José M. Pêgo

A trans-dimensional approach to the behavioral aspects of depression

Depression, a complex mood disorder, displays high comorbidity with anxiety and cognitive disorders. To establish the extent of inter-dependence between these behavioral domains, we here undertook a systematic analysis to establish interactions between mood [assessed with the forced-swimming (FST) and sucrose consumption tests (SCT)], anxiety [elevated-plus maze (EPM) and novelty suppressed feeding (NSF) tests] and cognition (spatial memory and behavioral flexibility tests) in rats exposed to unpredictable chronic-mild-stress (uCMS). Expectedly, uCMS induced depressive-like behavior, a hyperanxious phenotype and cognitive impairment; with the exception of the measure of anxiety in the EPM, these effects were attenuated by antidepressants (imipramine, fluoxetine). Measures of mood by the FST and SCT were strongly correlated, whereas no significant correlations were found between the different measures of anxiety (EPM and NSF); likewise, measures of cognition by spatial memory and behavioral flexibility tests were poorly correlated. Inter-domain analysis revealed significant correlations between mood (FST and SCT) and anxiety-like behavior (NSF, but not EPM). Furthermore, significant correlations were found between cognitive performance (reverse learning task) and mood (FST and SCT) and anxiety-like behavior (NSF). These results demonstrate interactions between different behavioral domains that crosscut the disciplines of psychiatry and neurology.

Transvesical thoracoscopy: A natural orifice translumenal endoscopic approach for thoracic surgery

BackgroundRecently there has been an increasing enthusiasm for using natural orifices translumenal endoscopic surgery (NOTES) to perform scarless abdominal procedures. We have previously reported the feasibility and safety of the transvesical endoscopic peritoneoscopy in a long-term survival porcine model as useful for those purposes. Herein, we report our successful experience performing transvesical and transdiaphragmatic endoscopic approach to the thoracic cavity in a long-term survival study in a porcine model.MethodsTransvesical and transdiaphragmatic endoscopic thoracoscopy was performed in six anesthetized female pigs. A 5 mm transvesical port was created on the bladder wall and an ureteroscope was advanced into the peritoneal cavity. After diaphragm inspection, we introduced through the left diaphragmatic dome a ureteroscope into the left thoracic cavity. In all animals, we performed thoracoscopy as well as peripheral lung biopsy. Animals were sacrificed by day 15 postoperatively.ResultsWe easily introduced a 9.8 Fr ureteroscope into the thoracic cavity that allowed us to visualize the pleural cavity and to perform simple surgical procedures such as lung biopsies without complications. There were neither respiratory distress episodes nor surgical complications to report. Postmortem examination revealed complete healing of vesical and diaphragmatic holes, whereas no signs of infection or adhesions were observed in the peritoneal or thoracic cavities.ConclusionThis study demonstrates the feasibility of transvesical thoracoscopy in porcine model. However, although this study extends the potential applications of NOTES to the thoracic cavity, new instruments and further work are needed to provide evidence that this could be translated to humans and with advantages for patients.

Stress and the Neuroendocrinology of Anxiety Disorders

Stress is a risk factor for depressive and anxiety disorders. Changes in lifestyle patterns that are associated with increased stress therefore place a greater burden on mental health. Stress challenges the organisms homeostatic mechanisms, triggering a cascade of events that should, normally, maintain or allow a return to equilibrium. Stressful events are perceived by sensory systems in the brain, facilitating evaluation and comparison of the existing and previous stimuli as well as the activation of hormones responsible for energy mobilization. The limbic system coordinates the release of corticosteroids, the primary stress hormones, by modulating activation of the hypothalamic paraventricular nucleus (PVN). The amygdala, a limbic structure related to emotional behavior, has a putative role in the evaluation of emotional events and formation of fearful memories; it is also a target of the neurochemical and hormonal mediators of stress. Clinical and experimental data have correlated changes in the structure/function of the amygdala with emotional disorders such as anxiety. In this chapter we review the neuroendocrinology of the stress response, focusing on the role of the limbic system in its establishment and supplementing that information with new experimental data that demonstrates the relationship between stress and anxiety disorders; we also discuss the structural changes that occur in the amygdala after stress.

