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1.
Neurobiol Dis ; 198: 106543, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38821376

RESUMO

Opioid system dysregulation in response to stress is known to lead to psychiatric disorders including major depression. Among three different types of opioid receptors, the mu-type receptors (mORs) are highly expressed in the habenula complex, however, the action of mORs in this area and its interaction with stress exposure is largely unknown. Therefore, we investigated the roles of mORs in the habenula using male rats of an acute learned helplessness (aLH) model. First, we found that mOR activation decreased both excitatory and inhibitory synaptic transmission onto the lateral habenula (LHb). Intriguingly, this mOR-induced synaptic depression was reduced in an animal model of depression compared to that of controls. In naïve animals, we found an unexpected interaction between mORs and the endocannabinoid (eCB) signaling occurring in the LHb, which mediates presynaptic alteration occurring with mOR activation. However, we did not observe presynaptic alteration by mOR activation after stress exposure. Moreover, selective mOR activation in the habenula before, but not after, stress exposure effectively reduced helpless behaviors compared to aLH animals. Our observations are consistent with clinical reports suggesting the involvement of mOR signaling in depression, and additionally reveal a critical time window of mOR action in the habenula for ameliorating helplessness symptoms.


Assuntos
Depressão , Habenula , Desamparo Aprendido , Receptores Opioides mu , Transmissão Sináptica , Animais , Habenula/metabolismo , Masculino , Receptores Opioides mu/metabolismo , Transmissão Sináptica/fisiologia , Ratos , Depressão/metabolismo , Ratos Sprague-Dawley , Estresse Psicológico/metabolismo , Modelos Animais de Doenças
2.
Int J Mol Sci ; 25(4)2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38397124

RESUMO

Depression is twice as prevalent in women as in men, however, most preclinical studies of depression have used male rodent models. This study aimed to examine how stress affects metabolic profiles depending on sex using a rodent depression model: sub-chronic variable stress (SCVS). The SCVS model of male and female mice was established in discovery and validation sets. The stress-induced behavioral phenotypic changes were similar in both sexes, however, the metabolic profiles of female plasma and brain became substantially different after stress, whereas those of males did not. Four stress-differential plasma metabolites-ß-hydroxybutyric acid (BHB), L-serine, glycerol, and myo-inositol-could yield biomarker panels with excellent performance to discern the stressed individuals only for females. Disturbances in BHB, glucose, 1,5-anhydrosorbitol, lactic acid, and several fatty acids in the plasma of stressed females implied a systemic metabolic shift to ß-oxidation in females. The plasma levels of BHB and corticosterone only in stressed females were observed not only in SCVS but also in an acute stress model. These results collectively suggest a sex difference in the metabolic responses by stress, possibly involving the energy metabolism shift to ß-oxidation and the HPA axis dysregulation in females.


Assuntos
Sistema Hipotálamo-Hipofisário , Caracteres Sexuais , Humanos , Masculino , Feminino , Camundongos , Animais , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Metabolômica , Encéfalo/metabolismo , Corticosterona , Estresse Psicológico/metabolismo
3.
Biochem Biophys Res Commun ; 637: 196-202, 2022 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-36403483

RESUMO

E3 ubiquitin ligase, HOIL1-interacting protein (HOIP), forms the linear ubiquitin chain assembly complex (LUBAC) with HOIL and SHANK-associated RH domain interactor and catalyzes linear ubiquitination, directly linking the N- and C-termini of ubiquitin. Recently, several studies have implicated linear ubiquitination in aging and Alzheimer disease (AD). However, little is currently known about the roles of HOIP in brain aging and AD pathology. Here, we investigated the role of linear ubiquitin E3 ligase (LUBEL), a Drosophila HOIP ortholog, in brain aging and amyloid ß (Aß) pathology in a Drosophila AD model. DNA double-strand breaks (DSBs) were increased in the aged brains of neuron-specific LUBEL-knockdown flies compared to the age-matched controls. Silencing of LUBEL in the neuron of AD model flies increased the neuronal apoptosis and neurodegeneration, whereas silencing in glial cells had no such effect. Aß aggregation levels and DSBs were also increased in the LUBEL-silenced AD model fly brains, but autophagy and proteostasis were not affected by LUBEL silencing. Collectively, our results suggest that LUBEL protects neurons from aging-induced DNA damage and Aß neurotoxicity.


Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Síndromes Neurotóxicas , Animais , Peptídeos beta-Amiloides/toxicidade , Drosophila melanogaster/genética , Ubiquitina , Ubiquitina-Proteína Ligases/genética , Encéfalo , Envelhecimento , Dano ao DNA , Doença de Alzheimer/genética , Drosophila
4.
FASEB J ; 35(12): e22041, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34780680

RESUMO

Mood disorders are more prevalent and often reported to be more severe in women; however, little is known about the underlying mechanisms of this sexual prevalence. To gain insight into the functional differences in female brains in response to stress, we systemically compared brain activation in male and female C57BL/6N mice after acute stress exposure. We measured c-Fos expression levels in 18 brain areas related to stress responses after a 3-h long restraint stress and found that activation was sexually dimorphic in several brain areas, including the nucleus accumbens, ventral tegmental area, nucleus reuniens, and medial part of the lateral habenula. Moreover, stress-activated a substantial number of cells in the medial prefrontal cortex, amygdala, and lateral part of the lateral habenula; however, the levels of activation were comparable in males and females, suggesting that the core stress responding machineries are largely shared. Pearson correlation analysis revealed several interesting connections between the analyzed areas that are implicated in stress responses and depression. Overall, stress strengthened intra-circuitries in the hippocampus, amygdala, and prefrontal cortex in female mice, whereas more longer-range connections were highlighted in stressed male mice. Our study provides a highly valuable neuroanatomical framework for investigating the circuit mechanism underlying the higher vulnerability to depression in women.


Assuntos
Encéfalo/patologia , Hipocampo/patologia , Vias Neurais , Restrição Física/efeitos adversos , Estresse Psicológico/fisiopatologia , Animais , Mapeamento Encefálico , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores Sexuais
5.
J Neurosci ; 38(14): 3394-3413, 2018 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-29483280

RESUMO

Nerve growth factor (NGF) exerts multiple functions on target neurons throughout development. The recent discovery of a point mutation leading to a change from arginine to tryptophan at residue 100 in the mature NGFß sequence (NGFR100W) in patients with hereditary sensory and autonomic neuropathy type V (HSAN V) made it possible to distinguish the signaling mechanisms that lead to two functionally different outcomes of NGF: trophic versus nociceptive. We performed extensive biochemical, cellular, and live-imaging experiments to examine the binding and signaling properties of NGFR100W Our results show that, similar to the wild-type NGF (wtNGF), the naturally occurring NGFR100W mutant was capable of binding to and activating the TrkA receptor and its downstream signaling pathways to support neuronal survival and differentiation. However, NGFR100W failed to bind and stimulate the 75 kDa neurotrophic factor receptor (p75NTR)-mediated signaling cascades (i.e., the RhoA-Cofilin pathway). Intraplantar injection of NGFR100W into adult rats induced neither TrkA-mediated thermal nor mechanical acute hyperalgesia, but retained the ability to induce chronic hyperalgesia based on agonism for TrkA signaling. Together, our studies provide evidence that NGFR100W retains trophic support capability through TrkA and one aspect of its nociceptive signaling, but fails to engage p75NTR signaling pathways. Our findings suggest that wtNGF acts via TrkA to regulate the delayed priming of nociceptive responses. The integration of both TrkA and p75NTR signaling thus appears to regulate neuroplastic effects of NGF in peripheral nociception.SIGNIFICANCE STATEMENT In the present study, we characterized the naturally occurring nerve growth factor NGFR100W mutant that is associated with hereditary sensory and autonomic neuropathy type V. We have demonstrated for the first time that NGFR100W retains trophic support capability through TrkA, but fails to engage p75NTR signaling pathways. Furthermore, after intraplantar injection into adult rats, NGFR100W induced neither thermal nor mechanical acute hyperalgesia, but retained the ability to induce chronic hyperalgesia. We have also provided evidence that the integration of both TrkA- and p75NTR-mediated signaling appears to regulate neuroplastic effects of NGF in peripheral nociception. Our study with NGFR100W suggests that it is possible to uncouple trophic effect from nociceptive function, both induced by wild-type NGF.


