Glucocorticoid receptor action in metabolic and neuronal function [version 1; referees: 3 approved]

Glucocorticoids via the glucocorticoid receptor (GR) have effects on a variety of cell types, eliciting important physiological responses via changes in gene expression and signaling. Although decades of research have illuminated the mechanism of how this important steroid receptor controls gene expression using in vitro and cell culture–based approaches, how GR responds to changes in external signals in vivo under normal and pathological conditions remains elusive. The goal of this review is to highlight recent work on GR action in fat cells and liver to affect metabolism in vivo and the role GR ligands and receptor phosphorylation play in calibrating signaling outputs by GR in the brain in health and disease. We also suggest that both the brain and fat tissue communicate to affect physiology and behavior and that understanding this “brain-fat axis” will enable a more complete understanding of metabolic diseases and inform new ways to target them

Vers une explication des effets mnémoniques des glucocorticoïdes ?

International audienceIf the engram of long-term memory is encoded by structural changes of neuronal circuits, they are expected to be present at distant time points after learning, to be specific of circuits activated by learning, and sensitive to behavioral contingencies. In this review we present new concepts that emerged from in vivo imaging studies that tracked the structural bases of the memory trace. A fine balance of spine formation and spine elimination needed for behavioral adaptation to new experience is regulated by glucocorticoids, which are secreted in synchrony with circadian rhythms and in response to stress. Disruption of glucocorticoid oscillations frequently observed in psychiatric disorders like depression and post-traumatic stress produces spine turnover defects and learning disabilities. These new findings provide a new framework for explaining the potent but complex mnemonic effects of glucocorticoids.Certains événements sont mieux mémorisés dans un contexte de stress. En effet, les mécanismes engagés par le stress facilitent la formation de la mémoire, mais ils peuvent aussi la détruire. C’est une des difficultés auxquelles se heurtent les stratégies d’identification de cibles médicamenteuses favorisant ou inhibant les effets mnémoniques des glucocorticoïdes. L’imagerie in vivo offre une vision nouvelle des bases structurales de la mémoire pendant les phases d’apprentissage et de la consolidation. La survie des traces de la mémoire dépend de la dose et du rythme d’exposition aux glucocorticoïdes. Ainsi, des rythmes biologiques de glucocorticoïdes anormalement haut ou bas peuvent endommager la plasticité des réseaux neuronaux nécessaires à la formation et à la consolidation de la mémoire. Ces découvertes offrent de nouvelles perspectives de travail pour mieux comprendre le développement de troubles mnésiques et de maladies neuropsychiatriques, telles que la dépression, qui se développent dans un contexte de stress

Vers une explication des effets mnémoniques des glucocorticoïdes ?

International audienceIf the engram of long-term memory is encoded by structural changes of neuronal circuits, they are expected to be present at distant time points after learning, to be specific of circuits activated by learning, and sensitive to behavioral contingencies. In this review we present new concepts that emerged from in vivo imaging studies that tracked the structural bases of the memory trace. A fine balance of spine formation and spine elimination needed for behavioral adaptation to new experience is regulated by glucocorticoids, which are secreted in synchrony with circadian rhythms and in response to stress. Disruption of glucocorticoid oscillations frequently observed in psychiatric disorders like depression and post-traumatic stress produces spine turnover defects and learning disabilities. These new findings provide a new framework for explaining the potent but complex mnemonic effects of glucocorticoids.Certains événements sont mieux mémorisés dans un contexte de stress. En effet, les mécanismes engagés par le stress facilitent la formation de la mémoire, mais ils peuvent aussi la détruire. C’est une des difficultés auxquelles se heurtent les stratégies d’identification de cibles médicamenteuses favorisant ou inhibant les effets mnémoniques des glucocorticoïdes. L’imagerie in vivo offre une vision nouvelle des bases structurales de la mémoire pendant les phases d’apprentissage et de la consolidation. La survie des traces de la mémoire dépend de la dose et du rythme d’exposition aux glucocorticoïdes. Ainsi, des rythmes biologiques de glucocorticoïdes anormalement haut ou bas peuvent endommager la plasticité des réseaux neuronaux nécessaires à la formation et à la consolidation de la mémoire. Ces découvertes offrent de nouvelles perspectives de travail pour mieux comprendre le développement de troubles mnésiques et de maladies neuropsychiatriques, telles que la dépression, qui se développent dans un contexte de stress

Régulation des recepteurs de la dopamine de sous-type D2 par la GIPC

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

The glucocorticoid footprint on the memory engram

International audienceThe complexity of the classical inverted U-shaped relationship between cortisol levels and responses transposable to stress reactivity has led to an incomplete understanding of the mechanisms enabling healthy and toxic effects of stress on brain and behavior. A clearer, more detailed, picture of those relationships can be obtained by integrating cortisol effects on large-scale brain networks, in particular, by focusing on neural network configurations from the perspective of inhibition and excitation. A unifying view of Semon and Hebb's theories of cellular memory links the biophysical and metabolic changes in neuronal ensembles to the strengthening of collective synapses. In that sense, the neuronal capacity to record, store, and retrieve information directly relates to the adaptive capacity of its connectivity and metabolic reserves. Here, we use task-activated cell ensembles or simply engram cells as an example to demonstrate that the adaptive behavioral responses to stress result from collective synapse strength within and across networks of interneurons and excitatory ones

Timing and crosstalk of glucocorticoid signaling with cytokines, neurotransmitters and growth factors

International audienceGlucocorticoid actions are tailored to the organs and cells responding thanks to complex integration with ongoing signaling mediated by cytokines, hormones, neurotransmitters, and growth factors. Disruption of: (1) the amount of signaling molecules available locally; (2) the timing with other signaling pathways; (3) the post-translational modifications on glucocorticoid receptors; and (4) the receptors-interacting proteins within cellular organelles and functional compartments, can modify the sensitivity and efficacy of glucocorticoid responses with implications in physiology, diseases and treatments. Tissue sensitivity to glucocorticoids is sustained by multiple systems that do not operate in isolation. We take the example of the interplay between the glucocorticoid and brain-derived neurotrophic factor signaling pathways to deconstruct context-dependent glucocorticoid responses that play key roles in physiology, diseases and therapies

Linking Mitochondria to Synapses: New Insights for Stress-Related Neuropsychiatric Disorders

International audienc

Glucocorticoid receptor action in metabolic and neuronal function

International audienceGlucocorticoids via the glucocorticoid receptor (GR) have effects on a variety of cell types, eliciting important physiological responses via changes in gene expression and signaling. Although decades of research have illuminated the mechanism of how this important steroid receptor controls gene expression using in vitro and cell culture-based approaches, how GR responds to changes in external signals in vivo under normal and pathological conditions remains elusive. The goal of this review is to highlight recent work on GR action in fat cells and liver to affect metabolism in vivo and the role GR ligands and receptor phosphorylation play in calibrating signaling outputs by GR in the brain in health and disease. We also suggest that both the brain and fat tissue communicate to affect physiology and behavior and that understanding this "brain-fat axis" will enable a more complete understanding of metabolic diseases and inform new ways to target them

Structural basis of glucocorticoid receptor signaling bias

International audienc