Physiology seminars

The regulation of body weight relies on homeostatic mechanisms that use a combination of internal signals and external cues to initiate and terminate food intake. Homeostasis depends on intricate communication between the body and the hypothalamus involving numerous neural and hormonal signals. However, there is growing evidence that higher-level cognitive function may also influence energy balance. For instance, research has shown that BMI is consistently linked to various brain, cognitive, and personality measures, implicating executive, reward, and attentional systems. Moreover, the rise in obesity rates over the past half-century is attributed to the affordability and widespread availability of highly processed foods, a phenomenon that contradicts the idea that food intake is solely regulated by homeostasis. I will suggest that prefrontal systems involved in value computation and motivation act to limit food overconsumption when food is scarce or expensive, but promote over-eating when food is abundant, an optimum strategy from an economic standpoint. I will review the genetic and neuroscience literature on the CNS control of body weight. I will present recent studies supporting a role of prefrontal systems in weight control. I will also present contradictory evidence showing that frontal executive and cognitive findings in obesity may be a consequence not a cause of increased hunger. Finally I will review the effects of obesity on brain anatomy and function. Chronic adiposity leads to cerebrovascular dysfunction, cortical thinning, and cognitive impairment. As the most common preventable risk factor for dementia, obesity poses a significant threat to brain health. I will conclude by reviewing evidence for treatment of obesity in adults to prevent brain disease.

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?

Understanding the brain is not only intrinsically fascinating, but also highly relevant to increase our well-being since our brain exhibits a power over the body that makes it capable both of provoking illness or facilitating the healing process. Bearing in mind this dark force, brain sciences have undergone and will undergo an important revolution, redefining its boundaries beyond the cranial cavity. During this presentation, we will discuss about the communication between the brain and other systems that shapes how we feel the external word and how we think. We are starting to unravel how our organs talk to the brain and how the brain talks back. That two-way communication encompasses a complex, body-wide system of nerves, hormones and other signals that will be discussed. This presentation aims at challenging a long history of thinking of bodily regulation as separate from "higher" mental processes. Four centuries ago, René Descartes famously conceptualized the mind as being separate from the body, it is time now to embody our mind.

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.

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.

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.

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.

Interoception, the sense of internal bodily signals, is essential for physiological homeostasis, cognition, and emotions. Human neuroimaging studies suggest insular cortex plays a central role in interoception, yet the cellular and circuit mechanisms of its involvement remain unclear. We developed a microprism-based cellular imaging approach to monitor insular cortex activity in behaving mice across different physiological need states. We combine this imaging approach with manipulations of peripheral physiology, circuit-mapping, cell type-specific and circuit-specific manipulation approaches to investigate the underlying circuit mechanisms. I will present our recent data investigating insular cortex activity during two physiological need states – hunger and thirst. These wereinduced naturally by caloric/fluid deficiency, or artificially by activation of specific hypothalamic “hunger neurons” and “thirst neurons”. We found that insular cortex ongoing activity faithfully represents current physiological state, independently of behavior or arousal levels. In contrast, transient responses to learned food- or water-predicting cues reflect a population-level “simulation” of future predicted satiety. Together with additional circuit-mapping and manipulation experiments, our findings suggest that insular cortex integrates visceral-sensory inputs regarding current physiological state with hypothalamus-gated amygdala inputs signaling availability of food/water. This way, insular cortex computes a prediction of future physiological state that can be used to guide behavioral choice.