Assuntos
Neuropatias Hereditárias Sensoriais e Autônomas/genética , Mutação de Sentido Incorreto , Fator de Crescimento Neural/genética , Nociceptividade , Receptor trkA/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Células 3T3 , Animais , Células Cultivadas , Células HEK293 , Neuropatias Hereditárias Sensoriais e Autônomas/metabolismo , Neuropatias Hereditárias Sensoriais e Autônomas/fisiopatologia , Humanos , Masculino , Camundongos , Fator de Crescimento Neural/metabolismo , Proteínas do Tecido Nervoso , Células PC12 , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptores de Fatores de Crescimento , Transdução de Sinais
6.
Proc Natl Acad Sci U S A ; 113(24): 6749-54, 2016 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-27226294

RESUMO

Neural Abelson-related gene-binding protein 2 (nArgBP2) was originally identified as a protein that directly interacts with synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3), a postsynaptic scaffolding protein critical for the assembly of glutamatergic synapses. Although genetic deletion of nArgBP2 in mice leads to manic/bipolar-like behaviors resembling many aspects of symptoms in patients with bipolar disorder, the actual function of nArgBP2 at the synapse is completely unknown. Here, we found that the knockdown (KD) of nArgBP2 by specific small hairpin RNAs (shRNAs) resulted in a dramatic change in dendritic spine morphology. Reintroducing shRNA-resistant nArgBP2 reversed these defects. In particular, nArgBP2 KD impaired spine-synapse formation such that excitatory synapses terminated mostly at dendritic shafts instead of spine heads in spiny neurons, although inhibitory synapse formation was not affected. nArgBP2 KD further caused a marked increase of actin cytoskeleton dynamics in spines, which was associated with increased Wiskott-Aldrich syndrome protein-family verprolin homologous protein 1 (WAVE1)/p21-activated kinase (PAK) phosphorylation and reduced activity of cofilin. These effects of nArgBP2 KD in spines were rescued by inhibiting PAK or activating cofilin combined with sequestration of WAVE. Together, our results suggest that nArgBP2 functions to regulate spine morphogenesis and subsequent spine-synapse formation at glutamatergic synapses. They also raise the possibility that the aberrant regulation of synaptic actin filaments caused by reduced nArgBP2 expression may contribute to the manifestation of the synaptic dysfunction observed in manic/bipolar disorder.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Espinhas Dendríticas/metabolismo , Sinapses/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Técnicas de Silenciamento de Genes , Camundongos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Sinapses/genética
7.
J Neurosci ; 37(25): 6021-6030, 2017 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-28539417

RESUMO

The lateral habenula (LHb) is a small part of the epithalamus that projects to monoamine centers in the brain. Previously, neurotransmission onto the LHb was shown to be abnormally potentiated in animal models of depression. However, synaptic plasticity in this brain area and the effect of stressor exposure on synaptic plasticity of the LHb have not been investigated. Thus, we explored whether the LHb undergoes dynamic changes in synaptic efficacy or not. First, we observed that a moderate LTP occurs in a fraction of LHb neurons obtained from naive Sprague Dawley rats. Interestingly, a single exposure to acute stressors, such as inescapable foot shock or restraint plus tail shock (RTS), significantly enhances the magnitude of LTP in the LHb. We also observed an increased number of LHb neurons expressing phosphorylated cAMP response element-binding protein (pCREB) after exposure to stressors, which may contribute to determine the threshold for LTP induction. LTP induction in the LHb resulted in an additional increase in the number of pCREB-expressing neurons in stress-exposed animals but not in naive control animals. Together, we showed that LHb neurons have heterogeneous propensity for synaptic potentiation at rest; however, a single exposure to stressors greatly facilitates LTP induction in the LHb, suggesting that fundamental alterations in synaptic plasticity in the LHb may occur in animal models of depression or post-traumatic stress disorder.SIGNIFICANCE STATEMENT Stress exposure is known to cause depression in human patients and animal models, although explanations at the cellular level remain to be elaborated. Here, we show that the lateral habenula (LHb) exhibits LTP after a pattern of brief strong stimulation. In addition, we show that stress exposure facilitates LTP in the LHb by lowering the threshold for LTP induction. We observed a selective increase in the number of neurons expressing pCREB in the LHb of animal models of depression. LTP induction results in a further increase in the density of pCREB-expressing neurons only after stress exposure. Our study provides the first evidence that animal models of depression exhibit altered synaptic plasticity of the LHb.


