Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.730
Filtrar
1.
Nat Commun ; 11(1): 4388, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873805

RESUMO

Presynaptic spike timing-dependent long-term depression (t-LTD) at hippocampal CA3-CA1 synapses is evident until the 3rd postnatal week in mice, disappearing during the 4th week. At more mature stages, we found that the protocol that induced t-LTD induced t-LTP. We characterized this form of t-LTP and the mechanisms involved in its induction, as well as that driving this switch from t-LTD to t-LTP. We found that this t-LTP is expressed presynaptically at CA3-CA1 synapses, as witnessed by coefficient of variation, number of failures, paired-pulse ratio and miniature responses analysis. Additionally, this form of presynaptic t-LTP does not require NMDARs but the activation of mGluRs and the entry of Ca2+ into the postsynaptic neuron through L-type voltage-dependent Ca2+ channels and the release of Ca2+ from intracellular stores. Nitric oxide is also required as a messenger from the postsynaptic neuron. Crucially, the release of adenosine and glutamate by astrocytes is required for t-LTP induction and for the switch from t-LTD to t-LTP. Thus, we have discovered a developmental switch of synaptic transmission from t-LTD to t-LTP at hippocampal CA3-CA1 synapses in which astrocytes play a central role and revealed a form of presynaptic LTP and the rules for its induction.


Assuntos
Astrócitos/metabolismo , Hipocampo/crescimento & desenvolvimento , Potenciação de Longa Duração/fisiologia , Transmissão Sináptica/fisiologia , Adenosina/metabolismo , Animais , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/citologia , Masculino , Camundongos , Técnicas de Patch-Clamp , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
2.
Nat Commun ; 11(1): 4276, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32848151

RESUMO

The structural organization of excitatory inputs supporting spike-timing-dependent plasticity (STDP) remains unknown. We performed a spine STDP protocol using two-photon (2P) glutamate uncaging (pre) paired with postsynaptic spikes (post) in layer 5 pyramidal neurons from juvenile mice. Here we report that pre-post pairings that trigger timing-dependent LTP (t-LTP) produce shrinkage of the activated spine neck and increase in synaptic strength; and post-pre pairings that trigger timing-dependent LTD (t-LTD) decrease synaptic strength without affecting spine shape. Furthermore, the induction of t-LTP with 2P glutamate uncaging in clustered spines (<5 µm apart) enhances LTP through a NMDA receptor-mediated spine calcium accumulation and actin polymerization-dependent neck shrinkage, whereas t-LTD was dependent on NMDA receptors and disrupted by the activation of clustered spines but recovered when separated by >40 µm. These results indicate that synaptic cooperativity disrupts t-LTD and extends the temporal window for the induction of t-LTP, leading to STDP only encompassing LTP.


Assuntos
Espinhas Dendríticas/fisiologia , Plasticidade Neuronal/fisiologia , Potenciais de Ação/fisiologia , Animais , Sinalização do Cálcio/fisiologia , Técnicas In Vitro , Potenciação de Longa Duração/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência por Excitação Multifotônica , Modelos Neurológicos , Células Piramidais/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia
3.
Life Sci ; 256: 118018, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32598935

RESUMO

Aim While stress causes brain dysfunction, crocin (as an active component of saffron) and exercise (as part of a healthy lifestyle) improve stress-induced memory impairment. The present study investigated the protective effects of crocin administration, exercise, and crocin-accompanied exercise on neuronal excitability and long-term potentiation (LTP) at the CA1 of hippocampus as well as serum corticosterone and glucose levels in rats subjected to chronic unpredictable stress (CUS). MAIN METHODS: Forty-eight male Wistar rats were randomly allocated to six groups: Control, Sham, CUS, CUS-Crocin30, CUS-Exercise, and CUS-Crocin30-Exercise. The chronic unpredictable stress and treadmill running at 20-21 m/min were applied 2 h/day and 1 h/day, respectively, for 21 days. Crocin (30 mg/kg) was daily intraperitoneally injected to the rats. Electrophysiological variables were recorded from the CA1 of hippocampus. While corticosterone and glucose levels were also measured. KEY FINDINGS: CUS and CUS-Exercise significantly attenuated excitability and LTP. Compared to the CUS and CUS-Exercise treatments, CUS-Crocin30 and CUS-Crocin30-Exercise led to significant increases in slope and amplitude of field excitatory postsynaptic potential. The changes in serum corticosterone and glucose levels nearly matched the electrophysiological data. SIGNIFICANCE: CUS was found to be a highly destructive stress as it failed to allow exercises to edify the CUS-induced memory deficit. This is while crocin (as a herbal drug) was found more effective than exercise (as a daily routine) in remedying the CUS-induced memory deficit. Also, although the treatment with crocin-accompanied exercise did help recovery from the CUS-induced memory deficit, the interaction of crocin administration and exercise had no synergic effects; the protective effect observed was due to crocin administration rather than the exercise.


