Impact of individual differences in glucocorticoid adaptation to stress on behavior, neurophysiology and metabolism

The stress system is a key modulator of homeostasis and allows organisms to adapt to environmental changes. Proper survival is dependent on the appropriate stress response, for example initiating food (energy) intake or provoking physical reaction. However, long-term activity of the stress system is related to cardiovascular diseases, metabolic syndromes as well as accelerated aging and cognitive impairments. In order to assess the impacts of stress regulation on cardiac, metabolic and aging health processes, we used lines of rats selected for their differential glucocorticoid responsiveness to stress during juvenile period, in the different experiments presented here. The three lines of rats showed low, intermediate or high response to stress and elicited differences in biobehavioral phenotypes. Cardiovascular diseases are highly exacerbated by stress exposure and autonomic imbalance. Reduced vagal modulation has been related to a lower stress flexibility and deleterious effects on cardiac health. In a first study, we investigated the autonomic nervous system modulation of heart rate in the three lines of rats (differing in their responsiveness to stress). Electrocardiographic recordings were performed at rest and following autonomic pharmacological manipulations. Rats with intermediate reactivity to stress had a higher resting parasympathetic (vagal) modulation and a reduced heart rate compared to rats with low or high stress responses. Furthermore, pharmacological treatments showed that the sympathetic regulation of the heart was not impaired in rats with low and high responsiveness to stress. Stress can affect social interactions and, in return, social interactions can be the cause of critical stress. Furthermore, since the stress system is related to key metabolic mediators, we investigated in a second study, the general metabolism of rats from the three lines. Moreover, we paired rats from the different lines together, in mixed-line dyads, and we evaluated the differences in social interactions and the long-term effects of mixed-line pairing on metabolism. We used indirect calorimetry and mitochondrial respirometry to measure energy expenditure and mitochondrial function. We observed that the selection for differences in glucocorticoid responsiveness induced constitutive differences in energy expenditure and fuel use. Moreover, we showed that the biobehavioral phenotypes affected the social interactions between the different lines. Finally, long-term mixed-line pairing affected global and central metabolism of the rats, with rats from the low and intermediate responsive lines being more susceptible to changes. In a final experiment, we studied the interaction of two risk factors for cognitive decline, the secretion of corticosterone and aging. Indeed, dysfunctions of the stress system contribute and facilitate aging and increased glucocorticoids induce cognitive alterations. We assessed anxiety, stress responsiveness, coping-style and cognitive functions in a Morris water-maze at early-aging. Results indicated that the phenotype of the lines were stable throughout life and that learning, swimming strategies and reversal ability were different between the lines. Overall, we showed that this model is suitable to study the systems related to stress regulation. Future research may use this animal model in order to investigate further the relationship between opposite stress regulation and health.

