Physiology seminars

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.

In the central nervous system, neuronal activity is a critical regulator of development and plasticity. Activity-dependent proliferation of healthy glial progenitors, oligodendrocyte precursor cells (OPCs), and the consequent generation of new oligodendrocytes contributes to adaptive myelination. This plasticity of myelin tunes neural circuit function and contributes to healthy cognition. The robust mitogenic effect of neuronal activity on normal oligodendroglial precursor cells, a putative cellular origin for many forms of glioma, suggests that dysregulated or “hijacked” mechanisms of myelin plasticity might similarly promote malignant cell proliferation in this devastating group of brain cancers. Indeed, neuronal activity promotes progression of both high-grade and low-grade glioma subtypes in preclinical models. Crucial mechanisms mediating activity-regulated glioma growth include paracrine secretion of BDNF and the synaptic protein neuroligin-3 (NLGN3). NLGN3 induces multiple oncogenic signaling pathways in the cancer cell, and also promotes glutamatergic synapse formation between neurons and glioma cells. Glioma cells integrate into neural circuits synaptically through neuron-to-glioma synapses, and electrically through potassium-evoked currents that are amplified through gap-junctional coupling between tumor cells This synaptic and electrical integration of glioma into neural circuits is central to tumor progression in preclinical models. Thus, neuron-glial interactions not only modulate neural circuit structure and function in the healthy brain, but paracrine and synaptic neuron-glioma interactions also play important roles in the pathogenesis of glial cancers. The mechanistic parallels between normal and malignant neuron-glial interactions underscores the extent to which mechanisms of neurodevelopment and plasticity are subverted by malignant gliomas, and the importance of understanding the neuroscience of cancer.

Like all neural tissue, the retina has a high metabolic demand, and requires a constant supply of oxygen. Second and third order neurons are supplied by the retinal circulation, whose characteristics are similar to brain circulation. However, the photoreceptor region, which occupies half of the retinal thickness, is avascular, and relies on diffusion of oxygen from the choroidal circulation, whose properties are very different, as well as the retinal circulation. By fitting diffusion models to oxygen measurements made with oxygen microelectrodes, it is possible to understand the relative roles of the two circulations under normal conditions of light and darkness, and what happens if the retina is detached or the retinal circulation is occluded. Most of this work has been done in vivo in rat, cat, and monkey, but recent work in the isolated mouse retina will also be discussed.

Beyond vision, light triggers a variety of non-image forming responses. Amongst these is the pupillary light reflex, commonly used by ophthalmologists to gauge the function of the optic nerve head. In my talk, I will share some of our latest work on optimizing the use of the pupillary light reflex to detect functional loss in ocular diseases in clinics.

Do all components of the living human eye have a measurable diurnal rhythm? In this talk I will discuss methodologies and results of studies on adolescents and young adults. I will also touch upon the associations between diurnal rhythms of the eye and behavioral activities.

A critical function of sensory systems is to reliably extract ethologically relevant features from the complex natural environment. A classic model to study feature detection is the direction-selective circuit of the mammalian retina. In this talk, I will discuss our recent work on how visual contexts dynamically influence the neural processing of motion signals in the direction-selective circuit in the mouse retina.

Since the discovery of the intrinsically photosensitive retinal ganglion cells (ipRGCs) – just two decades ago – substantial work has been carried out trying to understand their functioning. In this seminar, I’ll focus on pupillometry studies that have provided key clues about ipRGC behavior. Specifically, the interaction between the intrinsic response, rods, and cones will be discussed.

The research in my lab focuses on sensory signal processing, particularly in cases where sensory systems perform at or near the limits imposed by physics. Photon counting in the visual system is a beautiful example. At its peak sensitivity, the performance of the visual system is limited largely by the division of light into discrete photons. This observation has several implications for phototransduction and signal processing in the retina: rod photoreceptors must transduce single photon absorptions with high fidelity, single photon signals in photoreceptors, which are only 0.03 – 0.1 mV, must be reliably transmitted to second-order cells in the retina, and absorption of a single photon by a single rod must produce a noticeable change in the pattern of action potentials sent from the eye to the brain. My approach is to combine quantitative physiological experiments and theory to understand photon counting in terms of basic biophysical mechanisms. Fortunately there is more to visual perception than counting photons. The visual system is very adept at operating over a wide range of light intensities (about 12 orders of magnitude). Over most of this range, vision is mediated by cone photoreceptors. Thus adaptation is paramount to cone vision. Again one would like to understand quantitatively how the biophysical mechanisms involved in phototransduction, synaptic transmission, and neural coding contribute to adaptation.

In many butterflies, the ancestral trichromatic insect colour vision, based on UV-, blue- and green-sensitive photoreceptors, is extended with red-sensitive cells. Physiological evidence for red receptors has been missing in nymphalid butterflies, although some species can discriminate red hues well. In eight species from genera Archaeoprepona, Argynnis, Charaxes, Danaus, Melitaea, Morpho, Heliconius and Speyeria, we found a novel class of green-sensitive photoreceptors that have hyperpolarizing responses to stimulation with red light. These green-positive, red-negative (G+R–) cells are allocated to positions R1/2, normally occupied by UV and blue-sensitive cells. Spectral sensitivity, polarization sensitivity and temporal dynamics suggest that the red opponent units (R–) are the basal photoreceptors R9, interacting with R1/2 in the same ommatidia via direct inhibitory synapses. We found the G+R– cells exclusively in butterflies with red-shining ommatidia, which contain longitudinal screening pigments. The implementation of the red colour channel with R9 is different from pierid and papilionid butterflies, where cells R5–8 are the red receptors. The nymphalid red-green opponent channel and the potential for tetrachromacy seem to have been switched on several times during evolution, balancing between the cost of neural processing and the value of extended colour information.

As a developmental outpocket of the brain, the retina exhibits features commonly found in most brain areas, including neurovascular interactions. In this presentation I will discuss various pathways that contribute to neurovascular interactions in the mammalian retina and present newly uncovered elements that likely participate in these pathways. Information obtained from retina could improve our understanding of neurovascular coupling pathways throughout the brain.

The Hsieh lab focuses on the mechanisms that promote neural stem cell self-renewal and differentiation in embryonic and adult brain. Using mouse models, video-EEG monitoring, viral techniques, and imaging/electrophysiological approaches, we elucidated many of the key transcriptional/epigenetic regulators of adult neurogenesis and showed aberrant new neuron integration in adult rodent hippocampus contribute to circuit disruption and seizure development. Building on this work, I will present our recent studies describing how GABA-mediated Ca2+ activity regulates the production of aberrant adult-born granule cells. In a new direction of my laboratory, we are using human induced pluripotent stem cells and brain organoid models as approaches to understand brain development and disease. Mutations in one gene, Aristaless-related homeobox (ARX), are of considerable interest since they are known to cause a common spectrum of neurodevelopmental disorders including epilepsy, autism, and intellectual disability. We have generated cortical and subpallial organoids from patients with poly-alanine expansion mutations in ARX. To understand the nature of ARX mutations in the organoid system, we are currently performing cellular, molecular, and physiological analyses. I will present these data to gain a comprehensive picture of the effect of ARX mutations in brain development. Since we do not understand how human brain development is affected by ARX mutations that contribute to epilepsy, we believe these studies will allow us to understand the mechanism of pathogenesis of ARX mutations, which has the potential to impact the diagnosis and care of patients.

Dendrites play a central role in neuronal computation, and many complex mechanisms shape their structure, function, and connectivity. Dendrites can undergo plastic changes during development and learning, as well as during neurodevelopmental and neurodegenerative disease. We will discuss how the molecular and electrophysiological properties of dendrites enable them to perform complex computations important for sensory-motor processing and higher cognitive function, and how these can go awry.

In the past several years, I have been involved in building a biologically realistic model of the monkey visual cortex. Work on one of the input layers (4Ca) of the primary visual cortex (V1) is now nearly complete, and I would like to share some of what I have learned with the community. After a brief overview of the model and its capabilities, I would like to focus on three sets of results that represent three different aspects of the modeling. They are: (i) emergent E-I dynamics in local circuits; (ii) how visual cortical neurons acquire their ability to detect edges and directions of motion, and (iii) a view across the cortical surface: nonequilibrium steady states (in analogy with statistical mechanics) and beyond.

Stereopsis – deriving information about distance by comparing views from two eyes – is widespread in vertebrates but so far known in only class of invertebrates, the praying mantids. Understanding stereopsis which has evolved independently in such a different nervous system promises to shed light on the constraints governing any stereo system. Behavioral experiments indicate that insect stereopsis is functionally very different from that studied in vertebrates. Vertebrate stereopsis depends on matching up the pattern of contrast in the two eyes; it works in static scenes, and may have evolved in order to break camouflage rather than to detect distances. Insect stereopsis matches up regions of the image where the luminance is changing; it is insensitive to the detailed pattern of contrast and operates to detect the distance to a moving target. Work from my lab has revealed a network of neurons within the mantis brain which are tuned to binocular disparity, including some that project to early visual areas. This is in contrast to previous theories which postulated that disparity was computed only at a single, late stage, where visual information is passed down to motor neurons. Thus, despite their very different properties, the underlying neural mechanisms supporting vertebrate and insect stereopsis may be computationally more similar than has been assumed.

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.