Donnai-Barrow syndrome, a genetic disorder associated to LRP2 (low density lipoprotein receptor 2/megalin) mutations, is characterized by unexplained neurological symptoms and intellectual deficits. Megalin is a multifunctional endocytic clearance cell-surface receptor, mostly described in epithelial cells. This receptor is also expressed in the CNS, mainly in neurons, being involved in neurite outgrowth and neuroprotective mechanisms. Yet, the mechanisms involved in the regulation of megalin in the CNS are poorly understood. Using transthyretin knockout mice, a megalin ligand, we found that transthyretin positively regulates neuronal megalin levels in different CNS areas, particularly in the hippocampus. Transthyretin is even able to rescue megalin downregulation in transthyretin knockout hippocampal neuronal cultures, in a positive feedback mechanism via megalin. Importantly, transthyretin activates a regulated intracellular proteolysis mechanism of neuronal megalin, producing an intracellular domain, which is translocated to the nucleus, unveiling megalin C-terminal as a potential transcription factor, able to regulate gene expression. We unveil that neuronal megalin reduction affects physiological neuronal activity, leading to decreased neurite number, length and branching, and increasing neuronal susceptibility to a toxic insult. Finally, we unravel a new unexpected role of megalin in synaptic plasticity, by promoting the formation and maturation of dendritic spines, and contributing for the establishment of active synapses, both in in vitro and in vivo hippocampal neurons. Moreover, these structural and synaptic roles of megalin impact on learning and memory mechanisms, since megalin heterozygous mice show hippocampal-related memory and learning deficits in several behavior tests. Altogether, we unveil a complete novel role of megalin in the physiological neuronal activity, mainly in synaptic plasticity with impact in learning and memory. Importantly, we contribute to disclose the molecular mechanisms underlying the cognitive and intellectual disabilities related to megalin gene pathologies.
The development of substance abuse problems occurs due to a diverse combination of risk factors. Among these risks, studies have reported depression and early-life stress as of importance. These two factors often occur simultaneously, however, there is a lack of understanding of how their combined effect may impact vulnerability to drug abuse in adolescence. The present study used rats with different vulnerability to depression (Wistar and Wistar-Kyoto) to investigate the impact of maternal separation (MS) on emotional state and drug addiction vulnerability during the adolescence period. Mothers and their litters were subjected to MS (180 min/day) from postnatal day 2 to 14. The offspring emotional state was assessed by observing their exploratory behavior. Drug abuse vulnerability was assessed through conditioning to cocaine. MS impacted the emotional state in both strains. Wistar responded with increased exploration, while Wistar-Kyoto increased anxiety-like behaviours. Despite the different coping strategies displayed by the two strains when challenged with the behavioural tests, drug conditioning was equally impacted by MS in both strains. Early-life stress appears to affect drug abuse vulnerability in adolescence independently of a depression background, suggesting emotional state as the main driving risk factor. The development of substance abuse problems occurs due to an almost unpredictable combination of risk factors. Among the common risk factors, mental disorder and emotional stress are constantly cited as important 1,2. Among the main mental disorders, depression is one of the most common in adolescents, inspiring great concern due to its acute and long-lasting consequences 3. Depression in adolescence affects the physical, emotional and social development and can persist and recur into adulthood 4,5. Addiction and depression can be described as having a bidirectional relationship, in which individuals that use drugs for recreational purposes are more likely to develop depression, while individuals that suffer from depression are more likely to develop addiction due to the consumption of drugs (or alcohol) to cope with the depressive symptoms 6,7. Of note, depression and drug abuse comorbidity is highly prevalent in adolescence 8. Similarly to depression, emotional stress and its impact on one's physical and affective condition may lead to the development of addiction. Furthermore, it is known that early life stress, such as children carelessness and mistreatment, can also induce anxiety and depression in adulthood 9. This issue becomes especially relevant given the likelihood of the co-occurrence of these risk factors during early life. There is increased awareness about
Exposure to methamphetamine (Meth) has been classically associated with damage to neuronal terminals. However, it is now becoming clear that addiction may also result from the interplay between glial cells and neurons. Recently, we demonstrated that binge Meth administration promotes microgliosis and microglia pro-inflammation via astrocytic glutamate release in a TNF/IP3R2-Ca2+-dependent manner. Here, we investigated the contribution of neuronal cells to this process. As the crosstalk between microglia and neurons may occur by contact-dependent and/or contact-independent mechanisms, we developed co-cultures of primary neurons and microglia in microfluidic devices to investigate how their interaction affects Meth-induced microglia activation. Our results show that neurons exposed to Meth do not activate microglia in a cell-autonomous way but require astrocyte mediation. Importantly, we found that neurons can partially prevent Meth-induced microglia activation via astrocytes, which seems to be achieved by increasing arginase 1 expression and strengthening the CD200/CD200r pathway. We also observed an increase in synaptic individual area, as determined by co-localization of pre- and post-synaptic markers. The present study provides evidence that contact-dependent mechanisms between neurons and microglia can attenuate pro-inflammatory events such as Meth-induced microglia activation.
Avaliar a prevalência da Síndrome de Burnout entre os alunos de medicina da Universidade Vila Velhos (UVV) do 1º ao 8º períodos em 2018 relacionando com aspectos sociodemográficos. METODOLOGIA: Estudo observacional transversal quantitativo realizado com alunos selecionados aleatoriamente e que concordaram com os termos de Consentimento Livre e Esclarecido. Para avaliação da síndrome de Burnout foi utilizada a MBI-SS (Maslach Burnout Inventory-Student Survey). O ponto de corte foi o escore médio maior que 4 para Exaustão Emocional e Descrença e abaixo de 2 para Eficácia Profissional. RESULTADOS: O questionário foi respondido adequadamente por 334 alunos. A análise do MBI destacou que 63,7% dos alunos apresentaram alto nível de exaustão emocional, nível médio de descrença em 12,5% e baixa eficácia estudantil em 8,3%. A prevalência da Síndrome de Burnout foi de 3,3% e ocorreu principalmente em: homens (63,6%), sedentários (81,8%), do 5º ao 8º período (54,4%). CONCLUSÕES: Observa-se um alto risco de desenvolvimento da Síndrome de Burnout, sendo a dimensão "exaustão emocional" a que mais contribui. Portanto, investir em estratégias específicas de prevenção e tratamento é o caminho para enfrentar situações estressantes, bem como para alcançar a efetividade e a satisfação laboral antes mesmo de ingressarem no mercado de trabalho.Palavras-chaves: Síndrome de Burnout. Educação Médica.
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