Molecular Mechanisms in Hippocampus Involved on Object Recognition Memory Consolidation and Reconsolidation.

Acquired information is stabilized into long-term memory through a process known as consolidation. Though, after consolidation, when stored information is retrieved they can be again susceptible, allowing modification, updating and strengthening and to be re-stabilized they need a new process referred to as memory reconsolidation. However, the molecular mechanisms of recognition memory consolidation and reconsolidation are not fully understood. Also, considering that the study of the link between synaptic proteins is key to understanding of memory processes, we investigated, in male Wistar rats, molecular mechanisms in the hippocampus involved on object recognition memory (ORM) consolidation and reconsolidation. We verified that the blockade of AMPA receptors (AMPAr) and L-VDCCs calcium channels impaired ORM consolidation and reconsolidation when administered into CA1 immediately after sample phase or reactivation phase and that these impairments were blocked by the administration of AMPAr agonist and of neurotrophin BDNF. Also, the blockade of CaMKII impaired ORM consolidation when administered 3 h after sample phase but had no effect on ORM reconsolidation and its effect was blocked by the administration of BDNF, but not of AMPAr agonist. So, this study provides new evidence of the molecular mechanisms involved on the consolidation and reconsolidation of ORM, demonstrating that AMPAr and L-VDCCs are necessary for the consolidation and reconsolidation of ORM while CaMKII is necessary only for the consolidation and also that there is a link between BDNF and AMPAr, L-VDCCs and CaMKII as well as a link between AMPAr and L-VDCCs on ORM consolidation and reconsolidation.

The blockade of the serotoninergic receptors 5-HT5A, 5-HT6 and 5-HT7 in the basolateral amygdala, but not in the hippocampus facilitate the extinction of fear memory.

Extinction is the learned inhibition of retrieval. It is the mainstay of exposure therapy, which is widely used to treat drug addiction, phobias and fear-related pathologies such as post-traumatic stress disorder. The serotonin (5-HT) system is positioned to modulate the extinction circuitry via ascending 5-HT projections that innervate certain brain structures including the hippocampus and the basolateral amygdala (BLA). The most recently described serotoninergic receptors 5-HT5A, 5-HT6, 5-HT7 affect different memory processes and so are putative therapeutic targets for disorders related to cognition; however, their role in the extinction of contextual fear conditioning (CFC) has not been studied yet. Here we investigate the role of these receptors in the CA1 region of the hippocampus and the BLA in the extinction of CFC. For this, male rats were implanted with cannulae in the CA1 or in the BLA region through which they received immediately or 3 h after extinction training of CFC infusions of SB699551 (10 µg/side), 5-HT5A antagonist; WAY-208466 (0.04 µg/side), 5-HT6 agonist; SB-271046A (10 µg/side), 5-HT6 antagonist; AS-19 (5 µg/side), 5-HT7 agonist; SB-269970 (5 µg/side), 5-HT7 antagonist. After 24 h, animals were submitted to a 3 min extinction test. Results show that the infusion immediately after extinction training of 5-HT5A, 5-HT6 and 5-HT7 antagonists, and 3 h after extinction training of 5-HT5A and 5-HT7 antagonists in the BLA region, but not in CA1, facilitates the extinction of CFC memory.

Extinction learning with social support depends on protein synthesis in prefrontal cortex but not hippocampus.

Extinction of contextual fear conditioning (CFC) in the presence of a familiar nonfearful conspecific (social support), such as that of others tasks, can occur regardless of whether the original memory is retrieved during the extinction training. Extinction with social support is blocked by the protein synthesis inhibitors anisomycin and rapamycin and by the inhibitor of gene expression 5,6-dichloro-1-ß-d-ribofuranosylbenzimidazole infused immediately after extinction training into the ventromedial prefrontal cortex (vmPFC) but unlike regular CFC extinction not in the CA1 region of the dorsal hippocampus. So social support generates a form of learning that differs from extinction acquired without social support in terms of the brain structures involved. This finding may lead to a better understanding of the brain mechanisms involved in the social support of memories and in therapies for disorders related to dysfunctional fear memories. Thus, here we show that the consolidation of extinction memory with social support relies on vmPFC rather than hippocampus gene expression and ribosomal- and mammalian target of rapamycin-dependent protein synthesis. These results provide additional knowledge about the cellular mechanisms and brain structures involved on the effect of social support in changing behavior and fear extinction memory.

