Physiology seminars

My laboratory has made an intriguing discovery that mitochondrial stress in one tissue can be communicated to distal tissues. We find that mitochondrial stress in the nervous system triggers the production of entities known as mitokines. These mitokines are discharged from the nervous system, orchestrating a response in peripheral tissues that extends the lifespan of C. elegans. The revelation came as a surprise, given the prevalent belief that cell autonomous mechanisms would underlie the relationship between mitochondrial function and aging. It was also surprising given the prevailing dogma that mitochondrial function must be increased, not decreased, to improve health and longevity. Our work also underscores the fact that mitochondria, which originated as a microbial entity and later evolved into an intracellular symbiont, have retained their capacity for intercommunication, now facilitated by signals from the nervous system. We hypothesize that this communication has evolved as a mechanism to reduce infection from pathogens.

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.

On a fast timescale, neurons mostly interact by short, stereotypical electrical impulses or spikes. Why? A common answer is that spikes are useful for long-distance communication, to avoid alterations while traveling along axons. But as it turns out, spikes are seen in many places outside neurons: in the heart, in muscles, in plants and even in protists. From these examples, it appears that action potentials mediate some form of coordinated action, a timed event. From this perspective, spikes should not be seen simply as noisy implementations of underlying continuous signals (a sort of analog-to-digital conversion), but rather as events or actions. I will give a number of examples of functional spike-based interactions in living systems.

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.

Night shift work is associated with adverse health effects and leads to misalignment between timing cues from the environment and the endogenous circadian clock. In this presentation, I will discuss the effect of circadian misalignment induced by night shift work on peripheral 24-h rhythms on the transcriptome and metabolome in humans, presenting findings from both controlled laboratory studies and field studies. Furthermore, I will highlight the importance of taking into account interindividual differences in the response to circadian misalignment.

Brain aging leads to cognitive decline and is the main risk factor for sporadic forms of neurodegenerative diseases including Alzheimer’s disease. While brain cell- and tissue-intrinsic factors are likely key determinants of the aging process recent studies document a remarkable susceptibility of the brain to circulatory factors. Thus, blood borne factors from young mice or humans are sufficient to slow aspects of brain aging and improve cognitive function in old mice and, vice versa, factors from old mice are detrimental for young mice and impair cognition. We found evidence that the cerebrovasculature is an important target of circulatory factors and that brain endothelial cells show prominent age-related transcriptional changes in response to plasma. Furthermore, plasma proteins are taken up broadly into the young brain through receptor mediated transport which declines with aging. At the same time, brain derived proteins are detectable in plasma allowing us to measure physiological changes linked to brain aging in plasma. We are exploring the relevance of these findings for neurodegeneration and potential applications towards therapies.

We seek to determine how circadian rhythms and sleep are integrated with physiological processes to provide optimal fitness and health. Using initially a Drosophila model, and more recently also mammalian models, we have found that aspects of the blood brain barrier (BBB) are controlled by the circadian clock. BBB properties are also influenced by sleep:wake state in Drosophila, and, in fact, appear to be contribute to functions of sleep. This and other work, which implicates sleep in the regulation of metabolic processes, is providing insights into sleep function

For many animals, the sense of olfaction plays a major role in controlling sexual behaviors. Olfaction helps animals to detect mates, discriminate their status, and ultimately, decide on their behavioral output such as courtship behavior or aggression. Specific pheromone cues and receptors have provided a useful model to study how sensory inputs are converted into certain behavioral outputs. With the aid of recent advances in tools to record and manipulate genetically defined neurons, our understanding of the neural basis of sexual and social behavior has expanded substantially. I will discuss the current understanding of the neural processing of sex pheromones and the neural circuitry which controls sexual and social behaviors and ultimately reproduction, by focusing on rodent studies, mainly in mice, and the vomeronasal sensory system.

Dietary protein quantity and quality greatly impact metabolic health via evolutionary-conserved mechanisms that ensure avoidance of amino acid imbalanced food sources, promote hyperphagia when dietary protein density is low, and conversely produce satiety when dietary protein density is high. Growing evidence support the emerging concept of protein homeostasis in mammals, where protein intake is maintained within a tight range independently of energy intake to reach a target protein intake. The behavioural and neuroendocrine mechanisms underlying these adaptations are unclear and form the focus of our research.

The hippocampal formation has been implicated in both cognitive functions as well as the sensing and control of endocrine states. To identify a candidate activity pattern which may link such disparate functions, we simultaneously measured electrophysiological activity from the hippocampus and interstitial glucose concentrations in the body of freely behaving rats. We found that clusters of sharp wave-ripples (SPW-Rs) recorded from both dorsal and ventral hippocampus reliably predicted a decrease in peripheral glucose concentrations within ~10 minutes. This correlation was less dependent on circadian, ultradian, and meal-triggered fluctuations, it could be mimicked with optogenetically induced ripples, and was attenuated by pharmacogenetically suppressing activity of the lateral septum, the major conduit between the hippocampus and subcortical structures. Our findings demonstrate that a novel function of the SPW-R is to modulate peripheral glucose homeostasis and offer a mechanism for the link between sleep disruption and blood glucose dysregulation seen in type 2 diabetes and obesity.

