RESUMEN
Empathy is a potential motivation for prosocial behaviors that is related to many psychiatric diseases, such as major depressive disorder; however, its neural mechanisms remain unclear. To elucidate the relationship between empathy and stress, we established a chronic stress contagion (SC) procedure combined with chronic unpredictable mild stress (CUMS) to investigate (1) whether depressive rats show impaired empathy-like behavior toward fearful conspecifics, (2) whether frequent social contact with normal familiar conspecifics (social support) alleviates the negative effects of CUMS, and (3) the effect of long-term exposure to a depressed partner on emotional and empathic responses in normal rats. We found that the CUMS group showed less empathy-like behavior in the social transfer of fear model (STFM), as indicated by less social interaction with the demonstrator and reduced freezing behavior in the fear-expression test. Social contact partially alleviated depression-like behaviors and the negative effect of CUMS in the fear-transfer test. The normal rats who experienced stress contagion from daily exposure to a depressed partner for 3 weeks showed lower anxiety and increased social response in the fear-transfer test than the control group. We concluded that chronic stress impairs empathy-like behaviors, while social contact partially buffers the effect of CUMS. Thus, social contact or contagion of stress is mutually beneficial to both stressed individuals and nonstressed partners. Higher dopamine and lower norepinephrine levels in the basolateral amygdala probably contributed to these beneficial effects.
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Trastorno Depresivo Mayor , Empatía , Ratas , Animales , Conducta Animal , Emociones/fisiología , Ansiedad , Estrés Psicológico , Modelos Animales de Enfermedad , DepresiónRESUMEN
The estrogen (17ß-estradiol, E2) level in the hippocampus is higher and more stable in male rats than female rats. Both stress and estrogen affect spine plasticity, and many studies have demonstrated that peripheral estrogen treatment can prevent stress-induced spine loss in both males and females. Some in vitro studies have indicated that neural estrogen (nE2) participates in the modulation of spine plasticity in cultured neurons. However, whether nE2 regulates spine density in vivo in males is not clear, and the specific role of nE2 in stress-induced depression-like behaviors of male rats remains unknown. We delivered letrozole (a selective aromatase inhibitor that blocks the conversion of testosterone to estradiol) and estrogen into the hippocampus of rats and found that letrozole treatment induced the same depression-like behaviors in control rats as observed in chronic unpredictable mild stress (CUMS) rats. Estrogen treatment reversed/or alleviated depression-like behaviors induced by CUMS or letrozole infusion and elevated Kalirin-7 expression in hippocampus. Estrogen treatment also rescued letrozole-induced spine loss. Expression of GluN1 and PSD-95 also changed with Kalirin-7 and spine density. All these proteins were decreased in CUMS rats and letrozole infusion rats but increased in rats treated with estrogen. In conclusion, nE2 in the hippocampus plays an important role in CUMS-induced depression-like behaviors in male rats and Kalirin-7 is involved in this process. GluN1 and PSD-95 possibly mediate the regulation of Kalirin-7 by nE2, which ultimately leads to changes in spine density and depression-like behaviors.
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Depresión , Estrés Psicológico , Animales , Depresión/metabolismo , Estradiol/metabolismo , Estradiol/farmacología , Estrógenos/metabolismo , Estrógenos/farmacología , Femenino , Hipocampo/metabolismo , Letrozol , Masculino , Ratas , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismoRESUMEN
Phencynonate hydrochloride (PCH) is a drug that crosses the blood-brain barrier. Cellular experiments confirmed that PCH protects against glutamate toxicity and causes only weak central inhibition and limited side effects. As shown in our previous studies, PCH alleviates depression-like behaviours induced by chronic unpredictable mild stress (CUMS). Here we administered PCH at three different doses (4, 8 and 16 mg/kg) to male rats for two continuous days after CUMS and conducted behavioural tests to assess the dose-dependent antidepressant effects of PCH and its effects on the neuroplasticity in the hippocampus and medial prefrontal cortex (mPFC). Meanwhile, we measured the spine density and expression of related proteins to illustrate the mechanism of PCH. PCH treatment (8 mg/kg) significantly alleviated depression-like behaviours induced by CUMS. All doses of PCH treatment reversed the spine loss in prelimbic and CA3 regions induced by CUMS. Kalirin-7 expression was decreased in the hippocampus and mPFC of the CUMS group. The expression of the NR1 and NR2B subunits in the hippocampus, and NR2B in mPFC are increased by CUMS. PCH treatment (8 and 16 mg/kg) reversed all of these changes of Kalirin-7 in PFC and hippocampus, as well as NR1 and NR2B expression in the hippocampus. PCH is expected to be developed as a new type of rapid antidepressant. Its antidepressant effect may be closely related to the modulation of dendritic spine density in the prelimbic and CA3 regions and the regulation of Kalilin-7 and N-methyl-D-aspartic acid receptor levels in the hippocampus.
