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1.
Nat Immunol ; 25(4): 671-681, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38448779

RESUMO

Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus, present in up to 80% of patients and leading to a diminished quality of life. In the present study, we used a model of lupus-like cognitive impairment that is initiated when antibodies that crossreact with excitatory neuronal receptors penetrate the hippocampus, causing immediate, self-limited, excitotoxic death of hippocampal neurons, which is then followed by a significant loss of dendritic complexity in surviving neurons. This injury creates a maladaptive equilibrium that is sustained in mice for at least 1 year. We identified a feedforward loop of microglial activation and microglia-dependent synapse elimination dependent on neuronal secretion of high mobility group box 1 protein (HMGB1) which binds the receptor for advanced glycation end products (RAGE) and leads to microglial secretion of C1q, upregulation of interleukin-10 with consequent downregulation of leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1), an inhibitory receptor for C1q. Treatment with a centrally acting angiotensin-converting enzyme inhibitor or with an angiotensin-receptor blocker restored a healthy equilibrium, microglial quiescence and intact spatial memory.


Assuntos
Autoanticorpos , Proteína HMGB1 , Animais , Camundongos , Complemento C1q , Proteína HMGB1/metabolismo , Doenças Neuroinflamatórias , Qualidade de Vida , Receptor para Produtos Finais de Glicação Avançada/metabolismo
2.
Eur J Neurosci ; 39(6): 1009-1017, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24354924

RESUMO

The nucleus accumbens (NAc) is a critical brain region for the rewarding effects of drugs of abuse. Brain-derived neurotrophic factor (BDNF) can facilitate stress- and drug-induced neuroadaptation in the mesocorticolimbic system. BDNF-containing projections to the NAc originate from the ventral tegmental area (VTA) and the prefrontal cortex, and BDNF release activates tropomyosin-related kinase B (TrkB). In this study, we examined the necessity for BDNF-TrkB signaling in the NAc shell during social defeat stress-induced cross-sensitization to amphetamine. Adeno-associated virus expressing short hairpin RNA directed against TrkB (AAV-shTrkB) was infused bilaterally into the NAc shell to knock down TrkB, whereas AAV-GFP (green fluorescent protein) was used as the control virus. Rats were exposed to intermittent social defeat stress or handling procedures; amphetamine challenge was given at 10 days after the last defeat and locomotor activity was measured. Stressed rats that received the control virus showed cross-sensitization to amphetamine compared with the handled rats. In contrast, NAc TrkB knockdown prevented social defeat stress-induced cross-sensitization. TrkB knockdown in the NAc was found to reduce the level of phospho-extracellular signal-regulated kinase 1 in this region. NAc TrkB knockdown also prevented stress-induced elevation of BDNF and the glutamate receptor type 1 (GluA1) subunit of AMPA receptor in the VTA, as well as ΔFosB expression in the NAc. These findings indicated that BDNF-TrkB signaling in the NAc shell was required for social defeat stress-induced cross-sensitization. NAc TrkB-BDNF signaling also appeared to be involved in the regulation of GluA1 in the VTA, as well as in the NAc ΔFosB accumulation that could trigger cross-sensitization after social defeat stress.


Assuntos
Anfetamina/farmacologia , Sensibilização do Sistema Nervoso Central , Núcleo Accumbens/metabolismo , Receptor trkB/metabolismo , Estresse Psicológico/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Locomoção , Masculino , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor trkB/genética , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Comportamento Social , Estresse Psicológico/fisiopatologia
3.
Res Sq ; 2023 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-37292843

RESUMO

Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE), present in up to 80% of patients and leading to a diminished quality of life. We have developed a model of lupus-like cognitive impairment which is initiated when anti-DNA, anti-N-methyl D-aspartate receptor (NMDAR) cross- reactive antibodies, which are present in 30% of SLE patients, penetrate the hippocampus1. This leads to immediate, self-limited excitotoxic death of CA1 pyramidal neurons followed by a significant loss of dendritic arborization in the remaining CA1 neurons and impaired spatial memory. Both microglia and C1q are required for dendritic loss1. Here we show that this pattern of hippocampal injury creates a maladaptive equilibrium that is sustained for at least one year. It requires HMGB1 secretion by neurons to bind RAGE, a receptor for HMGB1 expressed on microglia, and leads to decreased expression of microglial LAIR-1, an inhibitory receptor for C1q. The angiotensin converting enzyme (ACE) inhibitor captopril, which can restore a healthy equilibrium, microglial quiescence, and intact spatial memory, leads to upregulation of LAIR-1. This paradigm highlights HMGB1:RAGE and C1q:LAIR-1 interactions as pivotal pathways in the microglial-neuronal interplay that defines a physiologic versus a maladaptive equilibrium.

