases, including glaucoma, that are now measurable in vivo with excellent repeatability and reproducibility. Incorporating this noninvasive cellular-scale imaging with objective measurements will significantly enhance existing clinical assessments, which is pivotal in facilitating the early detection of eye disease and understanding the mechanisms of neurodegeneration.
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Patients with inflammatory bowel disease, including ulcerative colitis (UC) and Crohn's disease, have a high incidence of psychiatric disorders, including depression and anxiety. However, the underlying pathogenic mechanism remains unknown. Dextran sulfate sodium (DSS)-treated mice, a model of UC, exhibit depressive-like behavior and reduced adenosine monophosphate-activated protein kinase (AMPK) activity, which regulates various physiological functions in the brain and gut. However, comprehensive studies on UC pathophysiology with co-occurring depression focused on brain-gut AMPK activity are lacking. Therefore, we aimed to investigate whether resveratrol (RES), an AMPK activator, prevented DSS-induced UC-like symptoms and depressive-like behavior. DSS treatment induced UC-like pathology and depressive-like behavior, as assessed via the tail suspension test. Moreover, western blotting and immunohistochemical studies revealed that DSS increased p-p70S6 kinase (Thr389), p62, tumor necrosis factor-α, interleukin (IL)-1ß, IL-18, NLR family pyrin domain containing 3 (NLRP3), cleaved caspase-1, cleaved Gasdermin-D (GSDMD), and cleaved caspase-3 expression levels in the rectum and hippocampus, and increased CD40, iNOS, and Kelch-like ECH-associated protein 1 expression levels, and the number of Iba1-positive cells in the hippocampus, and decreased p-AMPK and LC3II/I expression levels, and the number of NF-E2-related factor 2 (Nrf2)-positive cells, and reduced neurogenesis in the hippocampus. These changes were reversed by the RES administration. RES also enhanced PGC1α and SOD1 expression in the hippocampus of DSS-treated male mice. Moreover, NLRP3 staining was observed in the neurons and microglia, and cleaved GSDMD staining in neurons in the hippocampus of DSS-treated mice. Notably, RES prevented UC-like pathology and depressive-like behavior and enhancement of autophagy, decreased rectal and hippocampal inflammatory cytokines and inflammasome, and induced the Nrf2-PGC1α-SOD1 pathway in the hippocampus, resulting in neurogenesis in the hippocampal dentate gyrus. Our findings suggest that brain-gut AMPK activation may be an important therapeutic strategy in patients with UC and depression.
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Colitis Ulcerosa , Colitis , Enterocolitis , Humanos , Masculino , Ratones , Animales , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Superóxido Dismutasa-1/metabolismo , Encéfalo/metabolismo , Inflamasomas/metabolismo , Enterocolitis/patología , Hipocampo/metabolismo , Ratones Endogámicos C57BL , Colitis/inducido químicamente , Colitis/patología , Modelos Animales de EnfermedadRESUMEN
Post-stroke cognitive impairment (PSCI) of the complications after stroke has been shown to be involved in brain proinflammatory cytokines such as interleukin (IL)-1ß (IL-lß) and IL-18. In the present study, we examined using acetic acid-induced embolic cerebral infarct (ECI) mice whether post-stroke inflammasome activation is involved in the development of PSCI. In behavioral tests, long-term learning and memory assessed using the passive avoidance test were impaired after ECI. On the other hand, the impairment of short-term learning and memory assessed using the Y-maze test was not observed. Furthermore, the phosphorylated α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit glutamate receptor 1 (GluR1) at Ser 831 and Ser 845 protein was found to be significantly decreased in the dorsal hippocampus of ECI mice. In addition, the expression levels of ionized calcium-binding adapter protein 1 (Iba1), glial fibrillary acidic protein (GFAP), apoptosis-associated speck-like protein containing a caspase recruitment domain / target of methylation-induced silencing 1 (ASC/TMS1), Caspase-1, IL-1ß, IL-18 and tumor necrosis factor-α (TNF-α) were significantly increased in the dorsal hippocampus of ECI mice. These results indicate that development of PSCI after embolic cerebral infarction is due to a decrease in AMPA receptor subunit GluR1 at Ser831 and Ser845 through the inflammasome activation pathway in the dorsal hippocampus.