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Antidepresivos/farmacología , Compuestos Aza/farmacología , Depresión/tratamiento farmacológico , Glicolatos/farmacología , Receptores de Glutamato/genética , Animales , Antidepresivos/administración & dosificación , Compuestos Aza/administración & dosificación , Conducta Animal/efectos de los fármacos , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica , Glicolatos/administración & dosificación , Hipocampo/efectos de los fármacos , Masculino , Plasticidad Neuronal/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Estradiol (E2) is involved in the regulation of emotional behavior, cognitive function, and neuroplasticity. However, peripheral E2 and central E2 levels do not always fluctuate together. The relationships of peripheral and central E2 with cognitive function are not clear. The aim of this study was to investigate whether peripheral E2, hippocampal E2, or both play a critical role in novel object recognition (NOR), and whether Kalirin-7, an important regulator of spine plasticity, is involved in the modulation of E2 on cognitive behavior. Our results showed that ovariectomy (OVX) significantly reduced serum E2 levels in the 14 weeks following the procedure. However, hippocampal E2 levels did not decrease in the OVX group compared to the sham group until after 14 weeks. Consistent with the changes in hippocampal E2 levels, the investigation ratio in the NOR test and hippocampal Kalirin-7 expression was also not lower in the OVX group than in the sham group until 14 weeks after the procedure. To confirm the relationship between hippocampal E2 levels and NOR ability, we inhibited the production of hippocampal E2 via microinjection of letrozole (LTZ; an aromatase inhibitor) into the hippocampi of rats in the control group and 8-week OVX group. The data indicated that a reduction in E2 levels in the hippocampus significantly impaired NOR ability and simultaneously decreased Kalirin-7 levels in the hippocampus. In conclusion, our study strongly demonstrates that hippocampal E2, but not peripheral E2, plays a critical role in NOR ability and that Kalirin-7 may be involved in this mechanism. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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Estradiol , Hipocampo , Animales , Estrógenos , Femenino , Humanos , Plasticidad Neuronal , Ovariectomía , RatasRESUMEN
Physical inactivity, the fourth leading mortality risk factor worldwide, is associated with chronic mental illness. Identifying the mechanisms underlying different levels of baseline physical activity and the effects of these levels on the susceptibility to stress is very important. However, whether different levels of baseline physical activity influence the susceptibility and resilience to chronic social defeat stress (CSDS), and the underlying mechanisms in the brain remain unclear. The present study segregated wild-type mice into low baseline physical activity (LBPA) and high baseline physical activity (HBPA) groups based on short term voluntary wheel running (VWR). LBPA mice showed obvious susceptibility to CSDS, while HBPA mice were resilient to CSDS. In addition, the expression of tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) was lower in LBPA mice than in HBPA mice. Furthermore, activation of TH neurons in the VTA of LBPA mice by chemogenetic methods increased the levels of VWR and resilience to CSDS. In contrast, inhibiting TH neurons in the VTA of HBPA mice lowered the levels of VWR and increased their susceptibility to CSDS. Thus, this study suggests that different baseline physical activities might be mediated by the dopamine system. This system also affects the susceptibility and resilience to CSDS, possibly via alteration of the baseline physical activity. This perspective on the neural control and impacts on VWR may aid the development of strategies to motivate and sustain voluntary physical activity. Furthermore, this can maximize the impacts of regular physical activity toward stress-reduction and health promotion.
