Hypothermia therapy (HT) is used clinically following global cerebral ischemia (GCI) but its therapeutic mechanisms are not completely understood. An elucidation of such mechanisms may lead to novel therapeutic approaches that improve patient outcome. Using a murine model of GCI, we determined the effect of HT on the expression of inflammatory proteins in the hippocampus and serum. We also examined its effect on microglia/macrophage activation and neurodegeneration in the brain at 72 hours following ischemia, and its effect on long-term spatial memory/learning and contextual fear response. GCI led to increased neurodegeneration and microglia/macrophage activation in the hippocampus, and increased IL-1β and KC protein expression in the hippocampus at 72 hours. Hypothermia therapy attenuated these inflammatory responses. It also improved spatial learning/memory at 7 and 21 days, and preserved contextual fear response 21 days post-ischemia. Hypothermia therapy attenuated the post-ischemic inflammatory response, protected hippocampal neurons, and preserved long-term memory and learning.

Hypothermia therapy (HT) is used clinically following global cerebral ischemia (GCI) but its therapeutic mechanisms are not completely understood. An elucidation of such mechanisms may lead to novel therapeutic approaches that improve patient outcome. Using a murine model of GCI, we determined the effect of HT on the expression of inflammatory proteins in the hippocampus and serum. We also examined its effect on microglia/macrophage activation and neurodegeneration in the brain at 72 hours following ischemia, and its effect on long-term spatial memory/learning and contextual fear response. GCI led to increased neurodegeneration and microglia/macrophage activation in the hippocampus, and increased IL-1β and KC protein expression in the hippocampus at 72 hours. Hypothermia therapy attenuated these inflammatory responses. It also improved spatial learning/memory at 7 and 21 days, and preserved contextual fear response 21 days post-ischemia. Hypothermia therapy attenuated the post-ischemic inflammatory response, protected hippocampal neurons, and preserved long-term memory and learning.

Le stress en début de vie (ELS) est associé à une susceptibilité accrue au développement de troubles liés au stress, tels que le trouble dépressif majeur (TDM). L'amygdale latérale (AL), une région du cerveau importante pour la régulation des comportements émotionnels et cognitifs, est vulnérable aux effets du ELS. Cependant, les mécanismes par lesquels l'ELS altère le comportement ne sont pas très bien définis. Auparavant, de nombreuses études se sont concentrées sur les mécanismes neuronaux qui sous-tendent les troubles comportementaux induits par le stress, mais le rôle des cellules gliales dans ce circuit reste indéterminé. Pourtant, les astrocytes, un type de cellule gliale, sont des déterminants clés du comportement. Nous avons donc cherché à identifier le rôle des astrocytes dans les effets de l'ELS sur le comportement dépendant de l'AL. Pour ce faire, nous avons utilisé un modèle de rongeur avec séparation maternelle, limitation de la litière et de la nidification pour reproduire les effets de l'ELS sur le cerveau en développement afin d’évaluer ses effets à long terme sur les astrocytes et le comportement dépendant de l'amygdale latérale. Bien que l'ELS n'ait pas eu d'influence sur le comportement anxieux des souris, ce dernier a altéré de manière significative la détection des menaces, un processus cognitif qui implique la capacité de distinguer avec précision un son menaçant précédemment appris (le stimulus conditionné) d'un son non menaçant dans un contexte nouveau. De plus, la diminution de la sensibilité au stress des astrocytes par la suppression des récepteurs glucocorticoïdes astrocytaires a amélioré de manière significative la fonction cognitive chez les souris ELS et naïves. Globalement, nos résultats suggèrent que les astrocytes jouent un rôle central dans la régulation des effets de l'ELS sur les troubles cognitifs. Ces données soulignent l'importance des astrocytes comme cibles thérapeutiques potentielles pour atténuer le dysfonctionnement cognitif, un symptôme omniprésent de la psychopathologie. / Early Life Stress (ELS) is associated with an enhanced susceptibility to the development of stress-related disorders, such as major depressive disorder (MDD). The lateral amygdala (LA), a brain region important for the regulation of emotive and cognitive behaviours is vulnerable to the effects of ELS. However, the mechanisms by which ELS impairs behaviour are poorly defined. Previously, research has focused on the neuronal mechanisms underlying stress-induced behavioural impairments, however the role of glial cells in this circuitry remains undetermined. Astrocytes, a type of glial cell, are key determinants of behaviour. Hence, we aimed to identify the role of astrocytes in the effects of ELS on LA-dependent behaviour. To accomplish this, we used a rodent model of maternal separation and limited bedding and nesting to replicate the effects of ELS on the developing brain by assessing its long-term effects on astrocytes and lateral-amygdala dependent behaviour. Although ELS did not influence anxiety-like behaviour in mice, ELS significantly impaired threat-detection, a cognitive process involving the ability to accurately distinguish between a previously learned threatening tone (the conditioned stimulus) and a non-threatening tone in a novel context. Additionally, decreasing astrocyte stress sensitivity by deleting astrocyte glucocorticoid receptors significantly enhanced cognitive function in both ELS and naïve mice. Overall, our results suggest that astrocytes are pivotal in the regulation of the effects of ELS on cognitive impairment. This data highlights the importance of astrocytes as potential therapeutic targets for mitigating cognitive dysfunction, a pervasive symptom of psychopathology.