Physiology seminars

In this talk I will discuss our recent findings that sensory signals from the brain adjust the physiology and behavior of the nematode C. elegans, enabling this animal to deal with the lethal threat of hydrogen peroxide. Hydrogen peroxide (H2O2) is the most common chemical threat in the microbial battlefield. Prevention and repair of the damage that hydrogen peroxide inflicts on macromolecules are critical for health and survival. In the first part of the talk, I will discuss our findings that C. elegans represses their own H2O2 defenses in response to sensory perception of Escherichia coli, the nematode’s food source, because E. coli can deplete H2O2 from the local environment and thereby protect the nematodes. Thus, the E. coli self-defense mechanisms create a public good, an environment safe from the threat of H2O2, that benefits C. elegans. In the second part of the talk, I will discuss how the modulation of C. elegans’ sensory perception by the interplay of hydrogen peroxide and bacteria adjusts the nematode’s behavior to improve the nematode’s chances of finding a niche that provides both food and protection from hydrogen peroxide.

How the brain creates a painful experience remains a mystery. Solving this mystery is crucial to understanding the fundamental biological processes that underlie the perception of body integrity, and to creating better, non-addictive pain treatments. My laboratory’s goal is to resolve the neural basis of pain. We aim to understand the mechanisms by which our nervous system produces and assembles the sensory-discriminative, affective-motivational, and cognitive-evaluative dimensions of pain to create this unique and critically important experience. To capture every component of the pain experience, we examine the entirety of the pain circuitry, from sensory and spinal ascending pathways to cortical/subcortical circuits and brainstem descending pain modulation systems, at the molecular, cellular, circuit and whole-animal levels. For these studies, we have invented novel behavioral paradigms to interrogate the affective and cognitive dimensions of pain in mice while simultaneously imaging and manipulating nociceptive circuits. My laboratory also investigates how opioids suppress pain. Remarkably, despite their medical and societal significance, how opium poppy alkaloids such as morphine produce profound analgesia remains largely unexplained. By identifying where and how opioids act in neural circuits, we not only establish the mechanisms of action of one of the oldest drugs known to humans, but also reveal the critical elements of the pain circuitry for developing of novel analgesics and bringing an end to the opioid epidemic.

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.

Menstruation is a normal physiological process in women occurring as a result of changes in two ovarian produced hormones – estrogen and progesterone. As a result of these fluctuations, women experience different symptoms in their bodies – their immune system changes (Sekigawa et al, 2004), there are changes in their cardiovascular and digestive system (Millikan, 2006), as well as skin (Hall and Phillips, 2005). But these hormone fluctuations produce major changes in their behavioral pattern as well causing: anxiety, sadness, heightened irritability and anger (Severino and Moline, 1995) which is usually classified as premenstrual syndrome (PMS). In some cases these symptoms severely impair women’s lives and professional help is required. The official diagnosis according to DSM-5 (2013) is premenstrual dysphoric disorder (PMDD). Despite its ubiquitous presence the origins of PMS and PMDD are poorly understood. Some efforts to understand the underlying brain state during the menstruation cycle were performed by using TMS (Smith et al, 1999; 2002; 2003; Inghilleri et al, 2004; Hausmann et al, 2006). But all of these experiments suffer from major shortcomings - no control groups and small number of subjects. Our plan is to address all of these shortcomings and make this the biggest (to our knowledge) experiment of its kind which will, hopefully, provide us with some much needed answers.

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.

All mammals transition from breastfeeding to independent feeding during the lactation period. In humans and other mammals, this critical transition is important for later in life metabolic control and, consequently, for the development of many chronic conditions. Here, Dr. Dietrich will discuss the work of his lab studying the function of hypothalamic neurons involved in homeostatic control during the transition from breastfeeding to independent feeding. His work illuminates novel properties of hypothalamic neurons in early life, suggesting mechanisms by which early life events shape homeostatic regulation throughout the individual’s lifespan.

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.

Sympathetic nerve activation of adrenergic receptors on fat is the major pathway the brain uses to drive non-shivering thermogenesis in brown adipose tissue and lipolysis in white fat. There is accumulating evidence that the peripheral nerve architecture inside of organs is plastic (can be remodeled) but the factors and conditions that regulate or result in remodeling are largely unknown. Particularly for fat, it remains unclear if nerves in fat can be remodeled in step with hyperplasia/trophy of adipose tissue as result of a prolonged energy surfeit. This talk will discuss our recent work identifying the sympathetic nerve architecture in adipose tissue as highly plastic in response to the adipose hormone leptin, the brain circuitry leptin acts on to regulate this and the physiological effects remodeling of innervation has on fat tissue function.

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.

The increasing prevalence of obesity and type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating energy homeostasis to accelerate the identification of new medications. Recent reports indicate that obesity medication, 5-hydroxytryptamine (5-HT, serotonin)2C receptor (5-HT2CR) agonist lorcaserin improves glycemic control in association with weight loss in obese patients with T2D. We examined whether lorcaserin has a direct effect on insulin sensitivity and how this effect is achieved. We clarify that lorcaserin dose-dependently improves glycemic control in a mouse model of T2D without altering body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin’s glucoregulatory effects, via activation of brain pro-opiomelanocortin (POMC) peptides. We observed that lorcaserin reduces hepatic glucose production and improves insulin sensitivity. These data suggest that lorcaserin’s action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease.