Sensory experience and perceptual learning changes receptive field properties of cortical pyramidal neurons possibly mediated by long-term potentiation (LTP) of synapses. We have previously shown in the mouse somatosensory cortex (S1) that sensory-driven LTP in layer (L) 2/3 pyramidal neurons is dependent on higher order thalamic feedback from the posteromedial nucleus (POm), which is thought to convey contextual information from various cortical regions integrated with sensory input. We have followed up on this work by dissecting the cortical microcircuitry that underlies this form of LTP. We found that repeated pairing of Pom thalamocortical and intracortical pathway activity in brain slices induces NMDAr-dependent LTP of the L2/3 synapses that are driven by the intracortical pathway. Repeated pairing also recruits activity of vasoactive intestinal peptide (VIP) interneurons, whereas it reduces the activity of somatostatin (SST) interneurons. VIP interneuron-mediated inhibition of SST interneurons has been established as a motif for the disinhibition of pyramidal neurons. By chemogenetic interrogation we found that activation of this disinhibitory microcircuit motif by higher-order thalamic feedback is indispensable for eliciting LTP. Preliminary results in vivo suggest that VIP neuron activity also increases during sensory-evoked LTP. Together, this suggests that the higherorder thalamocortical feedback may help modifying the strength of synaptic circuits that process first-order sensory information in S1. To start characterizing the relationship between higher-order feedback and cortical plasticity during learning in vivo, we adapted a perceptual learning paradigm in which head-fixed mice have to discriminate two types of textures in order to obtain a reward. POm axons or L2/3 pyramidal neurons labeled with the genetically encoded calcium indicator GCaMP6s were imaged during the acquisition of this task as well as the subsequent learning of a new discrimination rule. We found that a subpopulation of the POm axons and L2/3 neurons dynamically represent textures. Moreover, upon a change in reward contingencies, a fraction of the L2/3 neurons re-tune their selectivity to the texture that is newly associated with the reward. Altogether, our data indicates that higher-order thalamic feedback can facilitate synaptic plasticity and may be implicated in dynamic sensory stimulus representations in S1, which depends on higher-order features that are associated with the stimuli.

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.

The long-term goal of my research is to study the mammalian retina as a model for the central nervous system (CNS) -- to understand how it functions in physiological conditions, how it is formed, how it breaks down in pathological conditions, and how it can be repaired. I have focused on two research themes: 1) Photoreceptor structure, synapse, circuits, and development, 2) Hibernation and metabolic adaptations in the retina and beyond. As the first neuron of the visual system, photoreceptors are vital for photoreception and transmission of visual signals. I am particularly interested in cone photoreceptors, as they mediate our daylight vision with high resolution color information. Diseases affecting cone photoreceptors compromise visual functions in the central macular area of the human retina and are thus most detrimental to our vision. However, because cones are much less abundant compared to rods in most mammals, they are less well studied. We have used the ground squirrel (GS) as a model system to study cone vision, taking advantage of their unique cone-dominant retina. In particular, we have focused on short-wavelength sensitive cones (S-cones), which are not only essential for color vision, but are also an important origin of signals for biological rhythm, mood and cognitive functions, and the growth of the eye during development. We are studying critical cone synaptic structures – synaptic ribbons, the synaptic connections of S-cones, and the development of S-cones with regard to their specific connections. These works will provide knowledge of normal retinal development and function, which can also be extended to the rest of CNS; for example, the mechanisms of synaptic targeting during development. In addition, such knowledge will benefit the development of optimal therapeutic strategies for regeneration and repair in cases of retinal degenerative disease. Many neurodegenerative diseases, including retinal diseases, are rooted in metabolic stress in neurons and/or glial cells. Using the same GS model, we aim to learn from this hibernating mammal, which possesses an amazing capability to adapt to the extreme metabolic conditions during hibernation. By exploring the mechanisms of such adaptation, we hope to discover novel therapeutic tactics for neurodegenerative diseases.

Birdsong emerges when a set of highly interconnected brain areas manage to generate a complex output. The similarities between birdsong production and human speech have positioned songbirds as unique animal models for studying learning and production of this complex motor skill. In this work, we developed a low dimensional model for a neural network in which the variables were the average activities of different neural populations within the nuclei of the song system. This neural network is active during production, perception and learning of birdsong. We performed electrophysiological experiments to record neural activity from one of these nuclei and found that the low dimensional model could reproduce the neural dynamics observed during the experiments. Also, this model could reproduce the respiratory motor patterns used to generate song. We showed that sparse activity in one of the neural nuclei could drive a more complex activity downstream in the neural network. This interdisciplinary work shows how low dimensional neural models can be a valuable tool for studying the emergence of complex motor tasks

Internal organs constantly exchange signals, and can respond with striking anatomical and functional transformations, even in fully developed organisms. We are exploring the mechanisms that drive and sustain such plasticity using the intestine and its neurons as experimental systems. I will present some of our recent work, which has characterised the enteric nervous system of Drosophila, and has explored its physiological plasticity as well as that of the intestine itself. This work has uncovered unexpected sexual dimorphisms, intestinal contributions to reproductive success and metabolic crosstalk between the gut and the brain. Interestingly, this crosstalk appears to be spatially constrained by the three dimensional arrangement of viscera, revealing a previously unrecognised layer of inter-organ signalling regulation. I may also describe our attempts to explore how broadly applicable our findings may be using mammalian systems.