Learning, Stress and the Role of Personality Profiles in Rats

Basira Salehi, Maria del Carmen Sandi Perez

Stress has been shown to modulate many aspects of physiology and behavior. In particular, substantial work has confirmed that stress is a strong modulator of learning and memory processes. It is more than a century that Yerkes and Dodson have shown that relationship between stress intensity and memory function follows an inverted-U-shaped curve; memory increases with stress to an optimal point, above or below which memory decreases. Despite the great popularity of the Yerkes-Dodson law, the validity of the law has been criticized due to significant methodological problems in the study performed by Yerkes and Dodson (1908) and their data being judged insufficient to substantiate conclusions, among other reasons. Moreover the existing evidence has not yet illustrated this phenomenon under the same experimental conditions for relational learning tasks. On the other hand, stress is not the only factor that modulates cognitive abilities. Different types of learning and memory might be affected by other factors such as individual differences in personality. While the relationship between personality and learning has been studied in human, animal studies addressed to understanding the relationship between personality and learning have been rare. In addition, exposure to stress during pregnancy can have deleterious emotional effects on women. However, the mechanisms underlying these emotional effects are not well understood, and the development of suitable animal models for stress-induced depression in females still remains scarce. The goal of this Thesis was to investigate how stress affects cognitive and emotional processes in different animal models, and to explore the importance of individual differences in the mediation of stress effects. On a first study, we investigated the relationship between stress intensity and memory function. For this purpose cognitive abilities of rats to learn a radial arm water maze were assessed under different stress intensities, using behavioural and endocrine approaches. Our results confirm, for the first time, the existence of an inverted-U-shape memory function according to stressor intensity during the early learning and memory phases in a hippocampus-dependent task. Furthermore, we present evidence that these stress effects are not shown uniformly by all individuals; rather, performance at either the high or the low stress intensities is differentially affected in individuals with different personality-like profiles. In a second study, we investigated whether different personality traits in the Wistar outbred strain of rats were associated with performance in specific types of learning and memory tasks that have been reported to depend on specific brain areas, such as the amygdala, hippocampus and prefrontal cortex (PFC). Using a wide variety of behavioral tests, we identified three personality factors: anxiety, exploration and locomotion. According to our results, the locomotion trait displayed no correlation with learning and memory. However curiosity trait predicted extinction of fear memories and spatial reversal learning, and the anxiety traits was related to extinction of fear. These results suggest that behavioral traits, anxiety and curiosity, might be linked to the functioning of specific brain areas (i.e. amygdala and PFC). Our findings are consistent with recent human studies showing that certain personality traits can predict academic achievement and point out the importance of constructing learning environments that could optimize individual strengths. In a third study, we used a model of stress during pregnancy in an attempt to mirror more closely than other experimental approaches based mainly on movement restraint procedures the human condition where stress is often persistently imposed by a male aggressive partner. For that purpose we used aggressive male rats that cohabitated with (and therefore can be considered a stressor) female rats during their pregnancy and, then, characterized the behaviour of these females after weaning. Similar to effects reported in humans, mother rats displayed anxiety-like and depressive-like behaviours, with the females presenting a high anxiety trait being the more vulnerable to the deleterious effects resulting from exposure to the aggressive male. These results propose an interesting animal model to study the effect of stress during pregnancy. Taken together, our results reinforce the view that stress has a strong impact on cognitive function and emotion. They also stress the importance of taking into account individual differences to characterize individuals with different vulnerability to be affected in both cognitive and emotional domain by exposure to stress. Our approach is novel and original in that it takes into account several behavioural (personality-like) traits simultaneously and shows the importance of different traits for different aspects of the relationship between stress, emotion and cognition. The approaches and findings provide valuable models to address the neurobiological mechanisms underlying stress effects on behavior.

EPFL2010

Low vagal tone in two rat models of psychopathology involving high or low corticosterone stress responses

Sriparna Ghosal, Jocelin Grosse, Damien Sébastien Huzard, Maria del Carmen Sandi Perez

The two stress-responsive physiological systems, autonomic nervous system (ANS) and hypothalamus-pituitary-adrenal (HPA) axis exert complementary and interrelated actions in the organism. Individuals that suffer stress-related psychopathologies frequently present simultaneous alterations –i.e., either low or high- responsiveness– in both systems. However, there is scarce evidence establishing whether a priori alterations in these systems –i.e., independent of previous stress exposure– may predispose to the development of psychopathologies possibly due to the lack of animal models simultaneously involving aberrant HPA and SNS responses. In this study, we describe two animal models selectively bred according to their differential (either high, ‘High’, or low, ‘Low’) glucocorticoid responsiveness to stress, in comparison to a third line of rats that displays intermediate (‘Inter’) glucocorticoid responses. The two extreme lines may be considered distinct models of psychopathology; the High line representing a model of constitutive mood alterations while the Low line a model of vulnerability to develop stress-induced psychopathologies. We recorded the electrocardiogram in rats from the three lines and quantified heart rate variability and vagal tone indexes during rest and stress challenges. Rats from both High and Low lines displayed higher heart rate and lower basal vagal tone than the Inter group, both at resting and following stress exposure. Specific pharmacological manipulations probing the relative contribution of sympathetic and parasympathetic components on HR modulation confirmed a relative lower vagal tone in High and Low lines and discarded differences in the sympathetic regulation of heart rate between the lines. Therefore, the two genetically-selected High and Low glucocorticoid rat lines emerge as two valuable preclinical models of psychopathology involving two key risk factors for psychiatric and cardiovascular disorders, namely dysregulations in the HPA axis and cardiac vagal functioning.

