Physiology seminars

There is no consensus on if sleep is for the brain, body or both. But the difference in how we feel following disrupted sleep or having a good night of continuous sleep is striking. Understanding how and why we sleep will likely give insights into many aspects of health. In this talk I will outline our recent work on how the prefrontal cortex can signal to the hypothalamus to regulate sleep preparatory behaviours and sleep itself, and how other brain regions, including the ventral tegmental area, respond to psychosocial stress to induce beneficial sleep. I will also outline our work on examining the function of the glymphatic system, and whether clearance of molecules from the brain is enhanced during sleep or wakefulness.

The field of human biology faces three major technological challenges. Firstly, the causation problem is difficult to address in humans compared to model animals. Secondly, the complexity problem arises due to the lack of a comprehensive cell atlas for the human body, despite its cellular composition. Lastly, the heterogeneity problem arises from significant variations in both genetic and environmental factors among individuals. To tackle these challenges, we have developed innovative approaches. These include 1) mammalian next-generation genetics, such as Triple CRISPR for knockout (KO) mice and ES mice for knock-in (KI) mice, which enables causation studies without traditional breeding methods; 2) whole-body/brain cell profiling techniques, such as CUBIC, to unravel the complexity of cellular composition; and 3) accurate and user-friendly technologies for measuring sleep and awake states, exemplified by ACCEL, to facilitate the monitoring of fundamental brain states in real-world settings and thus address heterogeneity in human.

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.

Since Darwin, comparative research has shown that most animals share basic timing capacities, such as the ability to process temporal regularities and produce rhythmic behaviors. What seems to be more exclusive, however, are the capacities to generate temporal predictions and to display anticipatory behavior at salient time points. These abilities are associated with subcortical structures like basal ganglia (BG) and cerebellum (CE), which are more developed in humans as compared to nonhuman animals. In the first research line, we investigated the basic capacities to extract temporal regularities from the acoustic environment and produce temporal predictions. We did so by adopting a comparative and translational approach, thus making use of a unique EEG dataset including 2 macaque monkeys, 20 healthy young, 11 healthy old participants and 22 stroke patients, 11 with focal lesions in the BG and 11 in the CE. In the second research line, we holistically explore the functional relevance of body-brain physiological interactions in human behavior. Thus, a series of planned studies investigate the functional mechanisms by which body signals (e.g., respiratory and cardiac rhythms) interact with and modulate neurocognitive functions from rest and sleep states to action and perception. This project supports the effort towards individual profiling: are individuals’ timing capacities (e.g., rhythm perception and production), and general behavior (e.g., individual walking and speaking rates) influenced / shaped by body-brain interactions?

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.

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.

Laboratory studies have shown that meaningful changes in light exposure lead to phase shifts in melatonin rhythm. In natural settings, however, light is a very complex signal. How melatonin responds to weekly- and seasonal-dependent variations in light exposure is still poorly understood. In this talk I will present results from a series of observational and intervention studies on the relationship between melatonin and light exposure in the field.

The arousal construct underlies a spectrum of behaviors that include sleep, exploration, feeding, sexual activity and adaptive stress. Pathological arousal conditions include stress, anxiety disorders, and addiction. The dynamics between arousal state transitions are modulated by norepinephrine neurons in the locus coeruleus, histaminergic neurons in the hypothalamus, dopaminergic neurons in the mesencephalon and cholinergic neurons in the basal forebrain. The hypocretin/orexin system in the lateral hypothalamus I will also present a new mechanism underlying sleep fragmentation during aging. Hcrt neurons are hyperexcitable in aged mice. We identify a potassium conductance known as the M-current, as a critical player in maintaining excitability of Hcrt neurons. Genetic disruption of KCNQ channels in Hcrt neurons of young animals results in sleep fragmentation. In contrast, treatment of aged animals with a KCNQ channel opener restores sleep/wake architecture. These data point to multiple circuits modulating sleep integrity across lifespan.