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Patients with inflammatory bowel disease (IBD) have higher rates of psychiatric pathology including depression. The dextran sulfate sodium (DSS)-treated mice exhibit IBD- and depressive-like phenotypes. A disturbed intestinal environment causes a decrease in serotonin and abnormal myelination in the brain, along with depressive-like behavior in rodents. However, the involvement of these factors in DSS-induced depressive-like behavior in mice remains unclear. In this study, we examined whether myelin proteins in the prefrontal cortex (PFC) and hippocampi were altered in DSS-treated mice, along with the changes in the serotonergic system in the PFC by western blotting and HPLC. The effects of brexpiprazole (Brx), a serotonin modulator, on DSS-induced depressive-like behavior using the tail-suspension test were evaluated. Subsequently, we investigated Brx's effects on the levels of myelin, nodal proteins, and neurotrophic molecules in the PFC with western blotting, and examined the altered node of Ranvier formation by immunohistochemistry. DSS-treated mice showed a reduction in myelin and nodal proteins, dysfunction of the serotonergic system, and impaired formation of the nodes of Ranvier in the PFC. Brx administration prevented the DSS-induced depressive-like behavior and demyelination in the PFC. However, the Brx-mediated effects were inhibited by the selective 5-HT1A antagonist, WAY100635, or the selective TrkB antagonist, ANA-12. Brx decreased the phosphorylation of ERK, CREB, and TrkB along with the expression of BDNF in the PFC of DSS-treated mice. Moreover, the effects of Brx were blocked by WAY100635. These findings indicated that myelination regulated by the activation of the ERK1/2-CREB-BDNF-TrkB pathway in the PFC may be involved in mediating the antidepressant effects of Brx.
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Colitis , Enfermedades Inflamatorias del Intestino , Ratones , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Serotonina/metabolismo , Corteza Prefrontal/metabolismo , Colitis/metabolismo , Enfermedades Inflamatorias del Intestino/metabolismo , Modelos Animales de Enfermedad , Depresión/tratamiento farmacológico , Depresión/prevención & control , Depresión/metabolismoRESUMEN
Alzheimer's disease is associated with marked olfactory dysfunction observed in the early stages. Clinical studies reported that acetylcholinesterase inhibitor donepezil (DNP) attenuated this deficit; however, the underlying mechanism remains unclear. Herein, we aimed to examine the effects and underlying mechanisms of DNP on olfactory deficits in zinc sulfate (ZnSO4) nasal-treated mice, which were used as a model of reversible olfactory impairment. We evaluated olfactory function using the buried food finding test and neurogenesis in the subventricular zone (SVZ) using immunohistochemistry. Finally, we measured the expression of doublecortin (DCX), neuronal nuclear antigen (NeuN), olfactory marker protein, tyrosine hydroxylase (TH), tryptophan hydroxylase 2, glutamic acid decarboxylase 67, p-α-synuclein (Ser129), α-synuclein, p-AMPK, p-p70S6 kinase (p70S6K) (Thr389), LC3 â ¡/â , and p-p62 in the olfactory bulb (OB) by western blotting. On day 7 after treatment, ZnSO4-treated mice exhibited prolonged time to find the buried food, cell proliferation enhancement in the SVZ, increased NeuN, p-α-synuclein (Ser129), and α-synuclein levels, and decreased DCX and TH levels in the OB; except for TH, these changes normalized on day 14 after treatment. Repeated administration of DNP prevented the ZnSO4-induced changes on day 7 after treatment. Moreover, DNP increased p-AMPK and LC3 â ¡/â , and decreased p-p70S6K and p-p62 (Ser351) levels in the OB, suggesting that DNP enhances autophagy in the OB. These findings indicate that DNP may help prevent olfactory dysfunction by autophagy that reduces α-synuclein aggregation via the AMPK/mTOC1 pathway.
