Seminars

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?

In most animals including in humans, emotions occur together with changes in the body, such as variations in breathing or heart rate, sweaty palms, or facial expressions. It has been suggested that this interoceptive information acts as a feedback signal to the brain, enabling adaptive modulation of emotions that is essential for survival. As such, fear, one of our basic emotions, must be kept in a functional balance to minimize risk-taking while allowing for the pursuit of essential needs. However, the neural mechanisms underlying this adaptive modulation of fear remain poorly understood. In this talk, I want to present and discuss the data from my PhD work where we uncover a crucial role for the interoceptive insular cortex in detecting changes in heart rate to maintain an equilibrium between the extinction and maintenance of fear memories in mice.

The gradual accumulation of hyperphosphorylated forms of the Tau protein (pTau) in the human brain correlate with cognitive dysfunction and neurodegeneration. I will present our recent findings on the consequences of human pTau aggregation in the hippocampal formation of a mouse tauopathy model. We show that pTau preferentially accumulates in deep-layer pyramidal neurons, leading to their neurodegeneration. In aged but not younger mice, pTau spreads to oligodendrocytes. During ‘goal-directed’ navigation, we detect fewer high-firing pyramidal cells, but coupling to network oscillations is maintained in the remaining cells. The firing patterns of individually recorded and labelled pyramidal and GABAergic neurons are similar in transgenic and non-transgenic mice, as are network oscillations, suggesting intact neuronal coordination. This is consistent with a lack of pTau in subcortical brain areas that provide rhythmic input to the cortex. Spatial memory tests reveal a reduction in short-term familiarity of spatial cues but unimpaired spatial working and reference memory. These results suggest that preserved subcortical network mechanisms compensate for the widespread pTau aggregation in the hippocampal formation. I will also briefly discuss ideas on the subcortical origins of spatial memory and the concept of the cortex as a monitoring device.

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.

Natural soundscapes such as from a forest, a busy restaurant, or a busy intersection are generally composed of a cacophony of sounds that the brain needs to interpret either independently or collectively. In certain instances sounds - such as from moving cars, sirens, and people talking - are perceived in unison and are recognized collectively as single sound (e.g., city noise). In other instances, such as for the cocktail party problem, multiple sounds compete for attention so that the surrounding background noise (e.g., speech babble) interferes with the perception of a single sound source (e.g., a single talker). I will describe results from my lab on the perception and neural representation of auditory textures. Textures, such as a from a babbling brook, restaurant noise, or speech babble are stationary sounds consisting of multiple independent sound sources that can be quantitatively defined by summary statistics of an auditory model (McDermott & Simoncelli 2011). How and where in the auditory system are summary statistics represented and the neural codes that potentially contribute towards their perception, however, are largely unknown. Using high-density multi-channel recordings from the auditory midbrain of unanesthetized rabbits and complementary perceptual studies on human listeners, I will first describe neural and perceptual strategies for encoding and perceiving auditory textures. I will demonstrate how distinct statistics of sounds, including the sound spectrum and high-order statistics related to the temporal and spectral correlation structure of sounds, contribute to texture perception and are reflected in neural activity. Using decoding methods I will then demonstrate how various low and high-order neural response statistics can differentially contribute towards a variety of auditory tasks including texture recognition, discrimination, and categorization. Finally, I will show examples from our recent studies on how high-order sound statistics and accompanying neural activity underlie difficulties for recognizing speech in background noise.

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.

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.

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.

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.

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.

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.