Information processing is energetically expensive. In the mammalian brain, it is unclear how information coding and energy usage are regulated during food scarcity. I addressed this in the visual cortex of awake mice using whole-cell recordings and two-photon imaging to monitor layer 2/3 neuronal activity and ATP usage. I found that food restriction reduced synaptic ATP usage by 29% through a decrease in AMPA receptor conductance. Neuronal excitability was nonetheless preserved by a compensatory increase in input resistance and a depolarized resting membrane potential. Consequently, neurons spiked at similar rates as controls, but spent less ATP on underlying excitatory currents. This energy-saving strategy had a cost since it amplified the variability of visually-evoked subthreshold responses, leading to a 32% broadening in orientation tuning and impaired fine visual discrimination. This reduction in coding precision was associated with reduced levels of the fat mass-regulated hormone leptin and was restored by exogenous leptin supplementation. These findings reveal novel mechanisms that dynamically regulate energy usage and coding precision in neocortex.

Neurons in the suprachiasmatic nucleus (SCN, the brain’s master circadian clock) display a 24 hour cycle in the their rate of action potential discharge whereby firing rates are high during the light phase and lower during the dark phase. Although it is generally agreed that this cycle of activity is a key mediator of the clock’s neural and humoral output, surprisingly little is known about how changes in clock electrical activity can mediate scheduled physiological changes at different times of day. Using opto- and chemogenetic approaches in mice we have shown that the onset of electrical activity in vasopressin releasing SCN neurons near Zeitgeber time 22 (ZT22) activates glutamatergic thirst-promoting neurons in the OVLT (organum vasculosum lamina terminalis) to promote water intake prior to sleep. This effect is mediated by activity-dependent release of vasopressin from the axon terminals of SCN neurons which acts as a neurotransmitter on OVLT neurons. More recently we found that the clock receives excitatory input from a different subset of sodium sensing neurons in the OVLT. Activation of these neurons by a systemic salt load delivered at ZT19 stimulated the electrical activity of SCN neurons which are normally silent at this time. Remarkably, this effect induced an acute reduction in non-shivering thermogenesis and body temperature, which is an adaptive response to the salt load. These findings provide information regarding the mechanisms by which the SCN promotes scheduled physiological rhythms and indicates that the clock’s output circuitry can also be recruited to mediate an unscheduled homeostatic response.

Recent breakthroughs in neurobiology indicate that time is ripe to understand the cellular-level mechanisms of conscious experience. Accordingly, we have recently proposed that conscious processing depends on the integration between top-down and bottom-up information streams and that there exists a specific cellular mechanism that gates this integration. I will first describe this cellular mechanism and demonstrate how it controls signal propagation within the thalamocortical system. Then I will show how this cellular-level mechanism provides a natural explanation for why conscious experience is modulated by top-down processing. Besides shining new light on the neural basis of consciousness, this perspective unravels the mechanisms of internally generated perception, such as dreams, imagery, and hallucinations.

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.

The brain is a prediction machine. Yet the world is never entirely predictable, for any animal. Unexpected events are surprising and this typically evokes prediction error signatures in animal brains. In humans such mismatched expectations are often associated with an emotional response as well. Appropriate emotional responses are understood to be important for memory consolidation, suggesting that valence cues more generally constitute an ancient mechanism designed to potently refine and generalize internal models of the world and thereby minimize prediction errors. On the other hand, abolishing error detection and surprise entirely is probably also maladaptive, as this might undermine the very mechanism that brains use to become better prediction machines. This paradoxical view of brain functions as an ongoing tug-of-war between prediction and surprise suggests a compelling new way to study and understand the evolution of consciousness in animals. I will present approaches to studying attention and prediction in the tiny brain of the fruit fly, Drosophila melanogaster. I will discuss how an ‘active’ sleep stage (termed rapid eye movement – REM – sleep in mammals) may have evolved in the first animal brains as a mechanism for optimizing prediction in motile creatures confronted with constantly changing environments. A role for REM sleep in emotional regulation could thus be better understood as an ancient sleep function that evolved alongside selective attention to maintain an adaptive balance between prediction and surprise. This view of active sleep has some interesting implications for the evolution of subjective awareness and consciousness.