Assuntos
Habenula/fisiopatologia , Potenciação de Longa Duração , Estresse Psicológico/fisiopatologia , Sinapses , Animais , Ansiedade/fisiopatologia , Ansiedade/psicologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Eletrochoque , Técnicas In Vitro , Masculino , Ratos , Ratos Sprague-Dawley , Restrição Física , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Estresse Psicológico/psicologia
8.
Nature ; 470(7335): 535-9, 2011 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-21350486

RESUMO

The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.


Assuntos
Depressão/patologia , Depressão/fisiopatologia , Desamparo Aprendido , Neurônios/metabolismo , Sinapses/metabolismo , Transmissão Sináptica , Tálamo/patologia , Animais , Aprendizagem da Esquiva , Estimulação Encefálica Profunda , Depressão/terapia , Modelos Animais de Doenças , Dopamina/metabolismo , Estimulação Elétrica , Potenciais Pós-Sinápticos Excitadores/fisiologia , Masculino , Modelos Neurológicos , Técnicas de Rastreamento Neuroanatômico , Terminações Pré-Sinápticas/metabolismo , Ratos , Ratos Sprague-Dawley , Recompensa , Tálamo/metabolismo , Área Tegmentar Ventral/fisiologia
9.
J Neurophysiol ; 113(5): 1493-500, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25505112

RESUMO

Lysophosphatidic acid (LPA) is one of the well-characterized, ubiquitous phospholipid molecules. LPA exerts its effect by activating G protein-coupled receptors known as LPA receptors (LPARs). So far, LPAR signaling has been critically implicated during early development stages, including the regulation of synapse formation and the morphology of cortical and hippocampal neurons. In adult brains, LPARs seem to participate in cognitive as well as emotional learning and memory. Recent studies using LPAR1-deficient mice reported impaired performances in a number of behavioral tasks, including the hippocampus-dependent spatial memory and fear conditioning tests. Nevertheless, the effect of LPAR activation in the synaptic transmission of central synapses after the completion of embryonic development has not been investigated. In this study, we took advantage of a novel extracellular agonist for LPARs called gintonin to activate LPARs in adult brain systems. Gintonin, a recently identified active ingredient in ginseng, has been shown to activate LPARs and mobilize Ca(2+) in an artificial cell system. We found that the activation of LPARs by application of gintonin acutely enhanced both excitatory and inhibitory transmission in central synapses, albeit through tentatively distinct mechanisms. Gintonin-mediated LPAR activation primarily resulted in synaptic enhancement and an increase in neuronal excitability in a phospholipase C-dependent manner. Our findings suggest that LPARs are able to directly potentiate synaptic transmission in central synapses when stimulated exogenously. Therefore, LPARs could serve as a useful target to modulate synaptic activity under pathological conditions, including neurodegenerative diseases.