Assuntos
Carotenoides/farmacologia , Transtornos da Memória/terapia , Condicionamento Físico Animal/fisiologia , Estresse Psicológico/terapia , Animais , Glicemia/metabolismo , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Corticosterona/sangue , Modelos Animais de Doenças , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Transtornos da Memória/etiologia , Distribuição Aleatória , Ratos , Ratos Wistar , Estresse Psicológico/complicações
4.
PLoS One ; 15(5): e0226790, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365120

RESUMO

Patients with DYT1 dystonia caused by the mutated TOR1A gene exhibit risk neutral behaviour compared to controls who are risk averse in the same reinforcement learning task. It is unclear whether this behaviour can be linked to changes in cortico-striatal plasticity demonstrated in animal models which share the same TOR1A mutation. We hypothesised that we could reproduce the experimental risk taking behaviour using a model of the basal ganglia under conditions where cortico-striatal plasticity was abnormal. As dopamine exerts opposing effects on cortico-striatal plasticity via different receptors expressed on medium spiny neurons (MSN) of the direct (D1R dominant, dMSNs) and indirect (D2R dominant, iMSNs) pathways, we tested whether abnormalities in cortico-striatal plasticity in one or both of these pathways could explain the patient's behaviour. Our model could generate simulated behaviour indistinguishable from patients when cortico-striatal plasticity was abnormal in both dMSNs and iMSNs in opposite directions. The risk neutral behaviour of the patients was replicated when increased cortico-striatal long term potentiation in dMSN's was in combination with increased long term depression in iMSN's. This result is consistent with previous observations in rodent models of increased cortico-striatal plasticity at in dMSNs, but contrasts with the pattern reported in vitro of dopamine D2 receptor dependant increases in cortico-striatal LTP and loss of LTD at iMSNs. These results suggest that additional factors in patients who manifest motor symptoms may lead to divergent effects on D2 receptor dependant cortico-striatal plasticity that are not apparent in rodent models of this disease.


Assuntos
Dopamina/genética , Distonia Muscular Deformante/genética , Chaperonas Moleculares/genética , Receptores de Dopamina D2/genética , Animais , Gânglios da Base/metabolismo , Gânglios da Base/fisiologia , Comportamento Animal/fisiologia , Ciências Biocomportamentais , Corpo Estriado/metabolismo , Corpo Estriado/fisiologia , Dopamina/metabolismo , Distonia Muscular Deformante/psicologia , Feminino , Humanos , Aprendizagem/fisiologia , Potenciação de Longa Duração/genética , Potenciação de Longa Duração/fisiologia , Masculino , Rigidez Muscular/genética , Rigidez Muscular/patologia , Mutação/genética , Vias Neurais/metabolismo , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Reforço Psicológico , Assunção de Riscos , Roedores/genética , Roedores/fisiologia , Sinapses/genética
5.
Nat Commun ; 11(1): 2014, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332733

RESUMO

Astrocytes support the energy demands of synaptic transmission and plasticity. Enduring changes in synaptic efficacy are highly sensitive to stress, yet whether changes to astrocyte bioenergetic control of synapses contributes to stress-impaired plasticity is unclear. Here we show in mice that stress constrains the shuttling of glucose and lactate through astrocyte networks, creating a barrier for neuronal access to an astrocytic energy reservoir in the hippocampus and neocortex, compromising long-term potentiation. Impairing astrocytic delivery of energy substrates by reducing astrocyte gap junction coupling with dominant negative connexin 43 or by disrupting lactate efflux was sufficient to mimic the effects of stress on long-term potentiation. Furthermore, direct restoration of the astrocyte lactate supply alone rescued stress-impaired synaptic plasticity, which was blocked by inhibiting neural lactate uptake. This gating of synaptic plasticity in stress by astrocytic metabolic networks indicates a broader role of astrocyte bioenergetics in determining how experience-dependent information is controlled.


