Physiology seminars

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.

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.

We see the last cookie in the box and think, can I take that? We reach a hand out. In the 2.1 seconds that this impulse travels through our brain, billions of neurons communicate with one another, sending blips of voltage through our sensory and motor regions. Neuroscientists call these blips “spikes.” Spikes enable us to do everything: talk, eat, run, see, plan, and decide. In The Spike, Mark Humphries takes readers on the epic journey of a spike through a single, brief reaction. In vivid language, Humphries tells the story of what happens in our brain, what we know about spikes, and what we still have left to understand about them. Drawing on decades of research in neuroscience, Humphries explores how spikes are born, how they are transmitted, and how they lead us to action. He dives into previously unanswered mysteries: Why are most neurons silent? What causes neurons to fire spikes spontaneously, without input from other neurons or the outside world? Why do most spikes fail to reach any destination? Humphries presents a new vision of the brain, one where fundamental computations are carried out by spontaneous spikes that predict what will happen in the world, helping us to perceive, decide, and react quickly enough for our survival. Traversing neuroscience’s expansive terrain, The Spike follows a single electrical response to illuminate how our extraordinary brains work.

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.

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.

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.

Sensory experience and perceptual learning changes receptive field properties of cortical pyramidal neurons possibly mediated by long-term potentiation (LTP) of synapses. We have previously shown in the mouse somatosensory cortex (S1) that sensory-driven LTP in layer (L) 2/3 pyramidal neurons is dependent on higher order thalamic feedback from the posteromedial nucleus (POm), which is thought to convey contextual information from various cortical regions integrated with sensory input. We have followed up on this work by dissecting the cortical microcircuitry that underlies this form of LTP. We found that repeated pairing of Pom thalamocortical and intracortical pathway activity in brain slices induces NMDAr-dependent LTP of the L2/3 synapses that are driven by the intracortical pathway. Repeated pairing also recruits activity of vasoactive intestinal peptide (VIP) interneurons, whereas it reduces the activity of somatostatin (SST) interneurons. VIP interneuron-mediated inhibition of SST interneurons has been established as a motif for the disinhibition of pyramidal neurons. By chemogenetic interrogation we found that activation of this disinhibitory microcircuit motif by higher-order thalamic feedback is indispensable for eliciting LTP. Preliminary results in vivo suggest that VIP neuron activity also increases during sensory-evoked LTP. Together, this suggests that the higherorder thalamocortical feedback may help modifying the strength of synaptic circuits that process first-order sensory information in S1. To start characterizing the relationship between higher-order feedback and cortical plasticity during learning in vivo, we adapted a perceptual learning paradigm in which head-fixed mice have to discriminate two types of textures in order to obtain a reward. POm axons or L2/3 pyramidal neurons labeled with the genetically encoded calcium indicator GCaMP6s were imaged during the acquisition of this task as well as the subsequent learning of a new discrimination rule. We found that a subpopulation of the POm axons and L2/3 neurons dynamically represent textures. Moreover, upon a change in reward contingencies, a fraction of the L2/3 neurons re-tune their selectivity to the texture that is newly associated with the reward. Altogether, our data indicates that higher-order thalamic feedback can facilitate synaptic plasticity and may be implicated in dynamic sensory stimulus representations in S1, which depends on higher-order features that are associated with the stimuli.

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.

Collective behavior of organisms creates environmental micro-niches that buffer them from environmental fluctuations e.g., temperature, humidity, mechanical perturbations, etc., thus coupling organismal physiology, environmental physics, and population ecology. This talk will focus on a combination of biological experiments, theory, and computation to understand how a collective of bees can integrate physical and behavioral cues to attain a non-equilibrium steady state that allows them to resist and respond to environmental fluctuations of forces and flows. We analyze how bee clusters change their shape and connectivity and gain stability by spread-eagling themselves in response to mechanical perturbations. Similarly, we study how bees in a colony respond to environmental thermal perturbations by deploying a fanning strategy at the entrance that they use to create a forced ventilation stream that allows the bees to collectively maintain a constant hive temperature. When combined with quantitative analysis and computations in both systems, we integrate the sensing of the environmental cues (acceleration, temperature, flow) and convert them to behavioral outputs that allow the swarms to achieve a dynamic homeostasis.