Assuntos
Encéfalo/metabolismo , Potenciais Pós-Sinápticos Excitadores , Potenciais Pós-Sinápticos Inibidores , Extratos Vegetais/farmacologia , Receptores de Ácidos Lisofosfatídicos/metabolismo , Sinapses/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Cálcio/metabolismo , Masculino , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley , Receptores de Ácidos Lisofosfatídicos/agonistas , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Fosfolipases Tipo C/metabolismo
10.
Neurobiol Stress ; 29: 100606, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38292517

RESUMO

Synaptic plasticity in the amygdala plays an essential role in the formation and inhibition of fear memory; however, this plasticity has mainly been studied in the lateral amygdala, making it largely uninvestigated in other subnuclei. Here, we investigated long-term potentiation (LTP) and long-term depression (LTD) in the basolateral amygdala (BLA) to the medial division of the central amygdala (CEm) synapses of juvenile C57BL/6N (B6) and 129S1/SvImJ (S1) mice. We found that in naïve B6 and S1 mice, LTP was not induced at the BLA to CEm synapses, whereas fear conditioning lowered the threshold for LTP induction in these synapses of both B6 and S1 mice. Interestingly, fear extinction disrupted the induction of LTP at the BLA to CEm synapses of B6 mice, whereas LTP was left intact in S1 mice. Both low-frequency stimulation (LFS) and modest LFS (mLFS) induced LTD in naïve B6 and S1 mice, suggesting that the BLA to CEm synapses express bidirectional plasticity. Fear conditioning disrupted both types of LTD induction selectively in S1 mice and LFS-LTD, presumably NMDAR-dependent LTD was partially recovered by fear extinction. However, mLFS-LTD which has been known to be endocannabinoid receptor 1 (CB1R)-dependent was not induced after fear extinction in both mouse strains. Our observations suggest that fear conditioning enhances LTP while fear extinction diminishes LTP at the BLA to the CEm synapses of B6 mice with successful extinction. Considering that S1 mice showed strong fear conditioning and impaired extinction, strong fear conditioning in the S1 strain may be related to disrupted LTD, and impaired extinction may be due to constant LTP and weak LFS-LTD at the BLA to CEm synapses. Our study contributes to the further understanding of the dynamics of synaptic potentiation and depression between the subnuclei of the amygdala in juvenile mice after fear conditioning and extinction.

11.
J Neurochem ; 126(2): 146-54, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23517499

RESUMO

Central synapses operate neurotransmission in several modes: synchronous/fast neurotransmission (neurotransmitters release is tightly coupled to action potentials and fast), asynchronous neurotransmission (neurotransmitter release is slower and longer lasting), and spontaneous neurotransmission (where small amounts of neurotransmitter are released without being evoked by an action potential). A substantial body of evidence from the past two decades suggests that seemingly identical synaptic vesicles possess distinct propensities to fuse, thus selectively serving different modes of neurotransmission. In efforts to better understand the mechanism(s) underlying the different modes of synaptic transmission, many research groups found that synaptic vesicles used in different modes of neurotransmission differ by a number of synaptic proteins. Synchronous transmission with higher temporal fidelity to stimulation seems to require synaptotagmin 1 and complexin for its Ca²âº sensitivity, RIM proteins for closer location of synaptic vesicles (SV) to the voltage operated calcium channels (VGCC), and dynamin for SV retrieval. Asynchronous release does not seem to require functional synaptotagmin 1 as a calcium sensor or complexins, but the activity of dynamin is indispensible for its maintenance. On the other hand, the control of spontaneous neurotransmission remains less clear as deleting a number of essential synaptic proteins does not abolish this type of synaptic vesicle fusion. VGCC distance from the SV seems to have little control on spontaneous transmission, while there is an involvement of functional synaptic proteins including synaptotagmins and complexin. Recently, presynaptic deficits have been proposed to contribute to a number of pathological conditions including cognitive and mental disorders. In this review, we evaluate recent advances in understanding the regulatory mechanisms of synaptic vesicle dynamics and in understanding how different molecular substrates maintain selective modes of neurotransmission. We also highlight the implications of these studies in understanding pathological conditions.