4.
Behav Brain Res ; 193(1): 126-31, 2008 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-18565602

RESUMO

The basolateral amygdala (BLA) is implicated in the neurobiology of emotion, and can also modulate the cognitive and habit memory processes mediated by the hippocampus and dorsal striatum, respectively. In a dual-solution task that can be acquired using either hippocampus-dependent or dorsal striatal-dependent learning, peripheral or intra-BLA infusion of the anxiogenic alpha(2)-adrenoreceptor antagonist RS 79948 biases rats towards the use of habit learning. In view of evidence that anxiety can promote relapse into habitual and maladaptive human behaviors, understanding the mechanism(s) by which emotional arousal can influence the relative use of multiple memory systems may prove clinically relevant. Therefore, the present experiments examined whether intra-BLA infusions of RS 79948 bias rats towards the use of habit learning directly by enhancing dorsal striatal function, or indirectly by impairing hippocampal function. Adult male Long-Evans rats were trained in one of two single-solution water plus-maze tasks. One version required the use of hippocampus-dependent "place" learning. A second version required the use of dorsal striatal-dependent "response" learning, and hippocampal mnemonic processes have been shown to interfere with acquisition of this task. Post-training intra-BLA infusions of RS 79948 (1.0 microg/0.5 microl) impaired acquisition of place learning. In contrast, intra-BLA infusions of RS 79948 enhanced response learning. Intra-BLA infusion of RS 79948 also produced an anxiogenic behavioral profile in an elevated plus-maze at the same dose (1.0 microg) that differentially influenced place and response learning. The findings suggest that intra-BLA infusion of an anxiogenic drug can influence the use of multiple memory systems by impairing hippocampus-dependent learning, thereby releasing habit memory from competing and/or inhibitory influences of cognitive memory.


Assuntos
Tonsila do Cerebelo/fisiologia , Comportamento Animal/fisiologia , Cognição/fisiologia , Emoções/fisiologia , Memória/fisiologia , Antagonistas de Receptores Adrenérgicos alfa 2 , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Emoções/efeitos dos fármacos , Reação de Fuga/efeitos dos fármacos , Reação de Fuga/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Isoquinolinas/administração & dosagem , Isoquinolinas/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Microinjeções , Naftiridinas/administração & dosagem , Naftiridinas/farmacologia , Ratos , Ratos Long-Evans , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologia
5.
Sci Rep ; 8(1): 126, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29317669

RESUMO

We previously found that genetic mutants with reduced expression or activity of Scn8a are resistant to induced seizures and that co-segregation of a mutant Scn8a allele can increase survival and seizure resistance of Scn1a mutant mice. In contrast, Scn8a expression is increased in the hippocampus following status epilepticus and amygdala kindling. These findings point to Scn8a as a promising therapeutic target for epilepsy and raise the possibility that aberrant overexpression of Scn8a in limbic structures may contribute to some epilepsies, including temporal lobe epilepsy. Using a small-hairpin-interfering RNA directed against the Scn8a gene, we selectively reduced Scn8a expression in the hippocampus of the intrahippocampal kainic acid (KA) mouse model of mesial temporal lobe epilepsy. We found that Scn8a knockdown prevented the development of spontaneous seizures in 9/10 mice, ameliorated KA-induced hyperactivity, and reduced reactive gliosis. These results support the potential of selectively targeting Scn8a for the treatment of refractory epilepsy.


Assuntos
Epilepsia do Lobo Temporal/genética , Epilepsia do Lobo Temporal/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Canal de Sódio Disparado por Voltagem NAV1.6/metabolismo , Convulsões/genética , Convulsões/metabolismo , Animais , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia do Lobo Temporal/diagnóstico , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Predisposição Genética para Doença , Hipocampo/metabolismo , Imuno-Histoquímica , Masculino , Camundongos , RNA Interferente Pequeno/genética , Convulsões/diagnóstico
6.
Arch Gen Psychiatry ; 61(12): 1259-68, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15583117