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Neuronas Dopaminérgicas , Derrota Social , Animales , Ratones , Ratones Endogámicos C57BL , Actividad Motora , Estrés Psicológico , Tirosina 3-Monooxigenasa , Área Tegmental VentralRESUMEN
D2 receptors (D2Rs) located in both pre- and postsynaptic membranes of medium spiny neurons (MSNs) in the nucleus accumbens (NAc) are involved in the stress response and associated behaviors. The role of D2Rs in chronic unpredictable stress (CUS)-induced depression-like behaviors is not clear. Quinpirole (a D2R agonist) and eticlopride (a D2R antagonist) were stereotactically delivered into the NAc before Sprague Dawley rats underwent CUS. CUS-induced depression-like behaviors were accompanied by a significant decrease in both the dopamine (DA) level and D2R expression in the NAc. Eticlopride reversed CUS-induced depression-like behavior and rescued the DA levels in the NAc, and microinjection of DA into the NAc of CUS individuals had the same effect as eticlopride. By contrast, delivery of quinpirole into the NAc of control animals induced depression-like behaviors accompanied by a decrease in the DA level in the NAc. These results show that DA plays a key role in CUS-induced depression-like behaviors and the D2R exerts a presynaptic negative feedback on DA levels during CUS. Microinjection of quinpirole into the NAc also decreased the level of the kalirin-7 protein in the NAc of both control and stressed animals, while eticlopride increased its level in the NAc of rats. In agreement with these results, intraperitoneal injection of eticlopride in mice also caused an increase in both the kalirin-7 protein level in the NAc and spine density in MSNs, while quinpirole reduced them. These results suggest that regulation of kalirin-7 through D2R in the NAc is a general pathway in rats and mice, and is involved in CUS-induced depression-like behaviors. Kalirin-7 may be directly regulated through the D2R postsynaptic pathway or indirectly through the presynaptic pathway in the NAc. The interaction between D2R and kalirin-7 needs to be investigated further.
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Depresión , Estrés Psicológico , Animales , Depresión/tratamiento farmacológico , Depresión/etiología , Factores de Intercambio de Guanina Nucleótido , Ratones , Núcleo Accumbens/metabolismo , Quinpirol/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/metabolismoRESUMEN
Voluntary exercise has been reported to have a therapeutic effect on many psychiatric disorders and social stress is known to impair social interaction. However, whether voluntary exercise could reverse deficits in social behaviors induced by chronic social defeat stress (CSDS) and the underlying mechanism remain unclear. The present study shows CSDS impaired social preference and induced social interaction deficiency in susceptible mice. Voluntary wheel running (VWR) reversed these effects. In addition, CSDS decreased the levels of tyrosine hydroxylase in the ventral tegmental area and the D2 receptor (D2R) in the nucleus accumbens (NAc) shell. These changes can be recovered by VWR. Furthermore, the recovery effect of VWR on deficits in social behaviors in CSDS mice was blocked by the microinjection of D2R antagonist raclopride into the NAc shell. Thus, these results suggest that the mechanism underlying CSDS-induced social interaction disorder might be caused by an alteration of the dopamine system. VWR may be a novel means to treat CSDS-induced deficits in social behaviors via modifying the dopamine system.
RESUMEN
Many studies have shown that the early social environment exerts long-term effects on the brain and also the parental behavior of adults. Oxytocin (OXT) is one of the most important neurotransmitters that regulate social behavior; howerve, whether the early social environment affects parental behavior via OXT remains unclear. Using socially monogamous adult mandarin voles (Microtus mandarinus), the present study found that 1) both paternal deprivation and early social deprivation significantly decreased OXT expression in both the paraventricular hypothalamic nucleus (PVN) and the supraoptic nucleus (SON) of F2 generation offspring; 2) systemic neonatal OXT injection in naïve animals promoted maternal but not paternal behavior in adult F2 offspring; 3) systemic neonatal OXT injection significantly increased ERα expression in both the medial preoptic area (MPOA) and the ventro medial hypothalamic nucleus (VMH) in female but not in male mandarin voles; 4) systemic neonatal administration of an OXT antagonist significantly reduced ERα expression in the bed nucleus of the stria terminalis (BNST), VMH, and the arcuate hypothalamic nucleus (Arc) in females and in all examined brain regions in males. In summary, the obtained data demonstrate that the early social environment could affect OXT level, which in turn leads to long-term effects on ERα expression in relevant brain regions, consequently affecting maternal behavior but not paternal behavior.