Neurodevelopment milestone abnormalities in rats exposed to stress in early life

Manipulation of the corticosteroid milieu by interfering with the mother-newborn relationship has received much attention because of its potential bearing on psychopathology later in life. In the present study, infant rats that were deprived of maternal contact between the 2nd and the 15th postnatal days (MS2-15) for 6 h/day were subjected to a systematic assessment of neurodevelopmental milestones between postnatal days 2 and 21. The analyses included measurements of physical growth and maturation and evaluation of neurological reflexes. Although some somatic milestones (e.g. eye opening) were anticipated, MS2-15 animals showed retardation in the acquisition of postural reflex, air righting and surface righting reflexes, and in the wire suspension test; the latter two abnormalities were only found in males. A gender effect was also observed in negative geotaxis, with retardation being observed in females but not males. To better understand the delay of neurological maturation in MS2-15 rats, we determined the levels of various monoamines in different regions of the brain stem, including the vestibular area, the substantia nigra, ventral tegmental area and dorsal raphe nuclei. In the vestibular region of MS2-15 rats the levels of 5-HT were reduced, while 5-HT turnover was increased. There was also a significant increase of the 5-HT turnover in MS2-15 animals in the raphe nuclei, mainly due to increased 5-hydroxyindoleacetic acid (5-HIAA) levels, and an increase of 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the ventral tegmental area (VTA) of stressed females. No significant differences were found in the immunohistochemical sections for tyrosine and tryptophan hydroxylase in these regions of the brain stem. In conclusion, the present results show that postnatal stress induces signs of neurological pathology that may contribute to the genesis of behavioral abnormalities later in life.

Induction of a Hyperanxious State by Antenatal Dexamethasone: A Case for Less Detrimental Natural Corticosteroids

BACKGROUND Synthetic glucocorticoids are commonly prescribed during pregnancy, despite a lack of systematic investigations of their potential impact on the developing brain and neurological and behavioral performance. METHODS Neuroendocrine parameters and behavior in the adult offspring of pregnant Wistar rats treated antenatally with either dexamethasone (DEX) or corticosterone (CORT) were monitored; DEX (.1 mg/kg and 1 mg/kg) and CORT (25 mg/kg) were given to pregnant rat dams on gestation days 18 and 19. RESULTS Despite normal basal levels of corticosterone, the adult offspring of mothers given DEX or CORT displayed abnormal responses in the dexamethasone-suppression test. Neither treatment influenced spatial memory performance, but both DEX and CORT facilitated development of depression-like behavior following chronic stress. The latter finding demonstrates that high-dose antenatal corticotherapy can impair the organisms resilience to stress in adulthood. Interestingly, comparison of the progeny of CORT-treated and DEX-treated mothers revealed that the latter were more anxious. CONCLUSIONS Since DEX and CORT differ in their affinity for glucocorticoid and mineralocorticoid receptors and corticosteroid-binding globulin, our findings emphasize the need to consider the pharmacologic properties of antenatal corticotherapies and demonstrate the potential long-term benefits of ligands that can bind to both receptors.

The bed nucleus of stria terminalis and the amygdala as targets of antenatal glucocorticoids: implications for fear and anxiety responses

RationaleSeveral human and experimental studies have shown that early life adverse events can shape physical and mental health in adulthood. Stress or elevated levels of glucocorticoids (GCs) during critical periods of development seem to contribute for the appearance of neurospyschiatric conditions such as anxiety and depression, albeit the underlying mechanisms remain to be fully elucidated.ObjectivesThe aim of the present study was to determine the long-term effect of prenatal exposure to dexamethasone- DEX (synthetic GC widely used in clinics) in fear and anxious behavior and identify the neurochemical, morphological and molecular correlates.ResultsPrenatal exposure to DEX triggers a hyperanxious phenotype and altered fear behavior in adulthood. These behavioral traits were correlated with increased volume of the bed nucleus of the stria terminalis (BNST), particularly the anteromedial subdivision which presented increased dendritic length; in parallel, we found an increased expression of synapsin and NCAM in the BNST of these animals. Remarkably, DEX effects were opposite in the amygdala, as this region presented reduced volume due to significant dendritic atrophy. Albeit no differences were found in dopamine and its metabolite levels in the BNST, this neurotransmitter was substantially reduced in the amygdala, which also presented an up-regulation of dopamine receptor 2.ConclusionsAltogether, our results show that in utero DEX exposure can modulate anxiety and fear behavior in parallel with significant morphological, neurochemical and molecular changes; importantly, GCs seem to differentially affect distinct brain regions involved in this type of behaviors.

Using mouse dynamics to assess stress during online exams

Stress is a highly complex, subjective and multidimensional phenomenon. Nonetheless, it is also one of our strongest driving forces, pushing us forward and preparing our body and mind to tackle the daily challenges, independently of their nature. The duality of the effects of stress, that can have positive or negative effects, calls for approaches that can take the best out of this biological mechanism, providing means for people to cope effectively with stress. In this paper we propose an approach, based on mouse dynamics, to assess the level of stress of students during online exams. Results show that mouse dynamics change in a consistent manner as stress settles in, allowing for its estimation from the analysis of the mouse usage. This approach will allow to understand how each individual student is affected by stress, providing additional valuable information for educational institutions to efficiently adapt and improve their teaching processes.

