Physiology seminars

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.

Establishment of precise neuronal connectivity in the neocortex relies on activity-dependent circuit reorganization during postnatal development. In the mouse somatosensory cortex layer 4, barrels are arranged in one-to-one correspondence to whiskers on the face. Thalamocortical axon termini are clustered in the center of each barrel. The layer 4 spiny stellate neurons are located around the barrel edge, extend their dendrites primarily toward the barrel center, and make synapses with thalamocortical axons corresponding to a single whisker. These organized circuits are established during the first postnatal week through activity-dependent refinement processes. However, activity pattern regulating the circuit formation is still elusive. Using two-photon calcium imaging in living neonatal mice, we found that layer 4 neurons within the same barrel fire synchronously in the absence of peripheral stimulation, creating a ''patchwork'' pattern of spontaneous activity corresponding to the barrel map. We also found that disruption of GluN1, an obligatory subunit of the N-methyl-D-aspartate (NMDA) receptor, in a sparse population of layer 4 neurons reduced activity correlation between GluN1 knockout neuron pairs within a barrel. Our results provide evidence for the involvement of layer 4 neuron NMDA receptors in spatial organization of the spontaneous firing activity of layer 4 neurons in the neonatal barrel cortex. In the talk I will introduce our strategy to analyze the role of NMDA receptor-dependent correlated activity in the layer 4 circuit formation.

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.

CA3-CA1 synapses in the hippocampus are the initial locus of episodic memory. The action of acetylcholine alters cellular excitability, modifies neuronal networks, and triggers secondary signaling that directly affects long-term plasticity (LTP) (the cellular underpinning of memory). It is therefore considered a critical regulator of learning and memory in the brain. Its action via M4 metabotropic receptors in the presynaptic terminal of the CA3 neurons and M1 metabotropic receptors in the postsynaptic spines of CA1 neurons produce rich dynamics across multiple timescales. We developed a model to describe the activation of postsynaptic M1 receptors that leads to IP3 production from membrane PIP2 molecules. The binding of IP3 to IP3 receptors in the endoplasmic reticulum (ER) ultimately causes calcium release. This calcium release from the ER activates potassium channels like the calcium-activated SK channels and alters different aspects of synaptic signaling. In an independent signaling cascade, M1 receptors also directly suppress SK channels and the voltage-activated KCNQ2/3 channels, enhancing post-synaptic excitability. In the CA3 presynaptic terminal, we model the reduction of the voltage sensitivity of voltage-gated calcium channels (VGCCs) and the resulting suppression of neurotransmitter release by the action of the M4 receptors. Our results show that the reduced initial release probability because of acetylcholine alters short-term plasticity (STP) dynamics. We characterize the dichotomy of suppressing neurotransmitter release from CA3 neurons and the enhanced excitability of the postsynaptic CA1 spine. Mechanisms underlying STP operate over a few seconds, while those responsible for LTP last for hours, and both forms of plasticity have been linked with very distinct functions in the brain. We show that the concurrent suppression of neurotransmitter release and increased sensitivity conserves neurotransmitter vesicles and enhances the reliability in plasticity. Our work establishes a relationship between STP and LTP coordinated by neuromodulation with acetylcholine.

Many animals are highly visual. They view their world through photoreceptors sensitive to different wavelengths of light. Animal survival and optimal behavioral performance may select for varying photoreceptor sensitivities depending on animal habitat or visual tasks. Our goal is to understand what drives visual diversity from both an evolutionary and molecular perspective. The group of more than 2000 cichlid fish species are an ideal system for examining such diversity. Cichlid are a colorful group of fresh water fishes. They have undergone adaptive radiation throughout Africa and the new world and occur in rivers and lakes that vary in water clarity. They are also behaviorally complex, having diverse behaviors for foraging, mate choice and even parental care. As a result, cichlids have highly diverse visual systems with cone sensitivities shifting by 30-90 nm between species. Although this group has seven cone opsin genes, individual species differ in which subset of the cone opsins they express. Some species show developmental shifts in opsin expression, switching from shorter to longer wavelength opsins through ontogeny. Other species modify that developmental program to express just one of the sets, causing the large sensitivity differences. Cichlids are therefore natural mutants for opsin expression. We have used cichlid diversity to explore the relationship between visual sensitivities and ecology. We have also exploited the genomic power of the cichlid system to identify genes and mutations that cause opsin expression shifts. Ultimately, our goal is to learn how different cichlid species see the world and whether differences matter. Behavioral experiments suggest they do indeed use color vision to survive and thrive. Cichlids therefore are a unique model for exploring how visual systems evolve in a changing world.