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Conducta Materna/efectos de los fármacos , Oxitocina/metabolismo , Aislamiento Social/psicología , Animales , Animales Recién Nacidos , Arvicolinae/metabolismo , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Receptor alfa de Estrógeno/metabolismo , Receptor alfa de Estrógeno/fisiología , Estrógenos/metabolismo , Femenino , Masculino , Conducta Materna/fisiología , Oxitocina/farmacología , Oxitocina/fisiología , Núcleo Hipotalámico Paraventricular/metabolismo , Conducta Paterna/efectos de los fármacos , Privación Paterna , Factores Sexuales , Conducta Social , Medio Social , Núcleo Supraóptico/metabolismo , Núcleo Hipotalámico Ventromedial/metabolismoRESUMEN
Serotonin 5-HT1B receptors (5-HT1BRs) are distributed in hippocampal CA1 and play a pivotal role in cognitive function. Activation of 5-HT1BRs regulates synaptic plasticity at the excitatory synapses in the hippocampus. However, the role and its underlying mechanism of 5-HT1BR activation-mediated glutamatergic synaptic plasticity in spatial memory are not fully understood. In this study, spatial memory of Sprague-Dawley (SD) rats was assessed in a Morris water maze after bilateral dorsal hippocampal CA1 infusion of the 5-HT1BR antagonist GR55562 (25⯵g/µL) or agonist CP93129 (25⯵g/µL). GR55562 did not affect the spatial memory acquisition but significantly increased the target quadrant preference during the memory consolidation probe performed 14 d after the training session, while CP93129 impaired the memory consolidation process. Moreover, GR55562 significantly increased, while CP93129 significantly decreased, the density of dendritic spines on the distal apical dendrites of CA1 pyramidal neurons. Furthermore, western blot experiments indicated that GR55562 significantly increased, but CP93129 significantly reduced, the expression of Kalirin-7 (Kal-7), PSD95, and GluA2/3 subunits of AMPA receptors. Our results suggest that Kal-7 and Kal-7-mediatedalteration of AMPA receptor subtype expression may play crucial roles in the impact of hippocampal CA1 5-HT1BR activation on spatial memory consolidation.
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Factores de Intercambio de Guanina Nucleótido/metabolismo , Consolidación de la Memoria/fisiología , Memoria Espacial/fisiología , Animales , Región CA1 Hipocampal/fisiología , Espinas Dendríticas/metabolismo , Regulación de la Expresión Génica/genética , Factores de Intercambio de Guanina Nucleótido/genética , Hipocampo/metabolismo , Masculino , Aprendizaje por Laberinto/fisiología , Plasticidad Neuronal , Células Piramidales/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1B/genética , Receptor de Serotonina 5-HT1B/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Serotonina/metabolismo , Sinapsis/metabolismoRESUMEN
Myostatin (MSTN) is not only a key negative regulator of skeletal muscle secretion, however is also an endocrine factor that is transmitted to bone. To investigate the effect and possible mechanism of weight-bearing treadmill running on bone with poorly controlled Type 1 diabetes, rats were randomly divided into three groups: Normal control (NC), diabetic mellitus (DM) and diabetic exercise training groups (DM-WTR). The DM-WTR rats were trained with weight-bearing running. The results demonstrated that the levels of serum insulin, body weight, bone mass, muscle mass, grip strength, and serum calcium in the DM-WTR rats were significantly increased, whereas the levels of blood glucose, alkaline phosphatase, and tartrate-resistant acid phosphatase were markedly reduced in the DM-WTR rats compared with the DM rats. Weight-bearing running inhibited streptozocin (STZ)-induced MSTN mRNA and protein expression in the diabetic rats. The mRNA and protein expression levels of activin type IIB receptor and mothers against decapentaplegic homolog 2/3 and its phosphorylation in femur DM-WTR rats were reduced compared with DM rats. In addition, weight-bearing running enhanced the STZ-induced Wnt and ß-catenin expression levels and reduced the STZ-induced glycogen synthase kinase (GSK)-3ß expression in diabetic rats' femora. In conclusion, the results suggested that weight-bearing running could partially ameliorate STZ-induced femur atrophy via MSTN downregulation, and this may be associated with the inactivation of Activin A Receptor Type 2B/Smad2/3 signaling pathways and the activation of the Wnt/GSK3ß/ß-catenin signaling pathway. Further studies are needed to verify these conclusions.
