Causal inference

Causal inference is the process of determining the independent, actual effect of a particular phenomenon that is a component of a larger system. The main difference between causal inference and inference of association is that causal inference analyzes the response of an effect variable when a cause of the effect variable is changed. The science of why things occur is called etiology, and can be described using the language of scientific causal notation. Causal inference is said to provide the evidence of causality theorized by causal reasoning. Causal inference is widely studied across all sciences. Several innovations in the development and implementation of methodology designed to determine causality have proliferated in recent decades. Causal inference remains especially difficult where experimentation is difficult or impossible, which is common throughout most sciences. The approaches to causal inference are broadly applicable across all types of scientific disciplines, and many

Multidisciplinary Investigation of the Gut-Brain Ecosystem in a Model of Alzheimer's Disease

Arielle Louise Planchette

The search for an understanding of the causal elements that lead to neurodegenerative diseases has motivated researchers for decades. Today, Alzheimer's disease is the most prevalent form of dementia and affects approximately fifty million people worldwide, with only 5% of patients carrying causal genetic mutations. In recent years, studies of animal models as well as observations in humans have brought the gut microbiome to the forefront of AD research, as a significant contributor to the development of Alzheimer's disease. In fact, the gut microbiome is now understood to be a modulator of health and disease in numerous areas of physiology, including energy metabolism, immunity, endocrinology, and most relevant to this thesis, brain health and cognition. The gut microbiome is a complex environment composed of symbiotic bacteria, fungi and viruses (the microbiota) that produce a wide range of signalling molecules that are interpreted both by members of the microbiota and by the host (the microbiome). The host-gut interface is an ecosystem that consists of bi-directional signals and pressures applied by both constituents in order to maintain symbiotic homeostasis. Significant deleterious effects on health occur when homeostasis is lost, which may take place due to a variety of factors. These include host genetic factors and environmental factors, such as diet. Modulation of the gut microbiome has become a potentially viable therapeutic avenue for Alzheimer's disease, though it currently remains at the early stage of discovery. In this thesis, I characterize the evolution of Alzheimer's disease in the 5xFAD mouse model, with a focus on the gut microbiome and on cognitive decline and brain biochemistry. Gut microbiota modulaiton was implemented using germ-free and low-complexity bacterial cocktails, in which I outline the effects microbiota modulation on hallmarks of AD and provide insights into the metabolite profile of the brain altered by the microbiota and AD. The work in this thesis was equally motivated by the development of diagnostic tools using microscopy techniques. Biochemical assessments of disease status and progression provide information pertaining to "what" is interacting and "how much" this affects disease. With microscopy, we may gain the additional knowledge of "where" physiological constituents are and how they interact with the surrounding environment. I describe a novel multi-modal microscopy pipeline that enables the observation of signals of interest in large volumes and at high resolution with a capacity to cross-reference regions of interest in both modalities. The pipeline, known as gutOPT, consists of a sample preparation workflow compatible with mesoscale optical projection tomography (OPT) of fluorescently-labelled targets and subsequent imaging of pre-selected regions of interest in high-resolution modalities, such as confocal microscopy.

EPFL2022

Genetic selection for low glucocorticoid responsiveness recapitulates PTSD-related phenotypes: a behavioral, neuroimaging and sleep-physiology study

Silvia Monari

Humans show inter-individual differences in vulnerability to develop post-traumatic stress disorder (PTSD) following exposure to trauma. Several critical biobehavioral features have been consistently described in PTSD patients, including blunted cortisol levels, smaller hippocampal size, sleep disturbances. However, because of the delay between trauma exposure and the onset of symptoms characteristic of PTSD, only a few longitudinal studies have tried to dissect whether these features constitute pre-trauma risk factors or consequences of the trauma. Enormous effort in animal and human studies has been dedicated to understanding mechanisms of conditioned fear and fear extinction, processes that are at the core of PTSD. However, the same progress has not been translated into psychiatric practice for PTSD. Deepening our understanding of the contribution of key factors to PTSD-related alterations can serve to develop effective treatments.In particular, with regard to low cortisol levels in PTSD pathophysiology, a causative role for blunted glucocorticoid responsiveness in PTSD has not been demonstrated yet.Here, we have addressed this question in lines of Wistar rats genetically-selected for their differential habituation of glucocorticoid responses to stress (LOW-, INTER-, HIGH-CORT Responder rats) and focused on fear extinction, a hallmark of PTSD symptomology, as one of the key features. As a first step, we looked whether divergent trajectories of glucocorticoid responsiveness were associated with brain volume abnormalities, prompted by the influential role of glucocorticoid in brain development. Notably, rats with low or high corticosterone responsiveness exhibit smaller hippocampi, regardless of trauma exposure, compared to rats with normative corticosterone levels. Similarly, the distribution of corticosteroid receptors in the hippocampus presented similarities between the LOW-CR and the HIGH-CR rats with higher mineralocorticoid receptors (MR) and less glucocorticoid receptors (GR). Although LOW- and HIGH-CR rats displayed a similar hippocampal profile at the structural and molecular levels, only LOW-CR male rats exhibited strong deficits in extinction consolidation compared to rats with 'normative' glucocorticoid responses (INTER-CR rats), and showed higher fear response both at few days and at several weeks after trauma exposure. We next tested the causal involvement of corticosterone in the fear extinction consolidation, and found that post-extinction corticosterone treatment markedly prevented the deficits in extinction memory and attenuated fear relapse. In addition, pharmacological inhibition of corticosterone levels during extinction memory consolidation, but not during training, in the INTER-CR rats led to extinction deficits at retrieval one day later. These results indicate that blunted corticosterone levels contribute to confer major vulnerability than having a small hippocampus, and that consolidation processes following extinction are mainly affected by low corticosterone levels.It is well known that glucocorticoids play an important role in memory consolidation processes and that sleep disturbances are a diagnostic criterion of PTSD. Therefore, we investigated in greater detail the sleep architecture in undisturbed condition and during the consolidation period of the extinction phase, which is known to be supported by sleep-dependent processes. In polysomnographic recordings, we found that rats with blunted corticos

EPFL2022

Multidisciplinary Investigation of the Gut-Brain Ecosystem in a Model of Alzheimer's Disease

Arielle Louise Planchette

EPFL2022

Genetic selection for low glucocorticoid responsiveness recapitulates PTSD-related phenotypes: a behavioral, neuroimaging and sleep-physiology study

Silvia Monari

EPFL2022

Without Commitment to an Ontology, There Could Be No Causal Inference

Multidisciplinary Investigation of the Gut-Brain Ecosystem in a Model of Alzheimer's Disease

Genetic selection for low glucocorticoid responsiveness recapitulates PTSD-related phenotypes: a behavioral, neuroimaging and sleep-physiology study

Multidisciplinary Investigation of the Gut-Brain Ecosystem in a Model of Alzheimer's Disease

Genetic selection for low glucocorticoid responsiveness recapitulates PTSD-related phenotypes: a behavioral, neuroimaging and sleep-physiology study

Without Commitment to an Ontology, There Could Be No Causal Inference