Métodos anestésicos intervencionistas no tratamento da dor oncológica / Interventional anesthetic methods for the treatment of oncologic pain

Introdução: A dor, sintoma comum em pacientes oncológicos, é mal controlada com a terapia convencional em cerca de 10% a 25% dos casos, levando a uma piora significativa da qualidade de vida. Para esses pacientes, a terapia intervencionista, como bloqueios nervosos, procedimentos neurolíticos ou cordotomia e aquelas que necessitam de tratamento contínuo, como a terapia de infusão, levam a bons resultados no controle da dor. Método: Esse artigo é uma revisão bibliográfica realizada entre os anos de 2010 até 2018 sobre métodos intervencionistas para o tratamento da dor em pacientes oncológicos. Resultados: Bloqueios de nervos periféricos são uma forma de tratar a dor relacionada ao câncer, uma única injeção ou série de injeções de anestésico local com ou sem adjuvantes, com a expectativa de alívio da dor de 2 a 6 semanas. Quase todas as regiões das extremidades superior e inferior e a maioria das áreas da cabeça, pescoço e tronco podem ser anestesiados por bloqueios de nervos periféricos. Neurólise com agentes químicos ou físicos é uma outra opção, utilizada para bloquear nervos espinhais ou cranianos e os plexos autonômicos, oferece alívio da dor por alguns meses. A neurólise química é realizada com álcool de alta concentração ou fenol, já a física é através da thermal radiofrequency lesioning (RFL) ou a crioanalgesia. Conclusão: O uso de medicamentos neuroaxiais, proporcionam redução da dose de analgésicos opioides se comparada a dose via oral necessária para obter analgesia semelhante. Isso reduz os efeitos secundários desagradáveis. Os candidatos à terapia neuroaxial contínua são aqueles com requisitos crescentes de opiáceos, dor de difícil controle ou intolerância ao plano analgésico escolhido.

Introduction: Cancer pain management by conventional therapy is ineffective in about 10-25% of cases, leading to a significant decrease in quality of life. interventional therapy, applying either one-time session of nerve blocks, neurolytic procedures, or cordotomy, or long-term treatments as infusion therapy is able to improve cancer pain management. Methodology: This article is a bibliographic review carried out between 2010 and 2018 on interventional methods for the treatment of pain in cancer patients. Results: Peripheral nerve blocks are a way to treat oncology pain. A single injection or a series of injections of local anesthetic with or without adjuvants, with an expectation of pain relief of 2 to 6 weeks. Almost all regions of the upper and lower extremities and most areas of the head, neck and trunk may be anesthetized by peripheral nerve blocks. Neurolysis with chemical or physical agents is another option used to block spinal or cranial nerves and autonomic plexuses offers pain relief for a few months. Chemical neurolysis is performed with high concentrated alcohol or phenol, yet the physical is usually through thermal radiofrequency lesioning (RFL) or cryoanalgesia. Conclusion: The use of neuroaxial drugs, provide a dose reduction of opioid analgesics use compared to the oral dose required to obtain similar analgesia. This reduces unpleasant side effects. The candidates for continuous neuroaxial therapy are those with increasing requirements for opioids, pain of difficult control or intolerance to the chosen analgesic plan.

Retinoblastoma: atualização sobre avaliação diagnóstica e tratamento / Retinoblastoma: diagnostic evaluation and treatment update