Assuntos
Astrócitos/metabolismo , Metabolismo Energético/fisiologia , Potenciação de Longa Duração/fisiologia , Neurônios/fisiologia , Estresse Psicológico/metabolismo , Adaptação Psicológica/fisiologia , Animais , Modelos Animais de Doenças , Feminino , Glucose/metabolismo , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Ácido Láctico/metabolismo , Masculino , Redes e Vias Metabólicas/fisiologia , Camundongos , Neocórtex/citologia , Neocórtex/metabolismo , Técnicas de Patch-Clamp
6.
Neuron ; 106(6): 992-1008.e9, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32320644

RESUMO

Astrocytes play essential roles in brain function by supporting synaptic connectivity and associated circuits. How these roles are regulated by transcription factors is unknown. Moreover, there is emerging evidence that astrocytes exhibit regional heterogeneity, and the mechanisms controlling this diversity remain nascent. Here, we show that conditional deletion of the transcription factor nuclear factor I-A (NFIA) in astrocytes in the adult brain results in region-specific alterations in morphology and physiology that are mediated by selective DNA binding. Disruptions in astrocyte function following loss of NFIA are most pronounced in the hippocampus, manifested by impaired interactions with neurons, coupled with diminution of learning and memory behaviors. These changes in hippocampal astrocytes did not affect basal neuronal properties but specifically inhibited synaptic plasticity, which is regulated by NFIA in astrocytes through calcium-dependent mechanisms. Together, our studies reveal region-specific transcriptional dependencies for astrocytes and identify astrocytic NFIA as a key transcriptional regulator of hippocampal circuits.


Assuntos
Astrócitos/metabolismo , Encéfalo/metabolismo , Cálcio/metabolismo , Regulação da Expressão Gênica , Aprendizagem/fisiologia , Fatores de Transcrição NFI/genética , Animais , Astrócitos/fisiologia , Encéfalo/citologia , Encéfalo/fisiopatologia , Tronco Encefálico/citologia , Tronco Encefálico/metabolismo , Tronco Encefálico/fisiopatologia , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiopatologia , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Camundongos , Camundongos Knockout , Vias Neurais , Plasticidade Neuronal , Neurônios , Bulbo Olfatório/citologia , Bulbo Olfatório/metabolismo , Bulbo Olfatório/fisiopatologia , Técnicas de Patch-Clamp , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Memória Espacial/fisiologia
7.
Ann Neurol ; 87(5): 763-773, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32129908

RESUMO

OBJECTIVE: Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder due to pathogenic mutations in the MECP2 gene. Motor impairment constitutes the core diagnostic feature of RTT. Preclinical studies have consistently demonstrated alteration of excitation/inhibition (E/I) balance and aberrant synaptic plasticity at the cortical level. We aimed to understand neurobiological mechanisms underlying motor deficit by assessing in vivo synaptic plasticity and E/I balance in the primary motor cortex (M1). METHODS: In 14 patients with typical RTT, 9 epilepsy control patients, and 11 healthy controls, we applied paired-pulse transcranial magnetic stimulation (TMS) protocols to evaluate the excitation index, a biomarker reflecting the contribution of inhibitory and facilitatory circuits in M1. Intermittent TMS-theta burst stimulation was used to probe long-term potentiation (LTP)-like plasticity in M1. Motor impairment, assessed by ad hoc clinical scales, was correlated with neurophysiological metrics. RESULTS: RTT patients displayed a significant increase of the excitation index (p = 0.003), as demonstrated by the reduction of short-interval intracortical inhibition and increase of intracortical facilitation, suggesting a shift toward cortical excitation likely due to GABAergic dysfunction. Impairment of inhibitory circuits was also confirmed by the reduction of long-interval intracortical inhibition (p = 0.002). LTP-like plasticity in M1 was abolished (p = 0.008) and scaled with motor disability (all p = 0.003). INTERPRETATION: TMS is a method that can be used to assess cortical motor function in RTT patients. Our findings support the introduction of TMS measures in clinical and research settings to monitor the progression of motor deficit and response to treatment. ANN NEUROL 2020;87:763-773.