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Trastornos del Olfato , Bulbo Olfatorio , Animales , Ratones , Bulbo Olfatorio/metabolismo , alfa-Sinucleína/metabolismo , Donepezilo/farmacología , Sulfato de Zinc/farmacología , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Acetilcolinesterasa/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , AutofagiaRESUMEN
Reduced activity of hippocampal silent information regulator protein 2 (SirT2) has been associated with the development of depression caused by disturbances in neuronal and synaptic plasticity. However, changes in the hippocampal SirTs in olfactory bulbectomized (OBX) mice, an animal model of depression, remain unknown. Therefore, this study examined depressive-like behaviors, hippocampal SirTs, synaptic plasticity-associated proteins, and cell proliferation in OBX mice. The OBX mice showed depressive-like behaviors; reduced SirT2, synaptophysin, and PSD95 levels; and reduced cell proliferation in the hippocampus. These data indicate that decreased hippocampal SirT2 may contribute to pathophysiological depression and strongly affect the psychological state.
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Bulbo Olfatorio , Sirtuina 2 , Animales , Depresión , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Ratones , Plasticidad Neuronal , Bulbo Olfatorio/cirugía , Sirtuina 2/metabolismoRESUMEN
The ability to adapt to stress is an essential defensive function of a living body, and disturbance of this ability in the brain may contribute to the development of affective illness. Previously, we reported that mice exposed to unadaptable restraint stress show emotional abnormality. Moreover, this emotional abnormality was alleviated by chronic treatment with flesinoxan, a serotonin (5-HT)1A receptor agonist. 5-HT1A receptor expression is regulated by several transcription factors such as nuclear deformed epidermal autoregulatory factor (NUDR/Deaf-1) and five prime repressors under dual repression binding protein 1 (Freud-1). The present study was designed to investigate the expression levels of 5-HT1A receptor and its transcription factors in the midbrain and hippocampus of stress-adaptive and -unadaptive mice. Mice were exposed to 14 days of repeated adaptable (1 h/day) or repeated unadaptable (4 h/day) restraint stress, or were left in their home cage (non-stressed groups). In a western blot analysis, a significant increase in the expression levels of 5HT1A receptor protein were observed in the hippocampal membrane fraction in stress-adaptive mice. In contrast, the expression levels of 5-HT1A receptor protein in stress-unadaptive mice were significantly increased in both cytoplasmic and membrane fraction of the midbrain. Furthermore, real-time PCR analysis revealed that, in the midbrain of stress-unadaptive mice, the expression levels of 5-HT1A receptor mRNA and Freud-1 or NUDR mRNA were significantly increased and decreased, respectively. These results suggest that increased expression of 5-HT1A receptor due to decrease in the expression of Freud-1 and NUDR in the midbrain may play a pivotal role in the emotional abnormality of stress-unadaptive mice.
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Receptor de Serotonina 5-HT1A , Factores de Transcripción , Animales , Regulación de la Expresión Génica , Mesencéfalo/metabolismo , Ratones , ARN Mensajero/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Receptores de Serotonina/metabolismo , Serotonina , Agonistas de Receptores de Serotonina , Factores de Transcripción/metabolismoRESUMEN
A therapeutic strategy through the gut-brain axis has been proven to be effective in treatment for depression. In our previous study, we demonstrated that Enterococcus faecalis 2001 (EF-2001) prevents colitis-induced depressive-like behavior through the gut-brain axis in mice. More recently, we found that demyelination in the prefrontal cortex (PFC) was associated with depressive-like behavior in an animal model of major depressive disorder, olfactory bulbectomized (OBX) mice. The present study investigated the effects of EF-2001 on depressive-like behaviors in OBX mice and the underlying molecular mechanisms from the perspective of myelination in the PFC. OBX mice exhibited depressive-like behaviors in the tail-suspension, splash, and sucrose preference tests, and decreased myelin and paranodal proteins along with mature oligodendrocytes in the PFC. These behavioral and biochemical changes were all prevented by treatment with EF-2001. Further, EF-2001 treatment increased brain-derived neurotrophic factor (BDNF) and leukemia inhibitory factor (LIF) in the PFC. Interestingly, an immunohistochemical analysis revealed enhanced phospho (p) -cAMP-responsive element binding protein (CREB) expression in neurons, p-nuclear factor-kappa B (NFκB) p65 (Ser536) expression in astrocytes, and p-signal transducer and activator of transcription 3 (STAT3) (Ty705) expression in mature oligodendrocytes in the PFC of OBX mice. From these results, we suggest that EF-2001 administration prevents depressive-like behaviors by regulating prefrontal cortical myelination via the enhancement of CREB/BDNF and NFκB p65/LIF/STAT3 pathways. Our findings strongly support the idea that a therapeutic strategy involving the gut microbiota may be a promising alternative treatment for alleviating symptoms of depression.
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Factor Neurotrófico Derivado del Encéfalo , Trastorno Depresivo Mayor , Animales , Antidepresivos/uso terapéutico , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/farmacología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/uso terapéutico , Depresión/tratamiento farmacológico , Trastorno Depresivo Mayor/tratamiento farmacológico , Modelos Animales de Enfermedad , Enterococcus faecalis/metabolismo , Hipocampo , Humanos , Factor Inhibidor de Leucemia/metabolismo , Factor Inhibidor de Leucemia/farmacología , Factor Inhibidor de Leucemia/uso terapéutico , Ratones , FN-kappa B/metabolismo , FN-kappa B/farmacología , FN-kappa B/uso terapéutico , Bulbo Olfatorio/metabolismo , Bulbo Olfatorio/cirugía , Corteza Prefrontal/metabolismo , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/farmacología , Factor de Transcripción STAT3/uso terapéuticoRESUMEN
Recent reports have implied that aberrant biochemical processes in the brain are frequently accompanied by subtle shifts in the cellular epigenetic profile that might underlie the pathogenic progression of psychiatric disorders. The aim of the present study was to examine the effect of trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, on the emotional abnormality induced by maladaptation to stress in mice. Mice were exposed to repeated restraint stress for 240 min/day for 14 days. We applied dosing schedules. In one schedule, from the 3rd day of stress exposure, mice were treated with TSA (1650 µM/4 µL, i.c.v.) immediately after the daily exposure to restraint stress. In the other schedule, from the 1st day of stress exposure, mice were treated with TSA 2 h before exposure to restraint stress. After the final exposure to restraint stress, the emotionality of mice was evaluated using the hole-board test. Mice that were exposed to restraint stress for 240 min/day for 14 days showed a decrease in head-dipping behavior. This decreased emotionality observed in stress-maladaptive mice was significantly recovered by chronic treatment with TSA 2 h before daily exposure to restraint stress, which confirmed the development of stress adaptation. On the other hand, no such stress adaptation was observed under chronic treatment with TSA immediately after daily stress exposure. A biochemical study showed that tryptophan hydroxylase, the rate-limiting enzyme in serotonin (5-HT) synthesis, was increased in midbrain containing raphe nuclei obtained from stress-adapted mice that were chronically treated with TSA 2 h before daily stress exposure. These findings suggest that an HDAC inhibitor may have a beneficial effect on stress adaptation by affecting 5-HT neural function in the brain and alleviate the emotional abnormality under conditions of excessive stress.
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Adaptación Psicológica/efectos de los fármacos , Emociones/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Estrés Psicológico/psicología , Adaptación Fisiológica/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos ICR , Restricción FísicaRESUMEN
Retinitis pigmentosa (RP) is the most common group of inherited retinal degenerative diseases, whose most debilitating phase is cone photoreceptor death. Perimetric and electroretinographic methods are the gold standards for diagnosing and monitoring RP and assessing cone function. However, these methods lack the spatial resolution and sensitivity to assess disease progression at the level of individual photoreceptor cells, where the disease originates and whose degradation causes vision loss. High-resolution retinal imaging methods permit visualization of human cone cells in vivo but have only recently achieved sufficient sensitivity to observe their function as manifested in the cone optoretinogram. By imaging with phase-sensitive adaptive optics optical coherence tomography, we identify a biomarker in the cone optoretinogram that characterizes individual cone dysfunction by stimulating cone cells with flashes of light and measuring nanometer-scale changes in their outer segments. We find that cone optoretinographic responses decrease with increasing RP severity and that even in areas where cone density appears normal, cones can respond differently than those in controls. Unexpectedly, in the most severely diseased patches examined, we find isolated cones that respond normally. Short-wavelength-sensitive cones are found to be more vulnerable to RP than medium- and long-wavelength-sensitive cones. We find that decreases in cone response and cone outer-segment length arise earlier in RP than changes in cone density but that decreases in response and length are not necessarily correlated within single cones.
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Oftalmoscopía/métodos , Retina/metabolismo , Células Fotorreceptoras Retinianas Conos/metabolismo , Retinitis Pigmentosa/metabolismo , Electrorretinografía , Proteínas del Ojo/metabolismo , HumanosRESUMEN
We previously reported that abnormal emotionality in stress-maladaptive mice was ameliorated by chronic treatment with flesinoxan, a 5-HT1A receptor agonist. Furthermore, the maintenance of hippocampal myelination appeared to contribute to the development of stress adaptation in mice. However, the effects of 5-HT1A receptor activation on myelination under the stress-maladaptive situations and the underlying mechanisms remain unknown. In the present study, we examined using flesinoxan whether activation of 5-HT1A receptor can reduce an abnormal emotional response by acting on oligodendrocytes to preserve myelin proteins in stress-maladaptive mice. Mice were exposed to repeated restraint stress for 4 h/day for 14 days as a stress-maladaptive model. Flesinoxan was given intraperitoneally immediately after the daily exposure to restraint stress. After the final exposure to restraint stress, the emotionality of mice was evaluated by the hole-board test. The expression levels of brain-derived neurotrophic factor (BDNF), phosphorylated-extracellular signal-regulated kinase (p-ERK), phosphorylated-cAMP response element-binding protein (p-CREB), myelin-associated glycoprotein (MAG), myelin basic protein (MBP) and oligodendrocyte transcription factor 2 (olig2) in the hippocampus was assessed by western blotting. Hippocampal oligodendrogenesis were examined by immunohistochemistry. Chronic treatment with flesinoxan suppressed the decrease in head-dipping behaviors in stress-maladaptive mice in the hole-board test. Under this condition, the decreases in MAG and MBP in the hippocampus recovered with increase in BDNF, p-ERK, p-CREB, and olig2. Furthermore, hippocampal oligodendrogenesis in stress-maladaptive mice was promoted by chronic treatment with flesinoxan. These findings suggest that 5-HT1A receptor activation may promote oligodendrogenesis and myelination via an ERK/CREB/BDNF signaling pathway in the hippocampus and reduces abnormal emotionality due to maladaptation to excessive stress.
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Hipocampo/metabolismo , Proteínas de la Mielina/metabolismo , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Estrés Fisiológico/fisiología , Animales , Conducta Exploratoria/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/patología , Masculino , Ratones , Oligodendroglía/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Restricción Física/fisiología , Agonistas de Receptores de Serotonina/farmacología , Estrés Fisiológico/efectos de los fármacos , Estrés Psicológico/metabolismoRESUMEN
Background Recent studies showing gadolinium deposition in multiple organs have raised concerns about the safety of gadolinium-based contrast agents (GBCAs). Purpose To explore whether gadolinium deposition in brain structures will cause any motor or behavioral alterations. Materials and Methods This study was performed from July 2019 to December 2020. Groups of 17 female BALB/c mice were each repeatedly injected with phosphate-buffered saline (control group, group A), a macrocyclic GBCA (group B), or a linear GBCA (group C) for 8 weeks (5 mmol per kilogram of bodyweight per week for GBCAs). Brain MRI studies were performed every other week to observe the signal intensity change caused by the gadolinium deposition. After the injection period, rotarod performance test, open field test, elevated plus-maze test, light-dark anxiety test, locomotor activity assessment test, passive avoidance memory test, Y-maze test, and forced swimming test were performed to assess the locomotor abilities, anxiety level, and memory. Among-group differences were compared by using one-way or two-way factorial analysis of variance with Tukey post hoc testing or Dunnett post hoc testing. Results Gadolinium deposition in the bilateral deep cerebellar nuclei was confirmed with MRI only in mice injected with a linear GBCA. At 8 weeks, contrast ratio of group C (0.11; 95% CI: 0.10, 0.12) was higher than that of group A (-2.1 × 10-3; 95% CI: -0.011, 7.5 × 10-3; P < .001) and group B (2.7 × 10-4; 95% CI: -8.2 × 10-3, 8.7 × 10-3; P < .001). Behavioral analyses showed that locomotor abilities, anxiety level, and long-term or short-term memory were not different in mice injected with linear or macrocyclic GBCAs. Conclusion No motor or behavioral alterations were observed in mice with brain gadolinium deposition. Also, the findings support the safety of macrocyclic gadolinium-based contrast agents. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Chen in this issue.
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Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Medios de Contraste/farmacología , Gadolinio/farmacología , Actividad Motora/efectos de los fármacos , Animales , Encéfalo/diagnóstico por imagen , Modelos Animales de Enfermedad , Femenino , Imagen por Resonancia Magnética/métodos , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos BALB CRESUMEN
Recent studies have reported that demyelination is associated with the development of depression. Olfactory bulbectomized (OBX) rodents are a useful experimental animal model for depressive disorder. However, little is known about the change in myelination in the brain of OBX mice. To address this question, we observed depressive-like behavior of OBX mice in the tail-suspension test, and determined the quantity of myelin proteins in the prefrontal cortex (PFC), striatum and hippocampus on day 14 or 21 after surgery. The number of nodes of Ranvier paired with the paranodal marker contactin-associated protein (Caspr), as well as the numbers of immature and mature oligodendrocytes in the PFC, were also measured on day 21 after surgery. We examined whether these behavioral and neurochemical changes observed in OBX mice were reversed by chronic administration of imipramine. OBX mice showed depressive-like behavior in the tail-suspension test together with a decrease in the levels of myelin proteins such as myelin basic protein, myelin-associated glycoprotein and cyclicnucleotide phosphodiesterase in the PFC on day 21 after surgery. The number of nodes of Ranvier and mature oligodendrocytes were also decreased in the PFC of OBX mice, while the number of immature oligodendrocytes was increased on day 21 after surgery. However, the number of immature oligodendrocytes in the PFC of OBX mice was decreased on day 35 after surgery. Administration of imipramine (20 mg/kg) for 2 weeks from day 21 after surgery improved OBX-induced depressive-like behavior and abnormal myelination in the PFC. The present findings suggest that the disturbance of myelin function in the PFC may contribute to the pathophysiology of depression, and further support the notion that it plays an important role in the psychological state.
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Conducta Animal , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/psicología , Depresión/psicología , Bulbo Olfatorio , Corteza Prefrontal/patología , Animales , Antidepresivos Tricíclicos/farmacología , Recuento de Células , Suspensión Trasera , Hipocampo/metabolismo , Imipramina/farmacología , Masculino , Ratones , Actividad Motora , Proteínas de la Mielina/metabolismo , Neostriado/metabolismo , OligodendroglíaRESUMEN
Deficits in olfaction are associated with neurodegenerative disorders such as Alzheimer's disease. A recent study reported that intranasal zinc sulfate (ZnSO4)-treated mice show olfaction and memory deficits. However, it remains unknown whether olfaction deficit-induced learning and memory impairment is associated with the cholinergic system in the brain. In this study, we evaluated olfactory function by the buried food find test, and learning and memory function by the Y-maze and passive avoidance tests in ZnSO4-treated mice. The expression of choline acetyltransferase (ChAT) protein in the olfactory bulb (OB), prefrontal cortex, hippocampus, and amygdala was assessed by western blotting. Moreover, we observed the effect of the acetylcholinesterase inhibitor physostigmine on ZnSO4-induced learning and memory deficits. We found that intranasal ZnSO4-treated mice exhibited olfactory dysfunction, while this change was recovered on day 14 after treatment. Both short-term and long-term learning and memory were impaired on days 4 and 7 after treatment with ZnSO4, whereas the former, but not the latter, was recovered on day 14 after treatment. A significant correlation was observed between olfactory function and short-term memory, but not long-term memory. Treatment with ZnSO4 decreased the ChAT level in the OB on day 4, and increased and decreased the ChAT levels in the OB and hippocampus on day 7, respectively. Physostigmine improved the ZnSO4-induced deficit in short-term, but not long-term, memory. Taken together, the present results suggest that short-term memory may be closely associated with olfactory function via the cholinergic system.
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Colina O-Acetiltransferasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Hipocampo , Trastornos de la Memoria , Memoria a Largo Plazo , Memoria a Corto Plazo , Trastornos del Olfato , Bulbo Olfatorio , Animales , Astringentes/farmacología , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/fisiopatología , Memoria a Largo Plazo/efectos de los fármacos , Memoria a Largo Plazo/fisiología , Memoria a Corto Plazo/efectos de los fármacos , Memoria a Corto Plazo/fisiología , Ratones , Trastornos del Olfato/inducido químicamente , Trastornos del Olfato/tratamiento farmacológico , Trastornos del Olfato/fisiopatología , Bulbo Olfatorio/efectos de los fármacos , Bulbo Olfatorio/metabolismo , Fisostigmina/farmacología , Sulfato de Zinc/farmacologíaRESUMEN
Purpose: Psychophysical and genetic testing provide substantial information about color vision phenotype and genotype. However, neither reveals how color vision phenotypes and genotypes manifest themselves in individual cones, where color vision and its anomalies are thought to originate. Here, we use adaptive-optics phase-sensitive optical coherence tomography (AO-PSOCT) to investigate these relationships. Methods: We used AO-PSOCT to measure cone function-optical response to light stimulation-in each of 16 human subjects with different phenotypes and genotypes of color vision (five color-normal, three deuteranopic, two protanopic, and six deuteranomalous trichromatic subjects). We classified three spectral types of cones (S, M, and L), and we measured cone structure-namely cone density, cone mosaic arrangement, and spatial arrangement of cone types. Results: For the different phenotypes, our cone function results show that (1) color normals possess S, M, and L cones; (2) deuteranopes are missing M cones but are normal otherwise; (3) protanopes are missing L cones but are normal otherwise; and (4) deuteranomalous trichromats are missing M cones but contain evidence of at least two subtypes of L cones. Cone function was consistent with the subjects' genotype in which only the first two M and L genes in the gene array are expressed and was correlated with the estimated spectral separation between photopigments, including in the deuteranomalous trichromats. The L/M cone ratio was highly variable in the color normals. No association was found between cone density and the genotypes and phenotypes investigated, and the cone mosaic arrangement was altered in the dichromats. Conclusions: AO-PSOCT is a novel method for assessing color vision phenotype and genotype in single cone cells.
Asunto(s)
Defectos de la Visión Cromática/genética , Visión de Colores/genética , Células Fotorreceptoras Retinianas Conos/metabolismo , Pigmentos Retinianos/metabolismo , Adulto , Percepción de Color/fisiología , Defectos de la Visión Cromática/metabolismo , Defectos de la Visión Cromática/patología , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Células Fotorreceptoras Retinianas Conos/patología , Tomografía de Coherencia Óptica/métodos , Adulto JovenRESUMEN
The note corrects an error that appeared in Equation 14 of the originally published article.
RESUMEN
SIGNIFICANCE: Adaptive optics optical coherence tomography (AO-OCT) technology enables non-invasive, high-resolution three-dimensional (3D) imaging of the retina and promises earlier detection of ocular disease. However, AO-OCT data are corrupted by eye-movement artifacts that must be removed in post-processing, a process rendered time-consuming by the immense quantity of data. AIM: To efficiently remove eye-movement artifacts at the level of individual A-lines, including those present in any individual reference volume. APPROACH: We developed a registration method that cascades (1) a 3D B-scan registration algorithm with (2) a global A-line registration algorithm for correcting torsional eye movements and image scaling and generating global motion-free coordinates. The first algorithm corrects 3D translational eye movements to a single reference volume, accelerated using parallel computing. The second algorithm combines outputs of multiple runs of the first algorithm using different reference volumes followed by an affine transformation, permitting registration of all images to a global coordinate system at the level of individual A-lines. RESULTS: The 3D B-scan algorithm estimates and corrects 3D translational motions with high registration accuracy and robustness, even for volumes containing microsaccades. Averaging registered volumes improves our image quality metrics up to 22 dB. Implementation in CUDA™ on a graphics processing unit registers a 512 × 512 × 512 volume in only 10.6 s, 150 times faster than MATLAB™ on a central processing unit. The global A-line algorithm minimizes image distortion, improves regularity of the cone photoreceptor mosaic, and supports enhanced visualization of low-contrast retinal cellular features. Averaging registered volumes improves our image quality up to 9.4 dB. It also permits extending the imaging field of view (â¼2.1 × ) and depth of focus (â¼5.6 × ) beyond what is attainable with single-reference registration. CONCLUSIONS: We can efficiently correct eye motion in all 3D at the level of individual A-lines using a global coordinate system.