Physiology seminars

The vagus nerve is a major pathway by which the brain and the body communicate. Electrical stimulation of the vagus nerve (VNS) is widely used as a therapeutic intervention for epilepsy and there is compelling evidence that it can enhance recovery following stroke. Our work demonstrates that VNS exerts a robust excitatory effect on the brain. First, we establish that VNS triggers an increase in arousal state as measured by behavioral state change. This behavioral state change is linked to an increase in excitatory activity within the cortex. We also show that cholinergic and noradrenergic neuromodulatory pathways are activated by VNS, providing a potential mechanism by which VNS may trigger cortical activation. Importantly, the effect of VNS on neuromodulation and cortical excitation persists in anesthetized mice, demonstrating that VNS-induced cortical activation cannot be fully explained by associated behavioral changes.

We have long known that rod and cone signals interact within the retina and can even contribute to color vision, but the extent of these influences has remained unclear. New results with more powerful methods of RNA expression profiling, specific cell labeling, and single-cell recording have provided greater clarity and are showing that rod and cone signals can mix at virtually every level of signal processing. These interactions influence the integration of retinal signals and make an important contribution to visual perception.

Core body temperature is regulated to a setpoint between 36.1 to 37.8°C, with an average fluctuation of 0.5°C during a 24-hour day. Despite mechanistic safeguards, major temperature deviations (1-3°C) from the setpoint occur in the body and in turn the brain. For unknown reasons, in most mammals (humans included), these increases in brain temperature are benign. However, macro-fluctuations in brain temperature in some cases result in deleterious outcomes such as seizures. In this talk, I will describe a mechanism for circuit-level adaptive regulation of cortical activity during macro-fluctuations in brain temperature. I will also discuss how this mechanism can be applied towards the understanding of the pathology of Autism Spectrum Disorder.

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.

Interoception, the sense of internal bodily signals, is essential for physiological homeostasis, cognition, and emotions. Human neuroimaging studies suggest insular cortex plays a central role in interoception, yet the cellular and circuit mechanisms of its involvement remain unclear. We developed a microprism-based cellular imaging approach to monitor insular cortex activity in behaving mice across different physiological need states. We combine this imaging approach with manipulations of peripheral physiology, circuit-mapping, cell type-specific and circuit-specific manipulation approaches to investigate the underlying circuit mechanisms. I will present our recent data investigating insular cortex activity during two physiological need states – hunger and thirst. These wereinduced naturally by caloric/fluid deficiency, or artificially by activation of specific hypothalamic “hunger neurons” and “thirst neurons”. We found that insular cortex ongoing activity faithfully represents current physiological state, independently of behavior or arousal levels. In contrast, transient responses to learned food- or water-predicting cues reflect a population-level “simulation” of future predicted satiety. Together with additional circuit-mapping and manipulation experiments, our findings suggest that insular cortex integrates visceral-sensory inputs regarding current physiological state with hypothalamus-gated amygdala inputs signaling availability of food/water. This way, insular cortex computes a prediction of future physiological state that can be used to guide behavioral choice.

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.

Eric Verdin examines advances in the biology of aging and their potential application to human health. The lecture distinguishes lifespan from healthspan and considers how research on aging mechanisms can inform the diagnosis and treatment of chronic diseases associated with getting older. Against the background of aging populations, Verdin explores the underlying causes of biological aging, the contributions of genetics and lifestyle, and approaches being investigated to extend healthy longevity. The discussion connects mechanistic research with the question of how a longer life can include more years of good health.

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.