Physiology seminars

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.

Popular notions of how the retina encodes visual stimuli typically focus on the center-surround receptive fields of retinal ganglion cells, the output neurons of the retina. In this view, the receptive field acts as a linear filter on the visual stimulus, highlighting spatial contrast and providing efficient representations of natural images. Yet, we also know that many ganglion cells respond vigorously to fine spatial gratings that should not activate the linear filter of the receptive field. Thus, ganglion cells may integrate visual signals nonlinearly across space. In this talk, I will discuss how these (and other) nonlinearities relate to the encoding of natural visual stimuli in the retina. Based on electrophysiological recordings of ganglion and bipolar cells from mouse and salamander retina, I will present methods for assessing nonlinear processing in different cell types and examine their importance and potential function under natural stimulation.

Many visual systems can process information in dynamically changing environments. In general, visual perception scales with changes in the visual stimulus, or contrast, irrespective of background illumination. This is achieved by adaptation. However, visual perception is challenged when adaptation is not fast enough to deal with sudden changes in overall illumination, for example when gaze follows a moving object from bright sunlight into a shaded area. We have recently shown that the visual system of the fly found a solution by propagating a corrective luminance-sensitive signal to higher processing stages. Using in vivo two-photon imaging and behavioural analyses we showed that distinct OFF-pathway inputs encode contrast and luminance. The luminance-sensitive pathway is particularly required when processing visual motion in contextual dim light, when pure contrast sensitivity underestimates the salience of a stimulus. Recent work in the lab has addressed the question how two visual pathways obtain such fundamentally different sensitivities, given common photoreceptor input. We are furthermore currently working out the network-based strategies by which luminance- and contrast-sensitive signals are combined to guide appropriate visual behaviour. Together, I will discuss the molecular, cellular, and circuit mechanisms that ensure contrast computation, and therefore robust vision, in fast changing visual scenes.

Recent developments in induced pluripotent stem cell (iPSC) technology have enabled easier access to human cells in vitro. With increasing availability of human iPSC-derived neurons, both healthy and disease cell lines, screening compounds for neurodegenerative diseases on human cells can potentially be performed in the earlier stages of drug discovery. To accelerate the functional characterization of iPSC-derived neurons and the effect of compounds, reproducible and relevant results are necessary. In this webinar, the speakers will: Introduce high-resolution functional imaging of human iPSC-derived neurons Showcase how to extract functional features of hundreds of cells in a cell culture sample label-free Discuss electrophysiological parameters for characterizing the differences among several human neuronal cell lines