2019

The Impact of Sleep Fragmentation on Sleep Homeostasis, Brain and Peripheral Energy Metabolism and Spatial Learning

Maxime Olivier Baud

The quality of sleep has recently come to the forefront of public health concerns in industrialized nations. Indeed, voluntary sleep curtailment is widespread, sleep disorders are increasingly recognized and both correlate with the current epidemiology of diabetes and obesity (Van Cauter and Knutson, 2008). Sleep fragmentation (SF) is a periodic disruption found in highly prevalent sleep-related breathing and movement disorders, where the sleeper might be aroused several hundred times per night. By roughly summing the prevalence of obstructive sleep apnea (OSA) syndromes and periodic limb movement disorders, two of the most common sleep disorders, we predict a total prevalence for SF of nearly 15% in the European active population. Overlooked cases and insufficient concern for the problematic bear a major socioeconomic burden because of the broad impact of excessive daytime sleepiness on productivity (Hossain and Shapiro, 2002), motor vehicle accidents (Aldrich, 1989) and medical complications (Spiegel et al., 2009). Recurrent interference with the natural architecture of sleep leads to sleepiness, difficulty in concentration and cognitive impairments such as decreased reaction times and poor working memory equivalent to a full night of sleep deprivation in severe cases (Bonnet, 1985, 1989; Stepanski, 2002). In addition, recent experimental evidence in humans has unraveled the unprecedented link between sleep of poor quality and dramatic endocrine imbalances such as deregulation of appetite controlling hormones, glucocorticoids and increase in sympathetic tone, ultimately leading to the development of insulin resistance (Spiegel et al., 2009; Stamatakis and Punjabi, 2010). Current animal models for the study of sleep pathology mostly involve short intervention often biased by stress induction and usually involving a complete period of sleep deprivation. These models do not tightly reflect the most common clinical pattern characterized by sleep perturbation over long periods of time. Therefore, paying attention to maximally avoid methodological stress, we designed a new device aiming at performing instrumental SF for fourteen days in mice. Our model mimics SF observed in sleep disorders since it has no major impact on circadian timing and total amount of sleep but clearly shortens individual sleep episodes. With this method, we approached three problematics that were insufficiently addressed in the literature. In our first study, we addressed the question of whether SF could trigger electrophysiological and molecular sleep homeostasis mechanisms in the short-term and whether these effects could be maintained in the long-term. We showed that SF leads to an anticipated homeostatic regulation of Slow Wave Activity (SWA), the sleep EEG hallmark of sleep homeostasis. Furthermore, EEG spectral analysis revealed an unexpected power increase in 4-40 Hz frequencies during sleep with a clear increase in the amplitude of slow waves and spindles. We concluded that sustained sleep pressure in SF leads to a global increase in cortical synchronization. We next explored whether these electrophysiological changes could impact on the expression of transcripts known to be regulated by sleep homeostasis (immediate early genes, clock-genes and heat shock proteins). Only heat shock proteins showed a consistent induction after one day but normalized after fourteen days of SF. These results point to the fact that electrophysiological and molecular aspects of sleep homeostasis are dissociable and that long-term sleep pressure triggers allostatic cellular processes of adaptation. In our second study, we explored the effects of long-term SF on general metabolism. We showed that SF led to a general imbalance in energy intake and expenditure, possibly through a slight elevation of brain temperature at rest. We also observed that glucocorticoids were slightly elevated at given circadian points and were accompanied by glucose intolerance. Altogether, this study brings evidence for the participation of SF in addition to intermittent hypoxia in the development of a metabolic syndrome in OSA patients. In the third study, we combined our chronic model with a spatial learning task spanning over several days (Morris Water Maze) in order to study the impact of SF on memory and metabolic plasticity. We showed that SF impaired proper memory consolidation supporting the idea that continuous sleep is required for specific mechanisms of memory trace post-processing. We also provide preliminary evidence that brain energy metabolism is not optimally responsive to neural activation after SF and that this effect might underlie the observed cognitive impairment. In conclusion, we showed that our animal SF model is suitable for studying the specific mechanisms underlying cognitive impairments and metabolic imbalance observed in sleep medicine. Our results underscore the existence of a global allostatic load in a wide range of systems during SF. Sensitization of the population to the prevalence of SF and its stealthy mode of presentation might improve its detection. Increased recognition of the problematic would be especially beneficial to cognitive development in school children with sleep apnea and might reduce accidents related to sleepiness. More specifically, we propose that screening sleep quality and effective correction of SF in patients with endocrine disorders has the potential to improve glucose metabolism and energy balance.

EPFL2011