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.

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.

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.

The hippocampal formation has been implicated in both cognitive functions as well as the sensing and control of endocrine states. To identify a candidate activity pattern which may link such disparate functions, we simultaneously measured electrophysiological activity from the hippocampus and interstitial glucose concentrations in the body of freely behaving rats. We found that clusters of sharp wave-ripples (SPW-Rs) recorded from both dorsal and ventral hippocampus reliably predicted a decrease in peripheral glucose concentrations within ~10 minutes. This correlation was less dependent on circadian, ultradian, and meal-triggered fluctuations, it could be mimicked with optogenetically induced ripples, and was attenuated by pharmacogenetically suppressing activity of the lateral septum, the major conduit between the hippocampus and subcortical structures. Our findings demonstrate that a novel function of the SPW-R is to modulate peripheral glucose homeostasis and offer a mechanism for the link between sleep disruption and blood glucose dysregulation seen in type 2 diabetes and obesity.

In this presentation, we will discuss the cellular and molecular properties of the retrotrapezoid nucleus (RTN), an integrative and interoceptive control node for the respiratory motor system. We will present the molecular profiling that has allowed definitive identification of a cluster of tonically active neurons that provide a requisite drive to the respiratory central pattern generator (CPG) and other pre-motor neurons. We will discuss the ionic basis for steady pacemaker-like firing, including by a large subthreshold oscillation; and for neuromodulatory influences on RTN activity, including by arousal state-dependent neurotransmitters and CO2/H+. The CO2/H+-dependent modulation of RTN excitability represents the sensory component of a homeostatic system by which the brain regulates breathing to maintain blood gases and tissue pH; it relies on two intrinsic molecular proton detectors, both a proton-activated G protein-coupled receptor (GPR4) and a proton-inhibited background K+ channel (TASK-2). We will also discuss downstream neurotransmitter signaling to the respiratory CPG, focusing especially on a newly-identified peptidergic modulation of the preBötzinger complex that becomes activated following birth and the initiation of air breathing. Finally, we will suggest how the cellular and molecular properties of RTN neurons identified in rodent models may contribute to understanding human respiratory disorders, such as congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS).

PIEZO ion channels detect force in cellular membranes. They are expressed in a wide variety of mammalian tissues, including the vasculature, lymphatic system, and the nervous system. We have found that PIEZO2 in sensory neurons is required for the mechanical senses of touch and proprioception, but our understanding of internal organ sensing, interoception, is far behind. I will describe our findings on the role of PIEZO ion channels in the lesser-known interoceptive senses in multiple organ systems.

Arguably one of the biggest mysteries in neuroscience is how the brain stores long-term memories. The major challenge for investigating the neural circuit underlying memory formation in the neocortex is the distributed nature of the resulting memory trace throughout the cortex. Here, we used a new behavioral paradigm that enabled us to generate memory traces in a specific cortical location and to specifically examine the mechanisms of memory formation in that region. We found that medial-temporal inputs arrive in neocortical layer 1 where the apical dendrites of cortical pyramidal neurons predominate. These dendrites have active properties that make them sensitive to contextual inputs from other areas that also send axons to layer 1 around the cortex. Blocking the influence of these medial-temporal inputs prevented learning and suppressed resulting dendritic activity. We conclude that layer 1 is the locus for hippocampal-dependent memory formation in the neocortex and propose that this process enhances the sensitivity of the tuft dendrites to contextual inputs.