Assuntos
Córtex Motor/fisiopatologia , Transtornos Motores/etiologia , Transtornos Motores/fisiopatologia , Síndrome de Rett/complicações , Síndrome de Rett/fisiopatologia , Feminino , Humanos , Potenciação de Longa Duração/fisiologia , Atividade Motora/fisiologia , Estimulação Magnética Transcraniana , Adulto Jovem
8.
Neuron ; 106(5): 842-854.e4, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32213321

RESUMO

Excitation in neural circuits must be carefully controlled by inhibition to regulate information processing and network excitability. During development, cortical inhibitory and excitatory inputs are initially mismatched but become co-tuned or balanced with experience. However, little is known about how excitatory-inhibitory balance is defined at most synapses or about the mechanisms for establishing or maintaining this balance at specific set points. Here we show how coordinated long-term plasticity calibrates populations of excitatory-inhibitory inputs onto mouse auditory cortical pyramidal neurons. Pairing pre- and postsynaptic activity induced plasticity at paired inputs and different forms of heterosynaptic plasticity at the strongest unpaired synapses, which required minutes of activity and dendritic Ca2+ signaling to be computed. Theoretical analyses demonstrated how the relative rate of heterosynaptic plasticity could normalize and stabilize synaptic strengths to achieve any possible excitatory-inhibitory correlation. Thus, excitatory-inhibitory balance is dynamic and cell specific, determined by distinct plasticity rules across multiple excitatory and inhibitory synapses.


Assuntos
Potenciais de Ação/fisiologia , Córtex Auditivo/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Inibição Neural/fisiologia , Plasticidade Neuronal/fisiologia , Células Piramidais/fisiologia , Animais , Sinalização do Cálcio , Potenciais Evocados , Potenciação de Longa Duração/fisiologia , Camundongos , Técnicas de Patch-Clamp , Sinapses/fisiologia
9.
J Neurosci ; 40(14): 2793-2807, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32102922

RESUMO

The spatiotemporal dynamics of excitatory neurotransmission must be tightly regulated to achieve efficient synaptic communication. By limiting spillover, glutamate transporters are believed to prevent excessive activation of extrasynaptically located receptors that can impair synaptic plasticity. While glutamate transporter expression is reduced in numerous neurodegenerative diseases, the contributions of transporter dysfunction to disease pathophysiology remain ambiguous as the fundamental relationship between glutamate dynamics and plasticity, and the mechanisms linking these two phenomena, remain poorly understood. Here, we combined electrophysiology and real-time high-speed imaging of extracellular glutamate transients during LTP induction and characterized the sensitivity of the relationship between glutamate dynamics during theta burst stimulation (TBS) and the resulting magnitude of LTP consolidation, both in control conditions and following selective and nonselective glutamate transporter blockade. Glutamate clearance times were negatively correlated with LTP magnitude following nonselective glutamate transporter inhibition but not following selective blockade of a majority of GLT-1, the brain's most abundant glutamate transporter. Although glutamate transporter inhibition reduced the postsynaptic population response to TBS, calcium responses to TBS were greatly exaggerated. The source of excess calcium was dependent on NMDARs, L-type VGCCs, GluA2-lacking AMPARs, and internal calcium stores. Surprisingly, inhibition of L-type VGCCs, but not GluA2-lacking AMPARs or ryanodine receptors, was required to restore robust LTP. In all, these data provide a detailed understanding of the relationship between glutamate dynamics and plasticity and uncover important mechanisms by which poor glutamate uptake can negatively impact LTP consolidation.SIGNIFICANCE STATEMENT Specific patterns of neural activity can promote long-term changes in the strength of synaptic connections through a phenomenon known as synaptic plasticity. Synaptic plasticity is well accepted to represent the cellular mechanisms underlying learning and memory, and many forms of plasticity are initiated by the excitatory neurotransmitter glutamate. While essential for rapid cellular communication in the brain, excessive levels of extracellular glutamate can negatively impact brain function. In this study, we demonstrate that pharmacological manipulations that increase the availability of extracellular glutamate during neural activity can have profoundly negative consequences on synaptic plasticity. We identify mechanisms through which excess glutamate can negatively influence synaptic plasticity, and we discuss the relevance of these findings to neurodegenerative diseases and in the aging brain.


