Structural and functional alterations in the prefrontal cortex after post-weaning social isolation: relationship with species-typical and deviant aggression

Although the inhibitory control of aggression by the prefrontal cortex (PFC) is the cornerstone of current theories of aggression control, a number of human and laboratory studies showed that the execution of aggression increases PFC activity; moreover, enhanced activation was observed in aggression-related psychopathologies and laboratory models of abnormal aggression. Here, we investigated these apparently contradictory findings in the post-weaning social isolation paradigm (PWSI), an established laboratory model of abnormal aggression. When studied in the resident-intruder test as adults, rats submitted to PWSI showed increased attack counts, increased share of bites directed towards vulnerable body parts of opponents (head, throat, and belly) and reduced social signaling of attacks. These deviations from species-typical behavioral characteristics were associated with a specific reduction in the thickness of the right medial PFC (mPFC), a bilateral decrease in dendritic and glial density, and reduced vascularization on the right-hand side of the mPFC. Thus, the early stressor interfered with mPFC development. Despite these structural deficits, aggressive encounters enhanced the activation of the mPFC in PWSI rats as compared to controls. A voxel-like functional analysis revealed that overactivation was restricted to a circumscribed sub-region, which contributed to the activation of hypothalamic centers involved in the initiation of biting attacks as shown by structural equation modeling. These findings demonstrate that structural alterations and functional hyperactivity can coexist in the mPFC of rats exposed to early stressors, and suggest that the role of the mPFC in aggression control is more complex than suggested by the inhibitory control theory.

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

Implication of individual differences in glucocorticoid responsiveness to stress in the development of psychopathology-like behaviour and underlying neurobiology

Sophie Elizabeth Walker

The period around puberty is a critical window in development. It is a time of neuroendocrine and neuroanatomical lability, rendering individuals highly sensitive to stress. Indeed, early adversity increases risk for psychopathology. The mechanisms via which this vulnerability is differentially translated between individuals are not yet understood. Wistar rats exposed to psychogenic stressors around puberty show increased psychopathology-like behaviors at adulthood. Like humans, not all rats exposed to this stress develop in the same way, particularly with regard to aggression. The actions of glucocorticoids, the end product of hypothalamic-pituitary-adrenal (HPA) axis activations, mediate some alterations induced by peripuberty stress (PPS). Here we thus focused on assessing if individual differences in glucocorticoid responsiveness to stress influenced outcome following stress. We exposed male rats to PPS and later measured socio-affective behaviors and brain structure with magnetic resonance imaging. By applying a profiling approach we discerned two distinct neurodevelopmental trajectories arising from PPS. One led to the development of pathological aggression and reduced mean diffusivity in infralimbic cortex, amygdala and hippocampus. The other led to increased anxiety-like behavior and reduced sociability, with no evidence of alterations in brain structure. We assessed glucocorticoid responsiveness to PPS across the protocol and found that impaired habituation was associated with a more aggressive profile. Impaired habituation of glucocorticoid responses, shown by â35% of people, is heritable and associated with self-report of psychopathology-related indices. Considering this and our findings, we asked if constitutive differences in habituation to repeated stress were implicated in vulnerability to psychopathology. To answer this question, we developed a new animal model. We selectively bred lines of rats, enriching for stress habituation (âlow-lineâ) and lack of stress habituation (âhigh-lineâ). Once the lines were established, we assessed socio-affective behaviors and neuroendocrine phenotype of the rats. High-line rats displayed more aggression, anxiety-like, and depression-like behaviors. High-line rats had a distinct neuroendocrine phenotype, with enhanced corticosterone reactivity to acute stress, but no evidence for general HPA axis hyperactivity, and altered expression of several HPA axis related genes. Finally, we studied the interaction of the two risk factors in the development of behavioral alterations. Low- and high-line rats were exposed to PPS, and socio-affective behaviors and basal activation of the brain were later assessed. Both factors enhanced levels of anxiety-like and aggressive behavior, as well as increasing activity across the prefrontal cortex in a manner that was associated with increased behavioral inhibition. PPS had a differential impact on the lines, enhancing aggression in the stress-habituating low-line but not in the already high-aggressive, high-line rats. In summary, we established incidence of differential neurobehavioral trajectories following PPS, trajectories associated with differential glucocorticoid responsiveness across the stress. Constitutively impaired stress habituation increased psychopathology-like behavior in its own right, and this was not enhanced by exposure to PPS. In contrast, constitutively strong habituation enhanced sensitivity to the programming effects of PPS.

EPFL2016

Alterations in brain microstructure in rats that develop abnormal aggression following peripubertal stress

Maria del Carmen Sandi Perez, Sophie Elizabeth Walker

Exposure to early adversity is implicated in the development of aggressive behaviour later in life in some but not all individuals. The reasons for the variability in response to such experiences are not clear but may relate to pre‐existing individual differences that influence their downstream effects. Applying structural magnetic resonance imaging (MRI) to a rat model of abnormal aggression induced by peripubertal stress, we examined whether individual differences in the development of an aggressive phenotype following stress exposure were underpinned by variation in the structure of aggression‐associated, corticolimbic brain regions. We also assessed whether responsiveness of the hypothalamic–pituitary–adrenal axis to stress was associated with neurobehavioural outcome following adversity. A subset of the rats exposed to peripubertal stress developed an aggressive phenotype, while the remaining rats were affected in other behavioural domains, such as increased anxiety‐like behaviours and reduced sociability. Peripubertal stress led to changes in tissue microstructure within prefrontal cortex, amygdala and hippocampal formation only in those individuals displaying an aggressive phenotype. Attenuated glucocorticoid response to stress during juvenility predicted the subsequent development of an aggressive phenotype in peripubertal stress‐exposed rats. Our study establishes a link between peripubertal stress exposure in rats and structural deviations in brain regions linked to abnormal aggression and points towards low glucocorticoid responsiveness to stress as a potential underlying mechanism. We additionally highlight the importance of considering individual differences in behavioural response to stress when determining neurobiological correlates.