Assuntos
Modelos Neurológicos , Transmissão Sináptica/fisiologia , Vesículas Sinápticas/fisiologia , Sinaptotagmina I/metabolismo , Potenciais de Ação/fisiologia , Animais , Cálcio/metabolismo , Humanos , Dinâmica não Linear , Sinapses/metabolismo
12.
Anim Cells Syst (Seoul) ; 27(1): 297-308, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38023591

RESUMO

Depressive disorders are more prevalent and severe in women; however, our knowledge of the underlying factors contributing to female vulnerability to depression remains limited. Additionally, females are notably underrepresented in studies seeking to understand the mechanisms of depression. Various animal models of depression have been devised, but only recently have females been included in research. In this comprehensive review, we aim to describe the sex differences in the prevalence, pathophysiology, and responses to drug treatment in patients with depression. Subsequently, we highlight animal models of depression in which both sexes have been studied, in the pursuit of identifying models that accurately reflect female vulnerability to depression. We also introduce explanations for the neural basis of sex differences in depression. Notably, the medial prefrontal cortex and the nucleus accumbens have exhibited sex differences in previous studies. Furthermore, other brain circuits involving the dopaminergic center (ventral tegmental area) and the serotonergic center (dorsal raphe nucleus), along with their respective projections, have shown sex differences in relation to depression. In conclusion, our review covers the critical aspects of sex differences in depression, with a specific focus on female vulnerability in humans and its representation in animal models, including the potential underlying mechanisms. Employing suitable animal models that effectively represent female vulnerability would benefit our understanding of the sex-dependent pathophysiology of depression.

13.
Front Cell Neurosci ; 17: 1278847, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38193032

RESUMO

The lateral habenula (LHb) is a well-established brain region involved in depressive disorders. Synaptic transmission of the LHb neurons is known to be enhanced by stress exposure; however, little is known about genetic modulators within the LHb that respond to stress. Using recently developed molecular profiling methods by phosphorylated ribosome capture, we obtained transcriptome profiles of stress responsive LHb neurons during acute physical stress. Among such genes, we found that KCNB1 (Kv2.1 channel), a delayed rectifier and voltage-gated potassium channel, exhibited increased expression following acute stress exposure. To determine the roles of KCNB1 on LHb neurons during stress, we injected short hairpin RNA (shRNA) against the kcnb1 gene to block its expression prior to stress exposure. We observed that the knockdown of KCNB1 altered the basal firing pattern of LHb neurons. Although KCNB1 blockade did not rescue despair-like behaviors in acute learned helplessness (aLH) animals, we found that KCNB1 knockdown prevented the enhancement of synaptic strength in LHb neuron after stress exposure. This study suggests that KCNB1 may contribute to shape stress responses by regulating basal firing patterns and neurotransmission intensity of LHb neurons.

14.
Nat Commun ; 14(1): 4321, 2023 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-37468558

RESUMO

Small humanin-like peptide 2 (SHLP2) is a mitochondrial-derived peptide implicated in several biological processes such as aging and oxidative stress. However, its functional role in the regulation of energy homeostasis remains unclear, and its corresponding receptor is not identified. Hereby, we demonstrate that both systemic and intracerebroventricular (ICV) administrations of SHLP2 protected the male mice from high-fat diet (HFD)-induced obesity and improved insulin sensitivity. In addition, the activation of pro-opiomelanocortin (POMC) neurons by SHLP2 in the arcuate nucleus of the hypothalamus (ARC) is involved in the suppression of food intake and the promotion of thermogenesis. Through high-throughput structural complementation screening, we discovered that SHLP2 binds to and activates chemokine receptor 7 (CXCR7). Taken together, our study not only reveals the therapeutic potential of SHLP2 in metabolic disorders but also provides important mechanistic insights into how it exerts its effects on energy homeostasis.


Assuntos
Hipotálamo , Neurônios , Masculino , Animais , Camundongos , Hipotálamo/metabolismo , Neurônios/metabolismo , Núcleo Arqueado do Hipotálamo/metabolismo , Peptídeos/farmacologia , Peptídeos/metabolismo , Dieta Hiperlipídica/efeitos adversos , Homeostase , Mitocôndrias/metabolismo , Pró-Opiomelanocortina/metabolismo , Metabolismo Energético/fisiologia
15.
Physiology (Bethesda) ; 26(1): 45-53, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21357902

RESUMO

Recent findings suggest that spontaneous neurotransmission is a bona fide pathway for interneuronal signaling that operates independent of evoked transmission via distinct presynaptic as well as postsynaptic substrates. This article will examine the role of spontaneous release events in neuronal signaling by focusing on aspects that distinguish this process from evoked neurotransmission, and evaluate the mechanisms that may underlie this segregation.


