stress response

How Intermittent Bioenergetic Challenges Enhance Brain and Body Health

Humans and other animals evolved in habitats fraught with a range of environmental challenges to their bodies and brains. Accordingly, cells and organ systems possess adaptive stress-responsive signaling pathways that enable them to not only withstand environmental challenges, but also to prepare for future challenges and function more efficiently. These phylogenetically conserved processes are the foundation of the hormesis principle in which repeated exposures to low to moderate amounts of an environmental challenge improve cellular and organismal fitness. Here I describe cellular and molecular mechanisms by which cells in the brain and body respond to intermittent fasting and exercise in ways that enhance performance and counteract aging and disease processes. Switching back and forth between adaptive stress response (during fasting and exercise) and growth and plasticity (eating, resting, sleeping) modes enhances the performance and resilience of various organ systems. While pharmacological interventions that engage a particular hormetic mechanism are being developed, it seems unlikely that any will prove superior to fasting and exercise.

Gut food cravings? How gut signals control appetite and metabolism

Gut-derived signals regulate metabolism, appetite, and behaviors important for mental health. We have performed a large-scale multidimensional screen to identify gut hormones and nutrient-sensing mechanisms in the intestine that regulate metabolism and behavior in the fruit fly Drosophila. We identified several gut hormones that affect fecundity, stress responses, metabolism, feeding, and sleep behaviors, many of which seem to act sex-specifically. We show that in response to nutrient intake, the enteroendocrine cells (EECs) of the adult Drosophila midgut release hormones that act via inter-organ relays to coordinate metabolism and feeding decisions. These findings suggest that crosstalk between the gut and other tissues regulates food choice according to metabolic needs, providing insight into how that intestine processes nutritional inputs and into the gut-derived signals that relay information regulating nutrient-specific hungers to maintain metabolic homeostasis.

Mechanisms to medicines in neurodegeneration

Dysregulation of protein synthesis both globally and locally in neurons and astrocytes is a key feature of neurodegenerative diseases. Aberrant signalling through the Unfolded Protein Response (UPR) and related Integrated Stress Response (ISR) have become major targets for neuroprotection in these disorders. In addition, other homeostatic mechanisms and stress responses, including the cold shock response, appear to regulate local translation and RNA splicing to control synapse maintenance and regeneration and can also be targeted therapeutically for neuroprotection. We have defined the role of UPR/ISR and the cold-shock response in neurodegenerative disorders and have developed translational strategies targeting them for new treatments for dementia.

Role of the gut microbiota in the development of alcohol use disorder

The gut microbiota is composed of a very large number of bacteria, viruses, fungi and yeasts that play an important role in the body, through the production of a series of metabolites (including neurotransmitters), and through an essential role in the barrier function of the gut and the regulation of immunity and stress response. In this lecture I will present, based mainly on human studies but also on preclinical studies, the evidence for a role of the gut microbiota in the development of alcohol use disorder. I will show the first results of trials to test the effects of nutritional approaches to address these deficits.

Gut Feelings: The Microbiota-Gut-Brain Axis Across the Lifespan

The microbiota-gut-brain axis is emerging as a research area of increasing interest for those investigating the biological and physiological basis of brain development and behaviour during early life, adolescence & ageing. The routes of communication between the gut and brain include the vagus nerve, the immune system, tryptophan metabolism, via the enteric nervous system or by way of microbial metabolites such as short chain fatty acids. Studies in animal models have shown that the development of an appropriate stress response is dependent on the microbiota. Developmentally, a variety of factors can impact the microbiota in early life including mode of birth delivery, antibiotic exposure, mode of nutritional provision, infection, stress as well as host genetics. Recently, the gut microbiota has been implicated in regulating the stress response, and social behaviour. Moreover, fundamental brain processes from adult hippocampal neurogenesis to myelination to microglia activation have been shown to be regulated by the microbiome. Further studies will focus on understanding the mechanisms underlying such brain effects and how they can be exploited by microbiota-targeted interventions including ‘psychobiotics’ and diet