RESUMO

BACKGROUND: The etiology of Tourette syndrome (TS) involves disturbances in the structure and function of the basal ganglia. The basal ganglia mediate habit learning. OBJECTIVE: To study habit learning in persons with TS. DESIGN: Patients with TS were compared with normal controls in performance on a probabilistic classification, or habit-learning task (weather prediction). SETTING: University research institute. PARTICIPANTS: One hundred twenty-three children and adults, 56 with a diagnosis of TS and 67 healthy control subjects. MAIN OUTCOME MEASURES: Habit learning was assessed by the extent of improvement in accuracy of predictions and reaction times over trial blocks during performance of the weather prediction task. Declarative learning was assessed by performance on 3 tasks that required intact declarative memory functioning. RESULTS: Children with TS were impaired at habit learning relative to normal controls (P = .01). This finding was replicated in the independent sample of adults with TS (P = .01). The rate of learning correlated inversely with the severity of tic symptoms across both samples (r = -0.34; P = .01). Thus, impaired learning accompanied more severe symptoms. Measures of declarative memory functioning, in contrast, were normal in the TS groups. CONCLUSIONS: Striatal learning systems are uniquely dysfunctional in both children and adults with TS. The correlation of habit learning with symptom severity suggests that the number and severity of tics are a function of the degree to which the system for habit learning is dysfunctional. Thus, both the deficits in habit learning and the tic symptoms of TS are likely to be consequences of the previously reported anatomical and functional disturbances of the striatum in children and adults who have TS. The existence of a well-developed animal model for this learning system, which permits study of the neural and molecular bases of habit learning, has important implications for the neurobiological study of TS and for the development of new or improved therapeutics for this condition.


Assuntos
Gânglios da Base/fisiopatologia , Memória/fisiologia , Aprendizagem por Probabilidade , Síndrome de Tourette/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Criança , Comorbidade , Sinais (Psicologia) , Feminino , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/epidemiologia , Transtorno Obsessivo-Compulsivo/fisiopatologia , Reconhecimento Visual de Modelos/fisiologia , Tempo de Reação/fisiologia , Índice de Gravidade de Doença , Análise e Desempenho de Tarefas , Síndrome de Tourette/diagnóstico , Síndrome de Tourette/epidemiologia , Tempo (Meteorologia)
7.
Front Cell Neurosci ; 9: 202, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26074771

RESUMO

Hearing loss due to mutations in the connexin gene family, which encodes gap junctional proteins, is a common form of hereditary deafness. In particular, connexin 26 (Cx26, GJB2) mutations are responsible for ~50% of non-syndromic hearing loss, which is the highest incidence of genetic disease. In the clinic, Cx26 mutations cause various auditory phenotypes ranging from profound congenital deafness at birth to mild, progressive hearing loss in late childhood. Recent experiments demonstrate that congenital deafness mainly results from cochlear developmental disorders rather than hair cell degeneration and endocochlear potential reduction, while late-onset hearing loss results from reduction of active cochlear amplification, even though cochlear hair cells have no connexin expression. However, there is no apparent, demonstrable relationship between specific changes in connexin (channel) functions and the phenotypes of mutation-induced hearing loss. Moreover, new experiments further demonstrate that the hypothesized K(+)-recycling disruption is not a principal deafness mechanism for connexin deficiency induced hearing loss. Cx30 (GJB6), Cx29 (GJC3), Cx31 (GJB3), and Cx43 (GJA1) mutations can also cause hearing loss with distinct pathological changes in the cochlea. These new studies provide invaluable information about deafness mechanisms underlying connexin mutation-induced hearing loss and also provide important information for developing new protective and therapeutic strategies for this common deafness. However, the detailed cellular mechanisms underlying these pathological changes remain unclear. Also, little is known about specific mutation-induced pathological changes in vivo and little information is available for humans. Such further studies are urgently required.

