Challenges in the use of animal models and perspectives for a translational view of stress and psychopathologies.

The neurobiology and development of treatments for stress-related neuropsychiatric disorders rely heavily on animal models. However, the complexity of these disorders makes it difficult to model them entirely, so only specific features of human psychopathology are emulated and these models should be used with great caution. Importantly, the effects of stress depend on multiple factors, like duration, context of exposure, and individual variability. Here we present a review on pre-clinical studies of stress-related disorders, especially those developed to model posttraumatic stress disorder, major depression, and anxiety. Animal models provide relevant evidence of the underpinnings of these disorders, as long as face, construct, and predictive validities are fulfilled. The translational challenges faced by scholars include reductionism and anthropomorphic/anthropocentric interpretation of the results instead of a more naturalistic and evolutionary understanding of animal behavior that must be overcome to offer a meaningful model. Other limitations are low statistical power of analysis, poor evaluation of individual variability, sex differences, and possible conflicting effects of stressors depending on specific windows in the lifespan.

Evaluation of the HPA Axis' Response to Pharmacological Challenges in Experimental and Clinical Early-Life Stress-Associated Depression.

Early-life stress (ELS) is associated with a higher risk of psychopathologies in adulthood, such as depression, which may be related to persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis. This study aimed to evaluate the effects of ELS on the functioning of the HPA axis in clinical and experimental situations. Clinically, patients with current depressive episodes, with and without ELS, and healthy controls, composed the sample. Subjects took a capsule containing placebo, fludrocortisone, prednisolone, dexamethasone or spironolactone followed by an assessment of plasma cortisol the morning after. Experimentally, male Wistar rats were submitted to ELS protocol based on variable, unpredictable stressors from postnatal day (PND)1 to PND21. On PND65 animals were behaviorally evaluated through the forced-swimming test (FST). At PND68, pharmacological challenges started, using mifepristone, dexamethasone, spironolactone, or fludrocortisone, and corticosterone levels were determined 3 h after injections. Cortisol response of the patients did not differ significantly from healthy subjects, regardless of their ELS history, and it was lower after fludrocortisone, prednisolone, and dexamethasone compared with placebo, indicating the suppression of plasma cortisol by all these treatments. Animals exposed to ELS presented altered phenotype as indicated by an increased immobility time in the FST when compared with control, but no significant long-lasting effects of ELS were observed on the HPA axis response. Limitations on the way the volunteers were sampled may have contributed to the lack of ELS effects on the HPA axis, pointing out the need for further research to understand these complex phenomena.

Oxidative stress and Na,K-ATPase activity differential regulation in brainstem and forebrain of Wistar Audiogenic rats may lead to increased seizure susceptibility.

The Wistar Audiogenic Rat (WAR) is a well-characterized seizure-prone, inbred rodent strain that, when acutely stimulated with high-intensity sounds, develops brainstem-dependent tonic-clonic seizures that can evolve to limbic-like, myoclonic (forebrain) seizures when the acoustic stimuli are presented chronically (audiogenic kindling). In order to investigate possible mechanisms underlying WAR susceptibility to seizures, we evaluated Na,K-ATPase activity, Ca-ATPase activity, Mg-ATPase activity, lipid membrane composition and oxidative stress markers in whole forebrain and whole brainstem samples of naïve WAR, as compared to samples from control Wistar rats. We also evaluated the expression levels of α1 and α3 isoforms of Na,K-ATPase in forebrain samples. We observed increased Na,K-ATPase activity in forebrain samples and increased oxidative stress markers (lipid peroxidation, glutathione peroxidase and superoxide dismutase) in brainstem samples of WAR. The Ca-ATPase activity, Mg-ATPase activity, lipid membrane composition and expression levels of α1 and α3 isoforms of Na,K-ATPase were unaltered. In view of previous data showing that the membrane potentials from naïve WAR's neurons are less negative than that from neurons from Wistar rats, we suggest that Na,K-ATPase increased activity might be involved in a compensatory mechanism necessary to maintain WAR's brains normal activity. Additionally, ongoing oxidative stress in the brainstem could bring Na,K-ATPase activity back to normal levels, which may explain why WAR's present increased susceptibility to seizures triggered by high-intensity sound stimulation.

Influências do Ambiente Sobre a Susceptibilidade às Crises Epilépticas: As Lições dos Modelos Experimentais / Environment influence over epileptic seizure susceptibility: the lessons from experimental models

O propósito principal desta revisão é discutir a influência do ambiente sobre a susceptibilidade a crises e a epilepsia. Nós estamos constantemente expostos a diversas condições que exercem influências, positivas e negativas, sobre a nossa qualidade de vida. Esses fatores externos são capazes de moldar nossos cérebros desde a vida intrauterina até a morte. Eventos estressantes são reconhecidos como fator desencadeador de crises em pacientes com epilepsia. Diversos estudos experimentais estão de acordo com esses achados clínicos e apontam a corticosterona como o principal fator pró-convulsivo. Entretanto, os dados experimentais são vastos e apenas com atenção podemos detectar as informações relevantes. Por outro lado, ambientes enriquecidos promovem alterações plásticas em nossos cérebros, particularmente através da neurogênese, e podem potencialmente reduzir a susceptibilidade a crises, o dano neuronal e a neurogênese anormal induzidos pelas próprias crises. Finalmente, a prática regular de exercício físico tem se mostrado capaz de reduzir a frequência de crises e retardar o processo epileptogênico em modelos animais de epilepsia, além de reduzir ou mesmo eliminar os efeitos do estresse.

The main purpose of this review is to bring out to discussion the environment influence over seizure susceptibility and epilepsy. We are constantly exposed to such different conditions that exert positive as well as negative influences in our quality of life. These external factors are able to shape our brains and neural circuits from intrauterine life until death. Stressful events are known as seizure precipitants in patients with epilepsy. Although several animal studies are in line with these clinical findings, pointing out that corticosterone is one of the major pro-convulsant factor, however the experimental data are vast and only with close attention we can detect the relevant information. On the other hand, enriched environments promote plastic changes in our brains, particularly through neurogenesis, that can potentially reduce seizure susceptibility, and the aberrant neurogenesis and neuronal damage both induced by the seizures themselves. Finally, regular practice of physical exercise has been shown to reduce seizure frequency and delay epileptogenic process in animal models of epilepsy, in addition to reduce, or even eliminate stress levels.