Segmental and regional quantification of 3D cellular density of human meniscus from osteoarthritic knee

The knee menisci have important roles in the knee joint. Complete healing of the meniscus remains a challenge in the clinics. Cellularity is one of the most important biological parameters that must be taken into account in regenerative strategies. However, knowledge on the 3D cellularity of the human meniscus is lacking in the literature. The aim of this study was to quantify the 3D cellular density of human meniscus from the osteoarthritic knee in a segmental and regional manner with respect to laterality. Human lateral menisci were histologically processed and stained with Giemsa for histomorphometric analysis. The cells were counted in an in‐depth fashion. 3D cellular density in the vascular region (27 199 cells/mm3) was significantly higher than in the avascular region (12 820 cells/mm3). The cells were observed to possess two distinct morphologies, roundish or flattened. The 3D density of cells with fibrochondrocyte morphology (14 705 cells/mm3) was significantly greater than the 3D density of the cells with fibroblast‐like cell morphology (5539 cells/mm3). The best‐fit equation for prediction of the 3D density of cells with fibrochondrocyte morphology was found to be:

Inflammatory response and long-term behavioral assessment after neonatal CO2-pneumothorax: study in a rodent model

BACKGROUND Carbon-dioxide (CO2)-pneumothorax during minimally invasive surgery induces well-known metabolic changes. However, little is known about its impact on the central nervous system. The aim of this work is to evaluate the acute impact of CO2-pneumothorax over central cytokine response and its long-term effect on animal behavior. METHODS This is an experimental study where neonatal Sprague-Dawley rats are submitted to CO2-pneumothorax. Peripheral and central cytokine response was evaluated 24h after insufflation, and peripheral immune cell phenotyping was evaluated 24h and 4weeks post-insufflation. Progenitor cell survival was evaluated in the hippocampal dentate gyrus, and the behavioral analysis was performed in adulthood to test cognition, anxious-like, and depressive-like behavior. RESULTS Significantly increased IL-10 levels were observed in the cerebrospinal-fluid (CSF) of animals submitted to CO2-pneumothorax, while no differences were found in serum. Regarding pro-inflammatory cytokines, no differences were observed in the periphery or centrally. CO2-pneumothorax event did not alter the survival of newborn cells in the hippocampal dentate gyrus, and no impact on long-term behavior was observed. CONCLUSIONS Neonatal animals submitted to CO2-pneumothorax present acutely increased CSF IL-10 levels. The CO2-pneumothorax seems to result in no significant outcome over neurodevelopment as no functional behavioral alterations were observed in adulthood.

Exposure to Ketamine Anesthesia Affects Rat Impulsive Behavior.

Introduction: Ketamine is a general anesthetic (GA) that activates several neurotransmitter pathways in various part of the brain. The acute effects as GA are the most well-known and sought-after: to induce loss of responsiveness and to produce immobility during invasive procedures. However, there is a concern that repeated exposure might induce behavioral changes that could outlast their acute effect. Most research in this field describes how GA affects cognition and memory. Our work is to access if general anesthesia with ketamine can disrupt the motivational behavior trait, more specifically measuring impulsive behavior. Methods: Aiming to evaluate the effects of exposure to repeat anesthetic procedures with ketamine in motivational behavior, we tested animals in a paradigm of impulsive behavior, the variable delay-to-signal (VDS). In addition, accumbal and striatal medium spiny neurons morphology was assessed. Results: Our results demonstrated that previous exposure to ketamine deep-anesthesia affects inhibitory control (impulsive behavior). Specifically, ketamine exposed animals maintain a subnormal impulsive rate in the initial periods of the delays. However, in longer delays while control animals progressively refrain their premature unrewarded actions, ketamine-exposed animals show a different profile of response with higher premature unrewarded actions in the last seconds. Animals exposed to multiple ketamine anesthesia also failed to show an increase in premature unrewarded actions between the initial and final periods of 3 s delays. These behavioral alterations are paralleled by an increase in dendritic length of medium spiny neurons of the nucleus accumbens (NAc). Conclusions: This demonstrates that ketamine anesthesia acutely affects impulsive behavior. Interestingly, it also opens up the prospect of using ketamine as an agent with the ability to modulate impulsivity trait.