8.
Behav Processes ; 118: 85-9, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26047523

RESUMO

Studies employing brain lesion or intracerebral drug infusions in rats have demonstrated a double dissociation between the roles of the hippocampus and dorsolateral striatum in place and response learning. The hippocampus mediates a rapid cognitive learning process underlying place learning, whereas the dorsolateral striatum mediates a relatively slower learning process in which stimulus-response habits underlying response learning are acquired in an incremental fashion. One potential implication of these findings is that hippocampus-dependent learning may benefit from a relative massing of training trials, whereas dorsal striatum-dependent learning may benefit from a relative distribution of training trials. In order to examine this hypothesis, the present study compared the effects of massed (30s inter-trial interval; ITI) or spaced (30min ITI) training on acquisition of a hippocampus-dependent place learning task, and a dorsolateral striatum-dependent response task in a plus-maze. In the place task rats swam from varying start points (N or S) to a hidden escape platform located in a consistent spatial location (W). In the response task rats swam from varying start points (N or S) to a hidden escape platform located in the maze arm consistent with a body-turn response (left). In the place task, rats trained with the massed trial schedule acquired the task quicker than rats trained with the spaced trial schedule. In the response task, rats trained with the spaced trial schedule acquired the task quicker than rats trained with the massed trial schedule. The double dissociation observed suggests that the reinforcement parameters most conducive to effective learning in hippocampus-dependent and dorsolateral striatum-dependent learning may have differential temporal characteristics.


Assuntos
Condicionamento Clássico , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Comportamento Espacial/fisiologia , Animais , Comportamento Animal , Corpo Estriado , Hipocampo/fisiologia , Masculino , Ratos , Ratos Long-Evans
9.
Neurobiol Learn Mem ; 82(3): 243-52, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15464407

RESUMO

The basolateral amygdala modulates the cognitive and habit memory processes mediated by the hippocampus and caudate nucleus, respectively. The present experiments used a plus-maze task that can be acquired using either hippocampus-dependent "place" learning or caudate-dependent "response" learning to examine whether peripheral or intra-basolateral amygdala injection of anxiogenic drugs would bias rats towards the use of a particular memory system. In Experiment 1, adult male Long-Evans rats were trained to swim from the same start point to an escape platform located in a consistent goal arm, and received pre-training peripheral injections of the alpha(2)-adrenoceptor antagonists yohimbine (2.5 or 5.0 mg/kg), RS 79948-197 (0.05, 0.1, or 0.2 mg/kg), or vehicle. On a drug-free probe trial from a novel start point administered 24h following acquisition, vehicle treated rats predominantly displayed hippocampus-dependent place learning, whereas rats previously treated with yohimbine (2.5, 5.0 mg/kg) or RS 79948-197 (0.1 mg/kg) predominantly displayed caudate-dependent response learning. In Experiment 2, rats receiving pre-training intra-basolateral amygdala infusions of RS 79948-197 (0.1 microg/0.5 microl) also predominantly displayed response learning on a drug-free probe trial. The findings indicate (1) peripheral injections of anxiogenic drugs can influence the relative use of multiple memory systems in a manner that favors caudate-dependent habit learning over hippocampus-dependent cognitive learning, and (2) intra-basolateral amygdala infusion of anxiogenic drugs is sufficient to produce this modulatory influence of emotional state on the use of multiple memory systems.


Assuntos
Tonsila do Cerebelo/fisiologia , Ansiedade/fisiopatologia , Núcleo Caudado/fisiologia , Hipocampo/fisiologia , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Antagonistas Adrenérgicos alfa , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Ansiedade/induzido quimicamente , Núcleo Caudado/efeitos dos fármacos , Relação Dose-Resposta a Droga , Reação de Fuga/efeitos dos fármacos , Reação de Fuga/fisiologia , Hipocampo/efeitos dos fármacos , Infusões Parenterais , Isoquinolinas , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Microinjeções , Naftiridinas , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Ratos , Ratos Long-Evans , Ioimbina
10.
Hippocampus ; 12(2): 280-4, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12000124

RESUMO

A post-training reversible lesion technique was used to examine the effects of neural inactivation of the dorsal hippocampus on place and response learning. Male Long-Evans rats trained in one of two versions of a water plus-maze task received post-training intra-hippocampal infusions of the local anesthetic drug bupivacaine (0.75% solution, 0.5 microl), or saline. Post-training intra-hippocampal infusions of bupivacaine attenuated acquisition of the place task and enhanced acquisition of the response task. Delayed (2-h) post-training infusions of bupivacaine did not affect retention in either task. The findings demonstrate (1) enhanced learning after reversible hippocampal lesions that is independent of treatment influences on non-mnemonic factors, and (2) inactivation of the dorsal hippocampus during the post-training memory consolidation period is sufficient to enhance response learning.


Assuntos
Condicionamento Psicológico/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Análise de Variância , Anestésicos Locais/farmacologia , Animais , Bupivacaína/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Microinjeções , Ratos , Ratos Long-Evans
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