Introdução: O retinoblastoma corresponde a 15% de todos os tumores que ocorrem no primeiro ano de vida. Avaliações oftalmológicas periódicas desde o nascimento até a primeira infância fazem parte do rastreamento proposto para a neoplasia. Quando diagnosticado no início de seu desenvolvimento, apresenta grandes chances de cura. Métodos: Revisão de literatura referente à fisiopatologia, epidemiologia, características clínicas, diagnóstico, tratamento e prognóstico de retinoblastoma, por meio de pesquisa no PubMed, de artigos publicados durante os últimos sete anos. Resultados: Desde 2003, a Classificação Internacional do Retinoblastoma vem sendo considerada a mais atualizada e lógica para estabelecer o estadiamento do tumor, pois consegue correlacionar-se com a estratégia terapêutica. O tratamento do retinoblastoma evoluiu muito. Observa-se grande avanço da quimioterapia. A radioterapia externa, por muito tempo considerada primeira linha, já não é mais usada, especialmente pelo risco de favorecer o surgimento de outras neoplasias nos pacientes com mutação germinativa no gene RB1. Conclusão: O retinoblastoma, apesar de considerado neoplasia rara, corresponde a parcela importante dos tumores da infância, especialmente nos primeiros anos de vida, e pode ser fatal se não for corretamente diagnosticado e manejado. A avaliação diagnóstica, classificação e o tratamento do tumor evoluíram muito nos últimos anos. Destaca-se, nesse cenário, o aprimoramento das técnicas de quimioterapia (intra-artéria oftálmica, intravítreo e sistêmica) e o avanço nos estudos em relação aos danos associados a radioterapia externa, que no momento apresenta indicações restritas. A necessidade de realizar rastreamento na infância segue sendo a melhor forma de diagnosticar alterações caraterísticas da neoplasia precocemente. Com diagnóstico precoce e tratamento correto, o prognóstico de melhora e a sobrevida pode ser superior a 90%.

Introduction: Retinoblastoma accounts for 15% of tumors that occur in the first year of life. Periodic ophthalmic examinations from birth to early childhood are considered a screening for neoplasia. When retinoblastoma is diagnosed early in its development, it presents great chances of cure. Methods: Review of literature on pathophysiology, epidemiology, clinical aspects, diagnosis, treatment and prognosis of retinoblastoma, through PubMed research, of articles published during the last seven years. Results: Since 2003, an International Classification of Retinoblastoma has been more rigorously applied to establish tumor staging, since it is possible to correlate it with a therapeutic strategy. Treatment of retinoblastoma has greatly improved. A great advance of chemotherapy is observed. External radiotherapy, for example, is no longer used, especially because of the risk of other cancers arising in patients with germline mutation in the RB1 gene. Conclusion: Although it is a rare neoplasia, retinoblastoma represents an important percentage of the cancers in childhood, especially in the first years of life. It is fatal if not well diagnosed and treated. A diagnostic evaluation, classification and treatment of the tumor has evolved a lot in the past few years. In this scenario, the improvement of chemotherapy techniques (intra-arterial technique, intravitreal and systemic) is highlighted. Furthermore, new studies have shown the damage associated with external radiotherapy, which at the moment has restricted indications. The need for screening in childhood is the key to early diagnose. With early diagnosis and correct treatment, prognosis of survival improves and may exceed 90%.

Extinction memory is facilitated by methylphenidate and regulated by dopamine and noradrenaline receptors.

Extinction is defined as the learned inhibition of retrieval and is the mainstay of exposure therapy, which is widely used to treat drug addiction, phobias and fear disorders. The psychostimulant, methylphenidate (MPH) is known to increase extracellular levels of noradrenaline and dopamine by blocking their reuptake and studies have demonstrated that MPH can modulate hippocampal physiology and/or functions including long-term potentiation (LTP), learning and memory. However, the influence of MPH on fear extinction memory has been insufficiently studied. Here we investigate the effect of MPH infused into the CA1 region of the hippocampus on extinction memory in animals normally incapable of showing contextual fear conditioning (CFC) extinction because of weak training, and the possible mechanisms through which it acts during this process. For this, male Wistar rats with infusion cannulae stereotaxically implanted in the CA1 region were submitted to a weak extinction protocol in a CFC apparatus. Animals that received intra-CA1 infusion of MPH (12.5µg/side) 20min before the extinction training (Ext Tr) expressed less freezing behavior than Veh-treated animals during both Ext Tr and extinction retention Test (Ext Test). Additionally, the administration of MPH+Timolol (1µg/side) or MPH+SCH23390 (1.5µg/side) intra-CA1 20min before the Ext Tr blocked the enhancing effect of the MPH on extinction learning. These results suggest that MPH in the CA1 region of the hippocampus is able to induce the consolidation of extinction memory and this process occurs through both ß-adrenergic and D1/D5 dopaminergic receptors.