Dysregulation of emotional processing and its integration with cognitive functions are central features of many mental/emotional disorders associated both with externalizing problems (aggressive, antisocial behaviors) and internalizing problems (anxiety, depression). As Dr. Joseph LeDoux, our invited speaker of this program, wrote in his famous book “Synaptic self: How Our Brains Become Who We Are”—the brain’s synapses—are the channels through which we think, act, imagine, feel, and remember. Synapses encode the essence of personality, enabling each of us to function as a distinctive, integrated individual from moment to moment. Thus, exploring the functioning of synapses leads to the understanding of the mechanism of (patho)physiological function of our brain. In this context, we have investigated the pathophysiology of psychiatric disorders, with particular emphasis on the synaptic function of model mice of various psychiatric disorders such as schizophrenia, autism, depression, and PTSD. Our current interest is how synaptic inputs are integrated to generate the action potential. Because the spatiotemporal organization of neuronal firing is crucial for information processing, but how thousands of inputs to the dendritic spines drive the firing remains a central question in neuroscience. We identified a distinct pattern of synaptic integration in the disease-related models, in which extra-large (XL) spines generate NMDA spikes within these spines, which was sufficient to drive neuronal firing. We experimentally and theoretically observed that XL spines negatively correlated with working memory. Our work offers a whole new concept for dendritic computation and network dynamics, and the understanding of psychiatric research will be greatly reconsidered. The second half of my talk is the development of a novel synaptic tool. Because, no matter how beautifully we can illuminate the spine morphology and how accurately we can quantify the synaptic integration, the links between synapse and brain function remain correlational. In order to challenge the causal relationship between synapse and brain function, we established AS-PaRac1, which is unique not only because it can specifically label and manipulate the recently potentiated dendritic spine (Hayashi-Takagi et al, 2015, Nature). With use of AS-PaRac1, we developed an activity-dependent simultaneous labeling of the presynaptic bouton and the potentiated spines to establish “functional connectomics” in a synaptic resolution. When we apply this new imaging method for PTSD model mice, we identified a completely new functional neural circuit of brain region A→B→C with a very strong S/N in the PTSD model mice. This novel tool of “functional connectomics” and its photo-manipulation could open up new areas of emotional/psychiatric research, and by extension, shed light on the neural networks that determine who we are.

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.

For many animals, the sense of olfaction plays a major role in controlling sexual behaviors. Olfaction helps animals to detect mates, discriminate their status, and ultimately, decide on their behavioral output such as courtship behavior or aggression. Specific pheromone cues and receptors have provided a useful model to study how sensory inputs are converted into certain behavioral outputs. With the aid of recent advances in tools to record and manipulate genetically defined neurons, our understanding of the neural basis of sexual and social behavior has expanded substantially. I will discuss the current understanding of the neural processing of sex pheromones and the neural circuitry which controls sexual and social behaviors and ultimately reproduction, by focusing on rodent studies, mainly in mice, and the vomeronasal sensory system.

Interoception, the sense of internal bodily signals, is essential for physiological homeostasis, cognition, and emotions. While human insular cortex (InsCtx) is implicated in interoception, the cellular and circuit mechanisms remain unclear. I will describe our recent work imaging mouse InsCtx neurons during two physiological deficiency states – hunger and thirst. InsCtx ongoing activity patterns reliably tracked the gradual return to homeostasis, but not changes in behavior. Accordingly, while artificial induction of hunger/thirst in sated mice via activation of specific hypothalamic neurons (AgRP/SFOGLUT) restored cue-evoked food/water-seeking, InsCtx ongoing activity continued to reflect physiological satiety. During natural hunger/thirst, food/water cues rapidly and transiently shifted InsCtx population activity to the future satiety-related pattern. During artificial hunger/thirst, food/water cues further shifted activity beyond the current satiety-related pattern. Together with circuit-mapping experiments, these findings suggest that InsCtx integrates visceral-sensory inputs regarding current physiological state with hypothalamus-gated amygdala inputs signaling upcoming ingestion of food/water, to compute a prediction of future physiological state.

This talk will focus on two areas. I will firstly discuss some new data, starting with insights from rare human genetic variants, which helps to clarify the role of the central melanocortin system in the acquisition of nutrients and their disposition into growth, the acquisition of lean mass and sexual maturation . I will then discuss some aspects of the emerging biology of GDF15; a sentinel hormone conveying information regarding a range of somatic stresses to the brain.

Dietary protein quantity and quality greatly impact metabolic health via evolutionary-conserved mechanisms that ensure avoidance of amino acid imbalanced food sources, promote hyperphagia when dietary protein density is low, and conversely produce satiety when dietary protein density is high. Growing evidence support the emerging concept of protein homeostasis in mammals, where protein intake is maintained within a tight range independently of energy intake to reach a target protein intake. The behavioural and neuroendocrine mechanisms underlying these adaptations are unclear and form the focus of our research.

Maintaining average activity level within a set-point range constitutes a fundamental property of central neural circuits. Accumulated evidence suggests that firing rate distributions and their means represent physiological variables regulated by homeostatic systems during sleep-wake cycle in central neural circuits. While intracellular Ca2+ has long been hypothesized as a feedback control signal, the source of Ca2+ and the molecular machinery enabling network-wide homeostatic responses remain largely unknown. I will present our hypothesis and framework on identifying homeostatic regulators in neural circuits. Next, I will show our new results on the role of mitochondria in the regulation of activity set-points and feedback responses. Finally, I will provide an evidence on state-dependent dysregulation of activity set-points at the presymptomatic disease stage in familial Alzheimer’s models.

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.