Assuntos
Ácido Glutâmico/fisiologia , Potenciação de Longa Duração/fisiologia , Neurônios/fisiologia , Transmissão Sináptica/fisiologia , Animais , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
10.
Clin Immunol ; 212: 108350, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31982645

RESUMO

Autoimmune thyroiditis (AIT)-related brain damage is one of most severe extrathyroidal manifestations of AIT, but the mechanism remains unclear. In this study, we confirmed that protein disulfide-isomerase A3 (PDIA3) is expressed in both thyroid and brain tissues of mouse, and found the significantly increased serum levels of anti-PDIA3 antibody (PDIA3Ab) in classical mouse models of thyroiditis. In addition, we investigated the PDIA3-specific autoimmune reaction in thyroid and brain tissues in a mouse model with high-serum PDIA3Ab induced by immunization with recombinant PDIA3 protein. PDIA3-immunized mice had elevated serum thyrotropin and impaired learning and memory. PDIA3-expressing cells had IgG deposition, and IgG colocalized with C3 in the thyroid and brain tissues of PDIA3-immunized mice, resulting in membrane attack complex formation. Our results suggest that PDIA3 protein may be a common autoantigen shared by the thyroid and brain tissues and involve in the thyroidal and intracerebral damage through activating complement system.


Assuntos
Autoanticorpos/imunologia , Encéfalo/imunologia , Encefalite/imunologia , Doença de Hashimoto/imunologia , Isomerases de Dissulfetos de Proteínas/imunologia , Glândula Tireoide/imunologia , Tireoidite Autoimune/imunologia , Animais , Apoptose/imunologia , Autoantígenos/imunologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Encéfalo/ultraestrutura , Modelos Animais de Doenças , Encefalite/patologia , Encefalite/fisiopatologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Doença de Hashimoto/patologia , Doença de Hashimoto/fisiopatologia , Potenciação de Longa Duração/fisiologia , Aprendizagem em Labirinto , Camundongos , Glândula Tireoide/patologia , Tireoidite Autoimune/patologia , Tireoidite Autoimune/fisiopatologia
12.
BMC Biol ; 18(1): 7, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31937327

RESUMO

BACKGROUND: Abnormal accumulation of amyloid ß1-42 oligomers (AßO1-42), a hallmark of Alzheimer's disease, impairs hippocampal theta-nested gamma oscillations and long-term potentiation (LTP) that are believed to underlie learning and memory. Parvalbumin-positive (PV) and somatostatin-positive (SST) interneurons are critically involved in theta-nested gamma oscillogenesis and LTP induction. However, how AßO1-42 affects PV and SST interneuron circuits is unclear. Through optogenetic manipulation of PV and SST interneurons and computational modeling of the hippocampal neural circuits, we dissected the contributions of PV and SST interneuron circuit dysfunctions on AßO1-42-induced impairments of hippocampal theta-nested gamma oscillations and oscillation-induced LTP. RESULTS: Targeted whole-cell patch-clamp recordings and optogenetic manipulations of PV and SST interneurons during in vivo-like, optogenetically induced theta-nested gamma oscillations in vitro revealed that AßO1-42 causes synapse-specific dysfunction in PV and SST interneurons. AßO1-42 selectively disrupted CA1 pyramidal cells (PC)-to-PV interneuron and PV-to-PC synapses to impair theta-nested gamma oscillogenesis. In contrast, while having no effect on PC-to-SST or SST-to-PC synapses, AßO1-42 selectively disrupted SST interneuron-mediated disinhibition to CA1 PC to impair theta-nested gamma oscillation-induced spike timing-dependent LTP (tLTP). Such AßO1-42-induced impairments of gamma oscillogenesis and oscillation-induced tLTP were fully restored by optogenetic activation of PV and SST interneurons, respectively, further supporting synapse-specific dysfunctions in PV and SST interneurons. Finally, computational modeling of hippocampal neural circuits including CA1 PC, PV, and SST interneurons confirmed the experimental observations and further revealed distinct functional roles of PV and SST interneurons in theta-nested gamma oscillations and tLTP induction. CONCLUSIONS: Our results reveal that AßO1-42 causes synapse-specific dysfunctions in PV and SST interneurons and that optogenetic modulations of these interneurons present potential therapeutic targets for restoring hippocampal network oscillations and synaptic plasticity impairments in Alzheimer's disease.


