Suppression of adult cytogenesis in the rat brain leads to sex-differentiated disruption of the HPA axis activity.

OBJECTIVES: The action of stress hormones, mainly glucocorticoids, starts and coordinates the systemic response to stressful events. The HPA axis activity is predicated on information processing and modulation by upstream centres, such as the hippocampus where adult-born neurons (hABN) have been reported to be an important component in the processing and integration of new information. Still, it remains unclear whether and how hABN regulates HPA axis activity and CORT production, particularly when considering sex differences. MATERIALS AND METHODS: Using both sexes of a transgenic rat model of cytogenesis ablation (GFAP-Tk rat model), we examined the endocrinological and behavioural effects of disrupting the generation of new astrocytes and neurons within the hippocampal dentate gyrus (DG). RESULTS: Our results show that GFAP-Tk male rats present a heightened acute stress response. In contrast, GFAP-Tk female rats have increased corticosterone secretion at nadir, a heightened, yet delayed, response to an acute stress stimulus, accompanied by neuronal hypertrophy in the basal lateral amygdala and increased expression of the glucocorticoid receptors in the ventral DG. CONCLUSIONS: Our results reveal that hABN regulation of the HPA axis response is sex-differentiated.

Allosteric modulation of AMPA receptors counteracts Tau-related excitotoxic synaptic signaling and memory deficits in stress- and Aß-evoked hippocampal pathology.

Despite considerable progress in the understanding of its neuropathology, Alzheimer's disease (AD) remains a complex disorder with no effective treatment that counteracts the memory deficits and the underlying synaptic malfunction triggered by the accumulation of amyloid beta (Aß) and Tau protein. Mounting evidence supports a precipitating role for chronic environmental stress and glutamatergic excitotoxicity in AD, suggesting that targeting of glutamate receptor signaling may be a promising approach against both stress and AD pathologies. In light of the limited cognitive benefit of the direct antagonism of NMDA receptors in AD, we here focus on an alternative way to modify glutamatergic signaling through positive allosteric modulation of AMPA receptors, by the use of a PAM-AMPA compound. Using non-transgenic animal model of Aß oligomer injection as well as the combined stress and Aß i.c.v. infusion, we demonstrate that positive allosteric modulation of AMPA receptors by PAM-AMPA treatment reverted memory, but not mood, deficits. Furthermore, PAM-AMPA treatment reverted stress/Aß-driven synaptic missorting of Tau and associated Fyn/GluN2B-driven excitotoxic synaptic signaling accompanied by recovery of neurotransmitter levels in the hippocampus. Our findings suggest that positive allosteric modulation of AMPA receptors restores synaptic integrity and cognitive performance in stress- and Aß-evoked hippocampal pathology. As the prevalence of AD is increasing at an alarming rate, novel therapeutic targeting of glutamatergic signaling should be further explored against the early stages of AD synaptic malfunction with the goal of attenuating further synaptic damage before it becomes irreversible.

Dysregulation of autophagy and stress granule-related proteins in stress-driven Tau pathology.

Imbalance of neuronal proteostasis associated with misfolding and aggregation of Tau protein is a common neurodegenerative feature in Alzheimer's disease (AD) and other Tauopathies. Consistent with suggestions that lifetime stress may be an important AD precipitating factor, we previously reported that environmental stress and high glucocorticoid (GC) levels induce accumulation of aggregated Tau; however, the molecular mechanisms for such process remain unclear. Herein, we monitor a novel interplay between RNA-binding proteins (RBPs) and autophagic machinery in the underlying mechanisms through which chronic stress and high GC levels impact on Tau proteostasis precipitating Tau aggregation. Using molecular, pharmacological and behavioral analysis, we demonstrate that chronic stress and high GC trigger mTOR-dependent inhibition of autophagy, leading to accumulation of Tau aggregates and cell death in P301L-Tau expressing mice and cells. In parallel, we found that environmental stress and GC disturb cellular homeostasis and trigger the insoluble accumulation of different RBPs, such as PABP, G3BP1, TIA-1, and FUS, shown to form stress granules (SGs) and Tau aggregation. Interestingly, an mTOR-driven pharmacological stimulation of autophagy attenuates the GC-driven accumulation of Tau and SG-related proteins as well as the related cell death, suggesting a critical interface between autophagy and the response of the SG-related protein in the neurodegenerative potential of chronic stress and GC. These studies provide novel insights into the RNA-protein intracellular signaling regulating the precipitating role of environmental stress and GC on Tau-driven brain pathology.