Sex-Specific Brain Transcriptional Signatures in Human MDD and their Correlates in Mouse Models of Depression

Major depressive disorder (MDD) is a sexually dimorphic disease. This sexual dimorphism is believed to result from sex-specific molecular alterations affecting functional pathways regulating the capacity of men and women to cope with daily life stress differently. Transcriptional changes associated with epigenetic alterations have been observed in the brain of men and women with depression and similar changes have been reported in different animal models of stress-induced depressive-like behaviors. In fact, most of our knowledge of the biological basis of MDD is derived from studies of chronic stress models in rodents. However, while these models capture certain aspects of the features of MDD, the extent to which they reproduce the molecular pathology of the human syndrome remains unknown and the functional consequences of these changes on the neuronal networks controlling stress responses are poorly understood. During this presentation, we will first address the extent by which transcriptional signatures associated with MDD compares in men and women. We will then transition to the capacity of different mouse models of chronic stress to recapitulate some of the transcriptional alterations associated with the expression of MDD in both sexes. Finally, we will briefly elaborate on the functional consequences of these changes at the neuronal level and conclude with an integrative perspective on the contribution of sex-specific transcriptional profiles on the expression of stress responses and MDD in men and women.

Deciphering the Dynamics of the Unconscious Brain Under General Anesthesia

General anesthesia is a drug-induced, reversible condition comprised of five behavioral states: unconsciousness, amnesia (loss of memory), antinociception (loss of pain sensation), akinesia (immobility), and hemodynamic stability with control of the stress response. Our work shows that a primary mechanism through which anesthetics create these altered states of arousal is by initiating and maintaining highly structured oscillations. These oscillations impair communication among brain regions. We illustrate this effect by presenting findings from our human studies of general anesthesia using high-density EEG recordings and intracranial recordings. These studies have allowed us to give a detailed characterization of the neurophysiology of loss and recovery of consciousness due to propofol. We show how these dynamics change systematically with different anesthetic classes and with age. As a consequence, we have developed a principled, neuroscience-based paradigm for using the EEG to monitor the brain states of patients receiving general anesthesia. We demonstrate that the state of general anesthesia can be rapidly reversed by activating specific brain circuits. Finally, we demonstrate that the state of general anesthesia can be controlled using closed loop feedback control systems. The success of our research has depended critically on tight coupling of experiments, signal processing research and mathematical modeling.

Blurring the boundaries between neuroscience and organismal physiology

Work in my laboratory is based on the assumptions that we do not know yet how all physiological functions are regulated and that mouse genetics by allowing to identify novel inter-organ communications is the most efficient ways to identify novel regulation of physiological functions. We test these two contention through the study of bone which is the organ my lab has studied since its inception. Based on precise cell biological and clinical reasons that will be presented during the seminar we hypothesized that bone should be a regulator of energy metabolism and reproduction and identified a bone-derived hormone termed osteocalcin that is responsible of these regulatory events. The study of this hormone revealed that in addition to its predicted functions it also regulates brain size, hippocampus development, prevents anxiety and depression and favors spatial learning and memory by signaling through a specific receptor we characterized. As will be presented, we elucidated some of the molecular events accounting for the influence of osteocalcin on brain and showed that maternal osteocalcin is the pool of this hormone that affects brain development. Subsequently and looking at all the physiological functions regulated by osteocalcin, i.e., memory, the ability to exercise, glucose metabolism, the regulation of testosterone biosynthesis, we realized that are all need or regulated in the case of danger. In other words it suggested that osteocalcin is an hormone needed to sense and overcome acute danger. Consonant with this hypothesis we next showed this led us to demonstrate that bone via osteocalcin is needed to mount an acute stress response through molecular and cellular mechanisms that will be presented during the seminar. overall, an evolutionary appraisal of bone biology, this body of work and experiments ongoing in the lab concur to suggest 1] the appearance of bone during evolution has changed how physiological functions as diverse as memory, the acute stress response but also exercise and glucose metabolism are regulated and 2] identified bone and osteocalcin as its molecular vector, as an organ needed to sense and response to danger.