Assuntos
Potenciais de Ação/fisiologia , Peptídeos beta-Amiloides/efeitos adversos , Hipocampo , Interneurônios/fisiologia , Potenciação de Longa Duração/fisiologia , Parvalbuminas/metabolismo , Fragmentos de Peptídeos/efeitos adversos , Somatostatina/metabolismo , Animais , Camundongos , Optogenética
13.
Sci Rep ; 10(1): 1368, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992760

RESUMO

Fusion transcripts can contribute to diversity of molecular networks in the human cortex. In this study, we explored the occurrence of fusion transcripts in normal human cortex along with single neurons and astrocytes. We identified 1305 non-redundant fusion events from 388 transcriptomes representing 59 human cortices and 329 single cells. Our results indicate while the majority of fusion transcripts in human cortex are intra-chromosomal (85%), events found in single neurons and astrocytes were primarily inter-chromosomal (80%). The number of fusions in single neurons was significantly higher than that in single astrocytes (p < 0.05), indicating fusion as a possible contributor towards transcriptome diversity in neuronal cells. The identified fusions were largely private and 4 specific recurring events were found both in cortex and in single neurons but not in astrocytes. We found a significant increase in the number of fusion transcripts in human brain with increasing age both in single cells and whole cortex (p < 0.0005 and < 0.005, respectively). This is likely one of the many possible contributors for the inherent plasticity of the adult brain. The fusion transcripts in fetal brain were enriched for genes for long-term depression; while those in adult brain involved genes enriched for long-term potentiation pathways. Our findings demonstrate fusion transcripts are naturally occurring phenomenon spanning across the health-disease continuum, and likely contribute to the diverse molecular network of human brain.


Assuntos
Envelhecimento/fisiologia , Astrócitos/metabolismo , Lobo Frontal/metabolismo , Substância Cinzenta/metabolismo , Neurônios/metabolismo , RNA Mensageiro/biossíntese , Transcriptoma/fisiologia , Adulto , Astrócitos/citologia , Feminino , Lobo Frontal/citologia , Substância Cinzenta/citologia , Humanos , Recém-Nascido , Potenciação de Longa Duração/fisiologia , Masculino , Neurônios/citologia
14.
Psychoneuroendocrinology ; 111: 104480, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31707294

RESUMO

The highly conserved transcription factor LIM-only 3 (Lmo3) is involved in important neurodevelopmental processes in several brain areas including the amygdala, a central hub for the generation and regulation of emotions. Accordingly, a role for Lmo3 in the behavioral responses to ethanol and in the display of anxiety-like behavior in mice has been demonstrated while the potential involvement of Lmo3 in the control of mood-related behavior has not yet been explored. Using a mouse model of Lmo3 depletion (Lmo3z), we here report that genetic Lmo3 deficiency is associated with altered performance in behavioral paradigms assessing anxiety-like and depression-like traits and additionally accompanied by impairments in learned fear. Importantly, long-term potentiation (LTP) in the basolateral amygdala (BLA), a proposed cellular correlate of fear learning, is impaired in Lmo3z mice. RNA-Seq analysis of BLA tissue and gene set enrichment analysis (GSEA) of differentially expressed genes in Lmo3z mice reveals a significant overlap between genes overexpressed in Lmo3z mice and those enriched in the amygdala of a cohort of patients suffering from major depressive disorder. Consequently, we propose that Lmo3 may play a role in the regulation of gene networks that are relevant to the regulation of emotions. Future work may aid to further explore the role of Lmo3 in the pathophysiology of affective disorders and its genetic foundations.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Tonsila do Cerebelo/metabolismo , Proteínas com Domínio LIM/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Afeto , Tonsila do Cerebelo/fisiologia , Animais , Ansiedade/genética , Transtornos de Ansiedade/genética , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Depressão/genética , Transtorno Depressivo Maior/genética , Medo/fisiologia , Feminino , Proteínas com Domínio LIM/metabolismo , Potenciação de Longa Duração/fisiologia , Masculino , Camundongos , Camundongos Knockout , Fatores de Transcrição/genética
15.
Adv Exp Med Biol ; 1131: 519-535, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646524