RESUMEN
Diabetic muscle atrophy causes a reduction of skeletal muscle size and strength, which affects normal daily activities. However, pulsed electromagnetic fields (PEMFs) can retard the atrophy of type II fibers (ActRIIB) in denervated muscles. Therefore, the purpose of the present study was to determine whether PEMFs can alleviate streptozotocin (STZ)induced diabetic muscle atrophy. To do this, 40 SpragueDawley (SD) rats were randomly divided into four groups (n=10 per group): The normal control group (NC; nondiabetic rats without treatment); the diabetic mellitus group (DM; STZinduced rats without treatment); the diabetic insulintreated group (DT; diabetic rats on insulin treatment, 68 U/d twice a day for 6 weeks) as a positive control; and the diabetic PEMFs therapy group (DP; diabetic rats with PEMFs exposure treatment, 15 Hz, 1.46 mT, 30 min/day for 6 weeks). Body weight, muscle strength, muscle mass and serum insulin level were significantly increased in the DP group compared with the DM group. PEMFs also decreased the blood glucose level and altered the activity of metabolic enzymes. PEMFs significantly increased the crosssectional area of muscle fiber. In addition, PEMFs significantly activated protein kinase B (Akt) and mammalian target of rapamycin (mTOR), and inhibited the activity of myostatin (MSTN), ActRIIB and forkhead box protein O1 (FoxO1) compared with the DM group. Thus indicating that the Akt/mTOR and Akt/FoxO1 signaling pathways may be involved in the promotion of STZinduced diabetic muscle atrophy by PEMFs. The results of the present study suggested that PEMFs stimulation may alleviate diabetic muscle atrophy in the STZ model, and that this is associated with alterations in multiple signaling pathways in which MSTN may be an integral factor. MSTNassociated signaling pathways may provide therapeutic targets to attenuate severe diabetic muscle wasting.
Asunto(s)
Complicaciones de la Diabetes/terapia , Diabetes Mellitus Experimental/terapia , Campos Electromagnéticos , Magnetoterapia , Atrofia Muscular/terapia , Animales , Complicaciones de la Diabetes/metabolismo , Complicaciones de la Diabetes/patología , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Masculino , Proteínas Musculares/metabolismo , Fuerza Muscular , Atrofia Muscular/etiología , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Proteínas del Tejido Nervioso/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Major depressive disorder (MDD) is one of the most common psychiatric disorder, but the underlying mechanisms are largely unknown. Increasing evidence shows that brain-derived neurotrophic factor (BDNF) plays an important role in the structural plasticity induced by depression. Considering the opposite effects of BDNF and its precursor proBDNF on neural plasticity, we hypothesized that the balance of BDNF and proBDNF plays a critical role in chronic unpredicted mild stress (CUMS)-induced depressive-like behaviors and structural plasticity in the rodent hippocampus. The aims of this study were to compare the functions of BDNF and proBDNF in the CUMS-induced depressive-like behaviors, and determine the effects of BDNF and proBDNF on expressions of kalirin-7, postsynaptic density protein 95 (PSD95) and NMDA receptor subunit NR2B in the hippocampus of stressed and naïve control rats, respectively. Our results showed that CUMS induced depressive-like behaviors, caused a decrease in the ratio of BDNF/proBDNF in the hippocampus and resulted in a reduction in spine density in hippocampal CA1 pyramidal neurons; these alterations were accompanied by a decrease in the levels of kalirin-7, PSD95 and NR2B in the hippocampus. Injection of exogenous BDNF into the CA1 area of stressed rats reversed CUMS-induced depressive-like behaviors and prevented CUMS-induced spine loss and decrease in kalirin-7, NR2B and PSD95 levels. In contrast, injection of exogenous proBDNF into the CA1 region of naïve rats caused depressive-like behavior and an accompanying decrease in both spine density and the levels of kalirin-7, NR2B and PSD95. Taken together, our results suggest that the ratio of BDNF to proBDNF in the hippocampus plays a key role in CUMS-induced depressive-like behaviors and alterations of dendritic spines in hippocampal CA1 pyramidal neurons. Kalirin-7 may play an important role during this process.