Work in my laboratory is based on the assumptions that we do not know yet how all physiological functions are regulated and that mouse genetics by allowing to identify novel inter-organ communications is the most efficient ways to identify novel regulation of physiological functions. We test these two contention through the study of bone which is the organ my lab has studied since its inception. Based on precise cell biological and clinical reasons that will be presented during the seminar we hypothesized that bone should be a regulator of energy metabolism and reproduction and identified a bone-derived hormone termed osteocalcin that is responsible of these regulatory events. The study of this hormone revealed that in addition to its predicted functions it also regulates brain size, hippocampus development, prevents anxiety and depression and favors spatial learning and memory by signaling through a specific receptor we characterized. As will be presented, we elucidated some of the molecular events accounting for the influence of osteocalcin on brain and showed that maternal osteocalcin is the pool of this hormone that affects brain development. Subsequently and looking at all the physiological functions regulated by osteocalcin, i.e., memory, the ability to exercise, glucose metabolism, the regulation of testosterone biosynthesis, we realized that are all need or regulated in the case of danger. In other words it suggested that osteocalcin is an hormone needed to sense and overcome acute danger. Consonant with this hypothesis we next showed this led us to demonstrate that bone via osteocalcin is needed to mount an acute stress response through molecular and cellular mechanisms that will be presented during the seminar. overall, an evolutionary appraisal of bone biology, this body of work and experiments ongoing in the lab concur to suggest 1] the appearance of bone during evolution has changed how physiological functions as diverse as memory, the acute stress response but also exercise and glucose metabolism are regulated and 2] identified bone and osteocalcin as its molecular vector, as an organ needed to sense and response to danger.

The long-term goal of my research is to study the mammalian retina as a model for the central nervous system (CNS) -- to understand how it functions in physiological conditions, how it is formed, how it breaks down in pathological conditions, and how it can be repaired. I have focused on two research themes: 1) Photoreceptor structure, synapse, circuits, and development, 2) Hibernation and metabolic adaptations in the retina and beyond. As the first neuron of the visual system, photoreceptors are vital for photoreception and transmission of visual signals. I am particularly interested in cone photoreceptors, as they mediate our daylight vision with high resolution color information. Diseases affecting cone photoreceptors compromise visual functions in the central macular area of the human retina and are thus most detrimental to our vision. However, because cones are much less abundant compared to rods in most mammals, they are less well studied. We have used the ground squirrel (GS) as a model system to study cone vision, taking advantage of their unique cone-dominant retina. In particular, we have focused on short-wavelength sensitive cones (S-cones), which are not only essential for color vision, but are also an important origin of signals for biological rhythm, mood and cognitive functions, and the growth of the eye during development. We are studying critical cone synaptic structures – synaptic ribbons, the synaptic connections of S-cones, and the development of S-cones with regard to their specific connections. These works will provide knowledge of normal retinal development and function, which can also be extended to the rest of CNS; for example, the mechanisms of synaptic targeting during development. In addition, such knowledge will benefit the development of optimal therapeutic strategies for regeneration and repair in cases of retinal degenerative disease. Many neurodegenerative diseases, including retinal diseases, are rooted in metabolic stress in neurons and/or glial cells. Using the same GS model, we aim to learn from this hibernating mammal, which possesses an amazing capability to adapt to the extreme metabolic conditions during hibernation. By exploring the mechanisms of such adaptation, we hope to discover novel therapeutic tactics for neurodegenerative diseases.

Birdsong emerges when a set of highly interconnected brain areas manage to generate a complex output. The similarities between birdsong production and human speech have positioned songbirds as unique animal models for studying learning and production of this complex motor skill. In this work, we developed a low dimensional model for a neural network in which the variables were the average activities of different neural populations within the nuclei of the song system. This neural network is active during production, perception and learning of birdsong. We performed electrophysiological experiments to record neural activity from one of these nuclei and found that the low dimensional model could reproduce the neural dynamics observed during the experiments. Also, this model could reproduce the respiratory motor patterns used to generate song. We showed that sparse activity in one of the neural nuclei could drive a more complex activity downstream in the neural network. This interdisciplinary work shows how low dimensional neural models can be a valuable tool for studying the emergence of complex motor tasks

Marmosets (Callithrix jacchus) are small South American monkeys which are being increasingly becoming adopted as animal models in neuroscience. Knowledge about the marmoset visual system has developed rapidly over the last decade. But what are the comparative advantages, and disadvantages involved in adopting this emerging model, as opposed to the more traditionally used macaque monkey? In this talk I will present case studies where the simpler brain morphology and short developmental cycle of the marmoset have been key factors in facilitating discoveries about the anatomy and physiology of the visual system. Although no single species provides the “ideal” animal model for invasive studies of the neural bases of visual processing, I argue that the development of robust methodologies for the study of the marmoset brain provides exciting opportunities to address long-standing problems in neuroscience.