Assuntos
Neurônios/fisiologia , Transmissão Sináptica/fisiologia , Animais , Transdução de Sinais
16.
Neuroscience ; 483: 95-103, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-34923037

RESUMO

FK501 binding protein 51 (FKBP5) is a stress response prolyl isomerase that inhibits the translocation of the glucocorticoid receptor (GR) heterocomplex to the nucleus. Previous studies have shown that the expression levels of FKBP5 are positively correlated with psychiatric disorders, including depression and post-traumatic stress disorder. In rodents, FKBP5 deletion in the brain leads to be resilient to stress-induced depression. The hippocampus is known to be one of the primary locations mediating stress responses in the brain by providing negative feedback signals to the hypothalamus-pituitary-adrenal gland axis. Therefore, we aimed to investigate the role of FKBP5 and its interaction with GRs in the hippocampus. We observed that FKBP5 deletion in the hippocampus resulted in a minimal change in synaptic transmission. In the hippocampus, GR activation alters the release probability in inhibitory synapses as well as the postsynaptic contribution of glutamate receptors in excitatory synapses; however, no such alterations were induced in the absence of FKBP5. FKBP5 deficiency causes insensitivity to activated GRs in the hippocampus suggesting that FKBP5 mediates synaptic changes caused by GR activation. Our study provides electrophysiological evidence of stress resilience observed in FKBP5-deficient mice.


Assuntos
Receptores de Glucocorticoides , Proteínas de Ligação a Tacrolimo , Animais , Proteínas de Transporte/metabolismo , Hipocampo/metabolismo , Camundongos , Sistema Hipófise-Suprarrenal/metabolismo , Receptores de Glucocorticoides/metabolismo , Estresse Psicológico/metabolismo , Transmissão Sináptica
17.
Exp Neurobiol ; 31(6): 376-389, 2022 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-36631846

RESUMO

The lateral septum (LS) is a forebrain structure that has been implicated in a wide range of behavioral and physiological responses to stress. However, the specific populations of neurons in the LS that mediate stress responses remain incompletely understood. Here, we show that neurons in the dorsal lateral septum (LSd) that express the somatostatin gene (hereafter, LSdSst neurons) are activated by diverse stressors. Retrograde tracing from LSdSst neurons revealed that these neurons are directly innervated by neurons in the locus coeruleus (LC), the primary source of norepinephrine well-known to mediate diverse stress-related functions in the brain. Consistently, we found that norepinephrine increased excitatory synaptic transmission onto LSdSst neurons, suggesting the functional connectivity between LSdSst neurons and LC noradrenergic neurons. However, optogenetic stimulation of LSdSst neurons did not affect stress-related behaviors or autonomic functions, likely owing to the functional heterogeneity within this population. Together, our findings show that LSdSst neurons are activated by diverse stressors and suggest that norepinephrine released from the LC may modulate the activity of LSdSst neurons under stressful circumstances.

18.
J Hazard Mater ; 426: 127815, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-34823950

RESUMO

As global plastic production continues to grow, microplastics released from a massive quantity of plastic wastes have become a critical environmental concern. These microplastic particles are found in a wide range of living organisms in a diverse array of ecosystems. In this study, we investigated the biological effects of polystyrene nanoplastic (PSNP) on development of the central nervous system using cultured neural stem cells (NSCs) and mice exposed to PSNP during developmental stages. Our study demonstrates that maternal administration of PSNP during gestation and lactating periods altered the functioning of NSCs, neural cell compositions, and brain histology in progeny. Similarly, PSNP-induced molecular and functional defects were also observed in cultured NSCs in vitro. Finally, we show that the abnormal brain development caused by exposure to high concentrations of PSNP results in neurophysiological and cognitive deficits in a gender-specific manner. Our data demonstrate the possibility that exposure to high amounts of PSNP may increase the risk of neurodevelopmental defects.


Assuntos
Microplásticos , Poluentes Químicos da Água , Animais , Encéfalo , Ecossistema , Feminino , Humanos , Lactação , Exposição Materna/estatística & dados numéricos , Camundongos , Plásticos/toxicidade , Poliestirenos/toxicidade , Poluentes Químicos da Água/análise
19.
J Neurosci ; 30(4): 1363-76, 2010 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-20107062

RESUMO

Synapses maintain synchronous, asynchronous, and spontaneous forms of neurotransmission that are distinguished by their Ca(2+) dependence and time course. Despite recent advances in our understanding of the mechanisms that underlie these three forms of release, it remains unclear whether they originate from the same vesicle population or arise from distinct vesicle pools with diverse propensities for release. Here, we used a reversible inhibitor of dynamin, dynasore, to dissect the vesicle pool dynamics underlying the three forms of neurotransmitter release in hippocampal GABAergic inhibitory synapses. In dynasore, evoked synchronous release and asynchronous neurotransmission detected after activity showed marked and unrecoverable depression within seconds. In contrast, spontaneous release remained intact after intense stimulation in dynasore or during prolonged (approximately 1 h) application of dynasore at rest, suggesting that separate recycling pathways maintain evoked and spontaneous synaptic vesicle trafficking. In addition, simultaneous imaging of spectrally separable styryl dyes revealed that, in a given synapse, vesicles that recycle spontaneously and in response to activity do not mix. These findings suggest that evoked synchronous and asynchronous release originate from the same vesicle pool that recycles rapidly in a dynamin-dependent manner, whereas a distinct vesicle pool sustains spontaneous release independent of dynamin activation. This result lends additional support to the notion that synapses harbor distinct vesicle populations with divergent release properties that maintain independent forms of neurotransmission.


Assuntos
Dinaminas/metabolismo , Hipocampo/metabolismo , Interneurônios/metabolismo , Transmissão Sináptica/fisiologia , Vesículas Sinápticas/metabolismo , Animais , Dinaminas/antagonistas & inibidores , Corantes Fluorescentes , Hipocampo/citologia , Hidrazonas/farmacologia , Interneurônios/citologia , Interneurônios/efeitos dos fármacos , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Coloração e Rotulagem , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/ultraestrutura , Membranas Sinápticas/efeitos dos fármacos , Membranas Sinápticas/metabolismo , Membranas Sinápticas/ultraestrutura , Transmissão Sináptica/efeitos dos fármacos , Vesículas Sinápticas/efeitos dos fármacos , Vesículas Sinápticas/ultraestrutura , Ácido gama-Aminobutírico/metabolismo
20.
Neuroscience ; 457: 20-26, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33359659

RESUMO

Exposure to stress activates glucocorticoid receptors in the brain and facilitates the onset of multitude psychiatric disorders. It has been shown that FK506 binding protein 51 (FKBP5) expression increases during glucocorticoid receptor (GR) activation in various brain regions including the medial prefrontal cortex (mPFC). FKBP5 knockout (KO) mice are reported to be resilient to stress, however, it remains uninvestigated whether FKBP5 loss affects neurotransmission and if so, what the functional consequences are. Here, we examined the impact of FKBP5 deletion in synaptic transmission of the mPFC. We found that GR activation significantly decreased excitatory neurotransmission in the mPFC, which was completely abolished upon FKBP5 deletion, in consistent with behavioral resilience observed in FKBP5 KO mice. Even though FKBP5 loss has minimal impact on neural excitability, we found that FKBP5 deletion distorts the excitatory/inhibitory balance in the mPFC. Our study suggests that FKBP5 deficiency leads to the mPFC insensitive to GR activation and provides a neurophysiological explanation for how FKBP5 deficiency may mediate stress resilience.


Assuntos
Receptores de Glucocorticoides , Proteínas de Ligação a Tacrolimo , Animais , Encéfalo/metabolismo , Camundongos , Córtex Pré-Frontal/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Transmissão Sináptica , Proteínas de Ligação a Tacrolimo/genética
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