Mitochondrial vesicle transport and the stress response in Parkinsons models

Neurocircuits in control of integrative physiology

This open colloquia session is part of the special workshop entitled "Obesity at the Interface of Neuroscience and Physiology II". Abstract: Proopiomelanocortin (POMC)- and agouti related peptide (AgRP)-expressing neurons in the arcuate nucleus of the hypothalamus (ARH) are critical regulators of food intake and energy homeostasis. They rapidly integrate the energy state of the organism through sensing fuel availability via hormones, nutrient components and even rapidly upon sensory food perception. Importantly, they not only regulate feeding responses, but numerous autonomic responses including glucose and lipid metabolism, inflammation and blood pressure. More recently, we could demonstrate that sensory food cue-dependent regulation of POMC neurons primes the hepatic endoplasmic reticulum (ER) stress response to prime liver metabolism for the postpramndial state. The presentation will focus on the regulation of these neurons in control of integrative physiology, the identification of distinct neuronal circuitries targeted by these cells and finally on the broad range implications resulting from dysregulation of these circuits as a consequence of altered maternal metabolism.

Recurrent network models of adaptive and maladaptive learning

During periods of persistent and inescapable stress, animals can switch from active to passive coping strategies to manage effort-expenditure. Such normally adaptive behavioural state transitions can become maladaptive in disorders such as depression. We developed a new class of multi-region recurrent neural network (RNN) models to infer brain-wide interactions driving such maladaptive behaviour. The models were trained to match experimental data across two levels simultaneously: brain-wide neural dynamics from 10-40,000 neurons and the realtime behaviour of the fish. Analysis of the trained RNN models revealed a specific change in inter-area connectivity between the habenula (Hb) and raphe nucleus during the transition into passivity. We then characterized the multi-region neural dynamics underlying this transition. Using the interaction weights derived from the RNN models, we calculated the input currents from different brain regions to each Hb neuron. We then computed neural manifolds spanning these input currents across all Hb neurons to define subspaces within the Hb activity that captured communication with each other brain region independently. At the onset of stress, there was an immediate response within the Hb/raphe subspace alone. However, RNN models identified no early or fast-timescale change in the strengths of interactions between these regions. As the animal lapsed into passivity, the responses within the Hb/raphe subspace decreased, accompanied by a concomitant change in the interactions between the raphe and Hb inferred from the RNN weights. This innovative combination of network modeling and neural dynamics analysis points to dual mechanisms with distinct timescales driving the behavioural state transition: early response to stress is mediated by reshaping the neural dynamics within a preserved network architecture, while long-term state changes correspond to altered connectivity between neural ensembles in distinct brain regions.

Cell-type specific chromatin profiling of human MDD disease signature identifies novel epigenetic mechanisms of astrocyte plasticity driving bidirectional stress response

Vascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue

The connection of MC3R neurons and their role in stress responses

FUS-mutation carrying amyotrophic lateral sclerosis patient-derived motoneurons display lower survival, accumulate more DNA damage, and show elevated integrated stress response

FENS Forum 2024

Aberrant cortical spine dynamics after concussive injury are reversed by integrated stress response inhibition

Light-induced stress response is impaired in the Retinitis Pigmentosa mouse model CerklKD/KO

Long-term Effects of Maternal Separation on alcohol intake and acute stress response in male and female mice

Multi-trajectory analysis uncovers adaptive and maladaptive psycho-physiological acute stress response patterns

The biophysical mechanism underlying epigenetically inherited stress response/unpredictability learning

FENS Forum 2024

The impact of THC on neurogenesis and stress response: An in vitro investigation in astrocytes

FENS Forum 2024

Modelling the stress response in SH-SY5Y-derived neurons: Disentangling the mineralocorticoid and glucocorticoid receptors

FENS Forum 2024

Neurons repurpose the integrated stress response effector GADD34 to enhance protein synthesis in response to neuronal activity

FENS Forum 2024