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Factor Neurotrófico Derivado del Encéfalo/metabolismo , Espinas Dendríticas/fisiología , Depresión/metabolismo , Plasticidad Neuronal/fisiología , Animales , Factor Neurotrófico Derivado del Encéfalo/fisiología , Espinas Dendríticas/metabolismo , Trastorno Depresivo Mayor/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Estrés PsicológicoRESUMEN
Neuroimaging studies show that patients with major depression have reduced volume of the orbitofrontal cortex (OFC). Although the serotonin (5-HT) 2A receptor, which is abundant in the OFC, has been implicated in depression, the underlying mechanisms in the development of stress-induced depression remain unclear. Kalirin-7 (Kal7) is an essential component of mature excitatory synapses for maintaining dendritic spines density, size and synaptic functions. The aim of this study was to investigate the role of orbitofrontal 5-HT and 5-HT2A receptors in depressive-like behaviors and their associations with Kal7 and dendritic spines using chronic unpredictable mild stress (CUMS), an established animal model of depression. CUMS had no effect on the levels of 5-HT or the 5-HT2A receptor in the OFC. However, CUMS or microinjection of the 5-HT2A/2C receptor agonist (±)-1-(2, 5-Dimethoxy-4-iodophenyl)- 2-aminopropane hydrochloride (DOI, 5 µg/0.5 µL) into the OFC induced depressive-like behaviors, including anhedonia in the sucrose preference test and behavioral despair in the tail suspension test, a significant reduction in body weight gain and locomotor activity in the open field test, which were accompanied by decreased expression of Kal7 and PSD95 as well as decreased density of dendritic spines in the OFC. These alterations induced by CUMS were reversed by pretreatment with the 5-HT2A receptor antagonist Ketanserin (Ket, 5 µg/0.5 µL into the OFC). These results suggest that CUMS alters structural plasticity through activation of the orbital 5-HT2A receptor and is associated with decreased expression of Kal7, thereby resulting in depressive-like behaviors in rats, suggesting an important role of Kal7 in the OFC in depression.
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Espinas Dendríticas , Depresión/metabolismo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Corteza Prefrontal/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Estrés Psicológico/metabolismo , Animales , Enfermedad Crónica , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/patología , Depresión/patología , Factores de Intercambio de Guanina Nucleótido/antagonistas & inhibidores , Infusiones Intraventriculares , Masculino , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/patología , Ratas , Agonistas del Receptor de Serotonina 5-HT2/administración & dosificación , Estrés Psicológico/patologíaRESUMEN
Depression, a severe psychiatric disorder, has been studied for decades, but the underlying mechanisms still remain largely unknown. Depression is closely associated with alterations in dendritic spine morphology and spine density. Therefore, understanding dendritic spines is vital for uncovering the mechanisms underlying depression. Several chronic stress models, including chronic restraint stress (CRS), chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), have been used to recapitulate depression-like behaviors in rodents and study the underlying mechanisms. In comparison with CRS, CUMS overcomes the stress habituation and has been widely used to model depression-like behaviors. CSDS is one of the most frequently used models for depression, but it is limited to the study of male mice. Generally, chronic stress causes dendritic atrophy and spine loss in the neurons of the hippocampus and prefrontal cortex. Meanwhile, neurons of the amygdala and nucleus accumbens exhibit an increase in spine density. These alterations induced by chronic stress are often accompanied by depression-like behaviors. However, the underlying mechanisms are poorly understood. This review summarizes our current understanding of the chronic stress-induced remodeling of dendritic spines in the hippocampus, prefrontal cortex, orbitofrontal cortex, amygdala, and nucleus accumbens and also discusses the putative underlying mechanisms.
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Encéfalo/fisiopatología , Espinas Dendríticas/fisiología , Trastorno Depresivo/fisiopatología , Modelos Animales de Enfermedad , Plasticidad Neuronal , Estrés Psicológico/complicaciones , Animales , Encéfalo/metabolismo , Espinas Dendríticas/metabolismo , Trastorno Depresivo/etiología , Trastorno Depresivo/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratas , Restricción FísicaRESUMEN
Repetin (RPTN) protein is a member of S100 family and is known to be expressed in the normal epidermis. Here we show that RPTN is ubiquitously expressed in both mouse and human brain, with relatively high levels in choroid plexus, hippocampus and prefrontal cortex. To investigate the expression of RPTN in neuropsychiatric disorders, we determined serum levels of RPTN in patients with schizophrenia (n = 88) or bipolar disorder (n = 34) and in chronic psychostimulant users (n = 91). We also studied its expression in a mouse model of chronic unpredictable mild stress (CUMS). The results showed that serum RPTN levels were significantly diminished in patients with schizophrenia and bipolar disorder or in psychostimulant users, compared with healthy subjects (n = 115) or age-matched controls (n = 92) (p < 0.0001). In CUMS mice, RPTN expression in hippocampus and prefrontal cortex was reduced with progression of the CUMS procedure; the serum RPTN level remained unchanged. Since CUMS is a model for depression and methamphetamine (METH) abuse induced psychosis recapitulates many of the psychotic symptoms of schizophrenia, the results from this study may imply that RPTN plays a potential role in emotional and cognitive processing; its decrease in serum may indicate its involvement in the pathogenesis of schizophrenia and bipolar disorder.
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Trastorno Bipolar/sangre , Encéfalo/metabolismo , Proteínas S100/sangre , Esquizofrenia/sangre , Adulto , Animales , Encéfalo/patología , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Trastornos Relacionados con Sustancias/sangreRESUMEN
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system (CNS) in mammalian, which involved in several mood disorders such as anxiety, depression and schizophrenia. Nowadays, there are growing evidences showed that the depression is concerned with a deficiency in brain GABA. However, there are numerous studies based on the monoamine hypothesis and glutamatergic dysfunction, while the study on GABA is relatively less and scattered. Our aim is to discuss the relationship between depression and GABA by introducing the role of GABA receptors and the interaction between GABA and 5-hydroxytryptamine, dopamine and glutamic acid. It provides new ideas for further study on the pathogenesis and therapy of depression.
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Depresión , Animales , Encéfalo , Dopamina , Ácido Glutámico , Humanos , Neurotransmisores , Serotonina , Ácido gamma-AminobutíricoRESUMEN
Major depressive disorder is the most prevalent psychiatric condition, but the cellular and molecular mechanisms underlying this disorder are largely unknown, although multiple hypotheses have been proposed. The aim of this study was to characterize the progressive alteration of neuronal plasticity in the male rat hippocampus during depression induced by chronic unpredictable mild stress (CUMS), an established animal model of depression. The data in the hippocampus were collected on days 7, 14 and 21 after the onset of three-week CUMS. When analyzed on day 21, three-week CUMS induced typically depressive-like behaviors, impaired LTP induction, and decreased basal synaptic transmission at hippocampal CA3-CA1 synapses recorded in vivo, which was accompanied by decreased density of dendritic spines in CA1 and CA3 pyramidal neurons. The levels of both Kalirin-7 and brain-derived neurotrophic factor (BDNF) in the hippocampus were decreased at the same time. On day 14 (middle phase), some depressive-like behaviors were observed, which was accompanied by depressed basal synaptic transmission and enhanced LTP induction at the CA3-CA1 synapses. However, BDNF expression was decreased without alteration of Kalirin7 expression in comparison with no-stress control. Depressed basal synaptic transmission occurred in the middle phase of CUMS may contribute to decreased expression of BDNF. On day 7, depressive-like behaviors were not observed, and LTP induction, spine density, Kalirin-7 and BDNF expression were not altered by CUMS in comparison with no-stress control. These results showed that the functional changes at CA3-CA1synapses occurred earlier than the structural alteration during three-week CUMS as a strategy of neural adaptation, and rats required three weeks to develop depressive-like behaviors during CUMS. Our results suggest an important role of Kalirin-7 in CUMS-mediated alterations in spine density, synaptic function and overall depressive-like behaviors on day 21.
Asunto(s)
Región CA1 Hipocampal/patología , Región CA3 Hipocampal/patología , Depresión/patología , Sinapsis/patología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Depresión/fisiopatología , Modelos Animales de Enfermedad , Potenciales Postsinápticos Excitadores/fisiología , Conducta Exploratoria , Preferencias Alimentarias , Factores de Intercambio de Guanina Nucleótido/metabolismo , Suspensión Trasera , Masculino , Aprendizaje por Laberinto , Red Nerviosa/patología , Red Nerviosa/ultraestructura , Ratas , Ratas Sprague-Dawley , Sacarosa/administración & dosificación , Edulcorantes/administración & dosificación , Sinapsis/ultraestructura , Factores de TiempoRESUMEN
Many receptors, including thermal receptors and mechanical receptors, are only activated by stimuli within a clearly defined range of intensities. Differences in the receptive ranges enable individual receptors and their sensory centers to precisely detect the intensity of the stimulus and changes in intensity. Baroreceptors are the sensory terminals of the baroreflex. It is well understood that an increasing number of baroreceptors are recruited to produce afferent action potentials as the blood pressure increases, indicating that individual baroreceptors have different pressure thresholds. The present study revealed that individual baroreceptors could stop their afferent signals when the blood pressure exceeds a certain level, indicating that individual baroreceptors are sensitive to a specific range of blood pressure. The receptive ranges of individual baroreceptors differ in terms of the total range, the lower threshold, and the upper threshold. Of 85 baroreceptors examined in this study, the upper thresholds for about half were within the physiological blood pressure range. These results indicate that supraphysiological blood pressure is unlikely to be encoded by the recruitment of more baroreceptors. Instead, supraphysiological blood pressure levels might be signaled by an increase in the frequency of action potentials or by other mechanisms. In conclusion, our results indicate that rabbit baroreceptors are activated by blood pressure levels within specific receptive ranges. These findings should encourage further studies to examine the role of population coding of blood pressure by baroreceptors in the baroreflex.
Asunto(s)
Aorta/inervación , Aorta/fisiología , Presión Sanguínea/fisiología , Presorreceptores/fisiología , Acetilcolina/farmacología , Potenciales de Acción/efectos de los fármacos , Vías Aferentes/fisiología , Animales , Barorreflejo/fisiología , Presión Sanguínea/efectos de los fármacos , Fibras Nerviosas/fisiología , Norepinefrina/farmacología , Presorreceptores/efectos de los fármacos , ConejosRESUMEN
The present study was to investigate the role of the quinolinic acid (QUIN) and its relationship with N-methyl-D-aspartic acid (NMDA) receptor and metabotropic glutamate receptor 1 (mGluR1) in depression induced by chronic unpredictable mild stress (CUMS) in hippocampus. CUMS-induced depression model was established in Sprague-Dawley rats. Intrahippocampal injections of QUIN, QUIN antagonist Ro61-8048, non-competitive NMDA receptor antagonist MK-801 and mGluR1 antagonist AIDA were respectively adopted by rat brain stereotaxic coordinates. The behavioral observations were conducted by measurement of weight changes, sucrose preference test, open-field test and tail suspension test. The concentration of glutamic acid (Glu) and the expression of its receptor subunits in hippocampus were detected by HPLC and Western blot, respectively. The QUIN content in hippocampus was determined by enzyme linked immunosorbent assay (ELISA). The result showed that CUMS significantly induced the depressive-like behaviors in rats, increased the contents of QUIN and Glu, and upregulated the expression of NMDA receptor subunits NR2B and mGluR1 in hippocampus. Microinjection of QUIN into hippocampus resulted in animal depressive-like behaviors, and increased the content of Glu and the expression of NR2B and mGluR1 significantly. QUIN antagonist Ro61-8048 effectively restrained the depression-like behaviors induced by CUMS, and decreased the content of Glu and the expression of NR2B and mGluR1 significantly. Intrahippocampal injections of MK-801 and AIDA effectively improved the depression-like behaviors induced by CUMS and decreased the Glu content. The results suggest that CUMS may contribute to the production and release of QUIN in hippocampal microglia. QUIN results in elevation of Glu level via NMDA receptor and mGluR1, and the increase of expression of NR2B and mGluR1 in hippocampus, which leads to depression-like behaviors in the end.
Asunto(s)
Depresión/tratamiento farmacológico , Ácido Glutámico/metabolismo , Hipocampo/efectos de los fármacos , Ácido Quinolínico/farmacología , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Conducta Animal , Maleato de Dizocilpina/farmacología , Hipocampo/metabolismo , Ratas , Ratas Sprague-Dawley , Estrés PsicológicoRESUMEN
Early life stress has a long-term negative impact on emotion, learning, memory and adult sexual behavior, and these deficits most likely impair pair bonding. Here, we investigated whether early social deprivation (ED) affects the formation of pair bonds in socially monogamous mandarin voles (Microtus mandarinus). In a partner preference test (PPT), ED-reared adult females and males did not show a preference for their partner, spent more time exploring the cage of an unfamiliar animal and directed high levels of aggression toward unfamiliar animals. In social interaction test, ED increased exploring behavior only in females, but increased movement around the partner and reduced inactivity in both males and females. Three days of cohabitation did not alter serum corticosterone levels in ED-reared males, but increased corticosterone levels in males that received bi-parental care (PC). Interestingly, serum corticosterone levels in ED- and PC-reared females declined after cohabitation. ED significantly increased basal serum corticosterone levels in males, but had no effect on females. ED significantly up-regulated the levels of dopamine and the mRNA expression of dopamine 1-type receptor (D1R) in the nucleus accumbens (NAcc) in females and males. ED suppressed dopamine 2-type receptor mRNA (D2R) expression in females, but increased this in males. After three days of cohabitation, levels of D1R mRNA and D2R mRNA expression changed in opposite directions in PC-reared voles, but in the same direction in ED-reared males, and only the expression of D2R mRNA increased in ED-reared females. Our results indicate that early social deprivation inhibits pair bonding at adulthood. This inhibition is possibly associated with sex-specific alterations in serum corticosterone, levels of dopamine and mRNA expression of two types of dopamine receptors in the NAcc.