RESUMO

The multifunctional Ca2+/calmodulin-dependent protein kinase type 2 (CaMK-II) was first discovered in brain tissue and shown to have a central role in long term potentiation, responding to Ca2+ elevations through voltage dependent channels. CaMK-II has a unique molecular mechanism that enables it to remain active in proportion to the degree (frequency and amplitude) of Ca2+ elevations, long after such elevations have subsided. Ca2+ is also a rapid activator of early development and CaMK-II is expressed and activated in early development. Using biochemical, pharmacological and genetic approaches, the functions of CaMK-II overlap remarkably well with those for Ca2+ elevations, post-fertilization. Conclusion. Activated CaMK-II plays a central role in decoding Ca2+ signals to activate specific events during early development; a majority of the known functions of elevated Ca2+ act though CaMK-II.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Potenciação de Longa Duração , Animais , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Crescimento e Desenvolvimento/fisiologia , Humanos , Potenciação de Longa Duração/fisiologia
16.
Cell Rep ; 29(13): 4295-4307.e6, 2019 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-31875541

RESUMO

A large number of experiments have indicated that precise spike times, firing rates, and synapse locations crucially determine the dynamics of long-term plasticity induction in excitatory synapses. However, it remains unknown how plasticity mechanisms of synapses distributed along dendritic trees cooperate to produce the wide spectrum of outcomes for various plasticity protocols. Here, we propose a four-pathway plasticity framework that is well grounded in experimental evidence and apply it to a biophysically realistic cortical pyramidal neuron model. We show in computer simulations that several seemingly contradictory experimental landmark studies are consistent with one unifying set of mechanisms when considering the effects of signal propagation in dendritic trees with respect to synapse location. Our model identifies specific spatiotemporal contributions of dendritic and axo-somatic spikes as well as of subthreshold activation of synaptic clusters, providing a unified parsimonious explanation not only for rate and timing dependence but also for location dependence of synaptic changes.


Assuntos
Córtex Cerebral/fisiologia , Dendritos/metabolismo , Potenciação de Longa Duração/fisiologia , Modelos Neurológicos , Células Piramidais/metabolismo , Sinapses/fisiologia , Potenciais de Ação/fisiologia , Animais , Córtex Cerebral/citologia , Simulação por Computador , Dendritos/ultraestrutura , Expressão Gênica , Hipocampo/citologia , Hipocampo/fisiologia , Técnicas de Patch-Clamp , Células Piramidais/ultraestrutura , Ratos , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismo , Sinapses/ultraestrutura , Transmissão Sináptica/fisiologia
17.
Int J Mol Sci ; 21(1)2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31878257

RESUMO

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelinating white matter lesions and neurodegeneration, with a variable clinical course. Brain network architecture provides efficient information processing and resilience to damage. The peculiar organization characterized by a low number of highly connected nodes (hubs) confers high resistance to random damage. Anti-homeostatic synaptic plasticity, in particular long-term potentiation (LTP), represents one of the main physiological mechanisms underlying clinical recovery after brain damage. Different types of synaptic plasticity, including both anti-homeostatic and homeostatic mechanisms (synaptic scaling), contribute to shape brain networks. In MS, altered synaptic functioning induced by inflammatory mediators may represent a further cause of brain network collapse in addition to demyelination and grey matter atrophy. We propose that impaired LTP expression and pathologically enhanced upscaling may contribute to disrupting brain network topology in MS, weakening resilience to damage and negatively influencing the disease course.


Assuntos
Esclerose Múltipla/metabolismo , Animais , Encéfalo/metabolismo , Humanos , Inflamação/metabolismo , Potenciação de Longa Duração/genética , Potenciação de Longa Duração/fisiologia , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia
18.
Elife ; 82019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31868584

RESUMO

Vascular endothelial growth factor (VEGF) is an angiogenic factor that play important roles in the nervous system, although it is still unclear which receptors transduce those signals in neurons. Here, we show that in the developing hippocampus VEGFR2 (also known as KDR or FLK1) is expressed specifically in the CA3 region and it is required for dendritic arborization and spine morphogenesis in hippocampal neurons. Mice lacking VEGFR2 in neurons (Nes-cre Kdrlox/-) show decreased dendritic arbors and spines as well as a reduction in long-term potentiation (LTP) at the associational-commissural - CA3 synapses. Mechanistically, VEGFR2 internalization is required for VEGF-induced spine maturation. In analogy to endothelial cells, ephrinB2 controls VEGFR2 internalization in neurons. VEGFR2-ephrinB2 compound mice (Nes-cre Kdrlox/+ Efnb2lox/+) show reduced dendritic branching, reduced spine head size and impaired LTP. Our results demonstrate the functional crosstalk of VEGFR2 and ephrinB2 in vivo to control dendritic arborization, spine morphogenesis and hippocampal circuitry development.


