Physiology seminars

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.

Arguably one of the biggest mysteries in neuroscience is how the brain stores long-term memories. The major challenge for investigating the neural circuit underlying memory formation in the neocortex is the distributed nature of the resulting memory trace throughout the cortex. Here, we used a new behavioral paradigm that enabled us to generate memory traces in a specific cortical location and to specifically examine the mechanisms of memory formation in that region. We found that medial-temporal inputs arrive in neocortical layer 1 where the apical dendrites of cortical pyramidal neurons predominate. These dendrites have active properties that make them sensitive to contextual inputs from other areas that also send axons to layer 1 around the cortex. Blocking the influence of these medial-temporal inputs prevented learning and suppressed resulting dendritic activity. We conclude that layer 1 is the locus for hippocampal-dependent memory formation in the neocortex and propose that this process enhances the sensitivity of the tuft dendrites to contextual inputs.

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

Rapid communication between the gut and the brain about recently consumed nutrients is critical for regulating food intake and maintaining energy homeostasis. We have shown that the infusion of nutrients directly into the gastrointestinal tract rapidly inhibits hunger-promoting AgRP neurons in the arcuate nucleus of the hypothalamus and suppresses subsequent feeding. The mechanism of this inhibition appears to be dependent upon macronutrient content, and can be recapitulated by a several hormones secreted in the gut in response to nutrient ingestion. In high-fat diet-induced obese mice, the response of AgRP neurons to nutrient-related stimuli are broadly attenuated. This attenuation is largely irreversible following weight loss and may represent a mechanism underlying difficulty with weight loss and propensity for weight regain in obesity.

Marmosets (Callithrix jacchus) are small South American monkeys which are being increasingly becoming adopted as animal models in neuroscience. Knowledge about the marmoset visual system has developed rapidly over the last decade. But what are the comparative advantages, and disadvantages involved in adopting this emerging model, as opposed to the more traditionally used macaque monkey? In this talk I will present case studies where the simpler brain morphology and short developmental cycle of the marmoset have been key factors in facilitating discoveries about the anatomy and physiology of the visual system. Although no single species provides the “ideal” animal model for invasive studies of the neural bases of visual processing, I argue that the development of robust methodologies for the study of the marmoset brain provides exciting opportunities to address long-standing problems in neuroscience.

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.

Vision starts in the retina where images are transformed and coded into neuronal activity relevant for the brain. These coding steps function optimally over a wide range of conditions: from bright day on the beach to a moonless night. Under these very different conditions, specific retinal mechanisms continue to select relevant aspects of the visual world and send this information to the brain. We are studying the neuronal processing involved in these selection and adaptation processes. This knowledge is essential for understanding how the visual system works and forms the basis for research dedicated to restoring vision in blind people.

By continuously producing electrical signals, neurones are amongst the most energy-demanding cells in the organism. Resting ionic levels are restored via metabolic pumps that receive the necessary energy from oxygen supplied by blood vessels. Intense spontaneous neural activity is omnipresent in the developing CNS. It occurs during short, well-defined periods that coincide precisely with the timing of angiogenesis. Such coincidence cannot be random; there must be a universal mechanism triggering spontaneous activity concurrently with blood vessels invading neural territories for the first time. However, surprisingly little is known about the role of neural activity per se in guiding angiogenesis. Part of the reason is that it is challenging to study developing neurovascular networks in tri-dimensional space in the brain. We investigate these questions in the neonatal mouse retina, where blood vessels are much easier to visualise because they initially grow in a plane, while waves of spontaneous neural activity (spreading via cholinergic starburst amacrine cells) sweep across the retinal ganglion cell layer, in close juxtaposition with the growing vasculature. Blood vessels reach the periphery by postnatal day (P) 7-8, shortly before the cholinergic waves disappear (at P10). We discovered transient clusters of auto-fluorescent cells that form an annulus around the optic disc, gradually expanding to the periphery, which they reach at the same time as the growing blood vessels. Remarkably, these cells appear locked to the frontline of the growing vasculature. Moreover, by recording waves with a large-scale multielectrode array that enables us to visualise them at pan-retinal level, we found that their initiation points are not random; they follow a developmental centre-to-periphery pattern similar to the clusters and blood vessels. The density of growing blood vessels is higher in cluster areas than in-between clusters at matching eccentricity. The cluster cells appear to be phagocytosed by microglia. Blocking Pannexin1 (PANX1) hemichannels activity with probenecid completely blocks the spontaneous waves and results in the disappearance of the fluorescent cell clusters. We suggest that these transient cells are specialised, hyperactive neurones that form spontaneous activity hotspots, thereby triggering retinal waves through the release of ATP via PANX1 hemichannels. These activity hotspots attract new blood vessels to enhance local oxygen supply. Signalling through PANX1 attracts microglia that establish contact with these cells, eventually eliminating them once blood vessels have reached their vicinity. The auto-fluorescence that characterises the cell clusters may develop only once the process of microglial phagocytosis is initiated.

The Chiu laboratory focuses on neuro-immune interactions in pain, itch, and tissue inflammation. Dr. Chiu’s research has uncovered molecular interactions between the nervous system, the immune system and microbes that modulates host defense. He has found that sensory neurons can directly detect bacterial pathogens and their toxins to produce pain. Neurons in turn release neuropeptides that modulate immune cells in host defense. These interactions occur at major tissue barriers in the body including the gut, skin and lungs. In this talk, he will discuss these major neuro-immune interactions and how understanding them could lead to novel approaches to treat pain or inflammation.

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.

Seizure onset is a critically important brain state transition that has proved very difficult to predict accurately from recordings of brain activity. I will present new data acquired using a range of optogenetic and imaging tools to characterize exactly how cortical networks change in the build-up to a seizure. I will show how intermittent optogenetic stimulation ("active probing") reveals a latent change in dendritic excitability that is tightly correlated to the onset of seizure activity. This data relates back to old work from the 1980s suggesting a critical role in epileptic pathophysiology for dendritic plateau potentials. Our data show how the precipitous nature of the transition can be understood in terms of multiple, synergistic positive feedback mechanisms.

Organisms sense light for purposes that range from recognizing objects to synchronizing activity with environmental cycles. What mechanisms serve these diverse tasks? This seminar will examine the specializations of two cell types. First are the foveal cone photoreceptors. These neurons are used by primates to see far greater detail than other mammals, which lack them. How do the biophysical properties of foveal cones support high-acuity vision? Second are the melanopsin retinal ganglion cells, which are conserved among mammals and essential for processes that include regulation of the circadian clock, sleep, and hormone levels. How do these neurons encode light, and is encoding customized for animals of different niches? In pursuing these questions, a broad goal is to learn how various levels of biological organization are shaped to behavioural needs.

The Ca2+ modulated pulsatile secretions of glucagon and insulin by pancreatic α and β cells play a key role in glucose metabolism and homeostasis. However, how different types of cells in the islet couple and coordinate to give rise to various Ca2+ oscillation patterns and how these patterns are being tuned by paracrine regulation are still elusive. Here we developed a microfluidic device to facilitate long-term recording of islet Ca2+ activity at single cell level and found that islets show heterogeneous but intrinsic oscillation patterns. The α and β cells in an islet oscillate in antiphase and are globally phase locked to display a variety of oscillation modes. A mathematical model of islet oscillation maps out the dependence of the oscillation modes on the paracrine interactions between α and β cells. Our study reveals the origin of the islet oscillation patterns and highlights the role of paracrine regulation in tuning them.

Synaptic scaling is a homeostatic normalization mechanism that preserves relative synaptic strengths by adjusting them with a common factor. This multiplicative change is believed to be critical, since synaptic strengths are involved in learning and memory retention. Further, this homeostatic process is thought to be crucial for neuronal stability, playing a stabilizing role in otherwise runaway Hebbian plasticity [1-3]. Synaptic scaling requires a mechanism to sense total neuron activity and globally adjust synapses to achieve some activity set-point [4]. This process is relatively slow, which places limits on its ability to stabilize network activity [5]. Here we show that this slow response is inevitable in realistic neuronal morphologies. Furthermore, we reveal that global scaling can in fact be a source of instability unless responsiveness or scaling accuracy are sacrificed." "A neuron with tens of thousands of synapses must regulate its own excitability to compensate for changes in input. The time requirement for global feedback can introduce critical phase lags in a neuron’s response to perturbation. The severity of phase lag increases with neuron size. Further, a more expansive morphology worsens cell responsiveness and scaling accuracy, especially in distal regions of the neuron. Local pools of reserve receptors improve efficiency, potentiation, and scaling, but this comes at a cost. Trafficking large quantities of receptors requires time, exacerbating the phase lag and instability. Local homeostatic feedback mitigates instability, but this too comes at the cost of reducing scaling accuracy." "Realization of the phase lag instability requires a unified model of synaptic scaling, regulation, and transport. We present such a model with global and local feedback in realistic neuron morphologies (Fig. 1). This combined model shows that neurons face a tradeoff between stability, accuracy, and efficiency. Global feedback is required for synaptic scaling but favors either system stability or efficiency. Large receptor pools improve scaling accuracy in large morphologies but worsen both stability and efficiency. Local feedback improves the stability-efficiency tradeoff at the cost of scaling accuracy. This project introduces unexplored constraints on neuron size, morphology, and synaptic scaling that are weakened by an interplay between global and local feedback.