Chronic Stress and Glucocorticoids: From Neuronal Plasticity to Neurodegeneration.

Stress and stress hormones, glucocorticoids (GCs), exert widespread actions in central nervous system, ranging from the regulation of gene transcription, cellular signaling, modulation of synaptic structure, and transmission and glial function to behavior. Their actions are mediated by glucocorticoid and mineralocorticoid receptors which are nuclear receptors/transcription factors. While GCs primarily act to maintain homeostasis by inducing physiological and behavioral adaptation, prolonged exposure to stress and elevated GC levels may result in neuro- and psychopathology. There is now ample evidence for cause-effect relationships between prolonged stress, elevated GC levels, and cognitive and mood disorders while the evidence for a link between chronic stress/GC and neurodegenerative disorders such as Alzheimer's (AD) and Parkinson's (PD) diseases is growing. This brief review considers some of the cellular mechanisms through which stress and GC may contribute to the pathogenesis of AD and PD.

Desenvolvimento de competências emocionais nos estudantes de enfermagem no primeiro ensino clínico / Development of emotional competencies in nursing students in their first clinical teaching

É no contacto com a prática clínica que o estudante desenvolve algumas competências que não são passíveis de se desenvolverem ao longo da componente teórica da formação inicial. Assim, logo no primeiro período de aprendizagem clínica devem ser adotadas estratégias promotoras do desenvolvimento de competências emocionais, já que a presença do estudante neste contexto e o contacto prolongado com o professor de enfermagem constituem fatores indicados para a implementação de programas que favoreçam o desenvolvimento da Inteligência Emocional (IE). Pretendendo analisar a influência do ambiente supervisivo, no desenvolvimento da IE, durante o 1º período de ensino clínico (EC), dos estudantes do Curso de Licenciatura em Enfermagem (CLE), foram elaboradas as seguintes hipóteses de investigação: A frequência do primeiro EC e o ambiente supervisivo contribuem para o desenvolvimento das competências emocionais dos estudantes e; as dimensões do ambiente supervisivo são preditoras do desenvolvimento das competências da IE dos estudantes durante o 1º EC. Adotou-se a metodologia quantitativa, pré-experimental com avaliação em dois momentos. Os dados foram colhidos com recurso aos questionários ?Capacidades da IE em enfermeiros?, (1º e 2º momentos) e CLES+T (2º momento). Os dados foram tratados estatisticamente a partir do IBM.SPSS.19. Cento e quarenta e um estudantes a realizar EC de fundamentos de enfermagem, no 1º semestre do ano letivo 2012-2013 constituem a amostra. Entre os principais resultados destaca-se que após o ensino clínico os estudantes evidenciam uma autoperceção mais baixa das capacidades autoconsciência, gestão das emoções e automotivação. Contudo, percecionam positivamente as suas competências emocionais e o ambiente de aprendizagem clínico. Há correlação negativa entre a autoconfiança e a componente relacional do professor de enfermagem e correlação positiva entre a empatia e o estilo de liderança do enfermeiro chefe, e, também, entre a gestão dos relacionamentos em grupos e o contexto pedagógico, a relação supervisiva e a componente relacional do professor de enfermagem. Conclui-se que os achados podem dever-se a algumas especificidades deste EC, bem como do modelo supervisivo adotado que importa continuar a explorar.