Assuntos
Dendritos/metabolismo , Efrina-B2/metabolismo , Hipocampo/metabolismo , Neurogênese/fisiologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Região CA3 Hipocampal , Espinhas Dendríticas/metabolismo , Células Endoteliais/metabolismo , Efrina-B2/genética , Regulação da Expressão Gênica no Desenvolvimento , Potenciação de Longa Duração/fisiologia , Camundongos , Neurogênese/genética , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Sinapses/fisiologia , Transcriptoma , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
19.
PLoS Biol ; 17(12): e3000525, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31841517

RESUMO

Ubiquitin-specific protease (USP) 6 is a hominoid deubiquitinating enzyme previously implicated in intellectual disability and autism spectrum disorder. Although these findings link USP6 to higher brain function, potential roles for USP6 in cognition have not been investigated. Here, we report that USP6 is highly expressed in induced human neurons and that neuron-specific expression of USP6 enhances learning and memory in a transgenic mouse model. Similarly, USP6 expression regulates N-methyl-D-aspartate-type glutamate receptor (NMDAR)-dependent long-term potentiation and long-term depression in USP6 transgenic mouse hippocampi. Proteomic characterization of transgenic USP6 mouse cortex reveals attenuated NMDAR ubiquitination, with concomitant elevation in NMDAR expression, stability, and cell surface distribution with USP6 overexpression. USP6 positively modulates GluN1 expression in transfected cells, and USP6 down-regulation impedes focal GluN1 distribution at postsynaptic densities and impairs synaptic function in neurons derived from human embryonic stem cells. Together, these results indicate that USP6 enhances NMDAR stability to promote synaptic function and cognition.


Assuntos
Memória/fisiologia , Plasticidade Neuronal/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Ubiquitina Tiolesterase/metabolismo , Animais , Encéfalo/metabolismo , Potenciais Pós-Sinápticos Excitadores , Hipocampo/metabolismo , Humanos , Potenciação de Longa Duração/fisiologia , Depressão Sináptica de Longo Prazo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/enzimologia , Neurônios/metabolismo , Neurônios/fisiologia , Sinapses/metabolismo , Sinapses/fisiologia , Ubiquitina Tiolesterase/genética
20.
Rev Assoc Med Bras (1992) ; 65(9): 1174-1180, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618333

RESUMO

OBJECTIVE: The study aims to explore the relationship between preoperative anxiety and chronic postoperative pain. METHODS: A total of forty rats were divided into four groups, control, single-prolonged stress alone, Hysterectomy alone, and SPS+ Hysterectomy. The paw withdrawal mechanical thresholds (PWMT) were examined. qRT-PCR and western blotting assay were performed to detect the GFAP expression in astrocytes isolated from the anterior cingulate cortex (ACC) region. In addition, the long-term potentiation (LTP) in ACC was examined. RESULTS: Rats in the SPS group or the Hysterectomy alone group had no significant effect on chronic pain formation, but SPS can significantly induce chronic pain after surgery. Astrocytes were still active, and the LTP was significantly increased three days after modeling in the SPS+Hysterectomy group. CONCLUSIONS: anxiety can induce chronic pain by activating astrocytes in the ACC region.


Assuntos
Ansiedade/complicações , Astrócitos/metabolismo , Dor Crônica/etiologia , Dor Pós-Operatória/etiologia , Animais , Dor Crônica/psicologia , Modelos Animais de Doenças , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Giro do Cíngulo/metabolismo , Membro Posterior , Histerectomia , Potenciação de Longa Duração/fisiologia , Limiar da Dor/fisiologia , Dor Pós-Operatória/psicologia , Período Pré-Operatório , Distribuição Aleatória , Ratos Sprague-Dawley , Estresse Psicológico/etiologia , Fatores de Tempo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA