Physiology seminars

Like all neural tissue, the retina has a high metabolic demand, and requires a constant supply of oxygen. Second and third order neurons are supplied by the retinal circulation, whose characteristics are similar to brain circulation. However, the photoreceptor region, which occupies half of the retinal thickness, is avascular, and relies on diffusion of oxygen from the choroidal circulation, whose properties are very different, as well as the retinal circulation. By fitting diffusion models to oxygen measurements made with oxygen microelectrodes, it is possible to understand the relative roles of the two circulations under normal conditions of light and darkness, and what happens if the retina is detached or the retinal circulation is occluded. Most of this work has been done in vivo in rat, cat, and monkey, but recent work in the isolated mouse retina will also be discussed.

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.

Gut-derived signals regulate metabolism, appetite, and behaviors important for mental health. We have performed a large-scale multidimensional screen to identify gut hormones and nutrient-sensing mechanisms in the intestine that regulate metabolism and behavior in the fruit fly Drosophila. We identified several gut hormones that affect fecundity, stress responses, metabolism, feeding, and sleep behaviors, many of which seem to act sex-specifically. We show that in response to nutrient intake, the enteroendocrine cells (EECs) of the adult Drosophila midgut release hormones that act via inter-organ relays to coordinate metabolism and feeding decisions. These findings suggest that crosstalk between the gut and other tissues regulates food choice according to metabolic needs, providing insight into how that intestine processes nutritional inputs and into the gut-derived signals that relay information regulating nutrient-specific hungers to maintain metabolic homeostasis.

The hypothalamus controls diverse homeostatic functions including fertility. Neural episode generators are required to drive the intermittent pulsatile and surge profiles of reproductive hormone secretion that control gonadal function. Studies in genetic mouse models have been fundamental in defining the neural circuits forming these central pattern generators and the full range of in vitro and in vivo optogenetic and chemogenetic methodologies have enabled investigation into their mechanism of action. The seminar will outline studies defining the hypothalamic “GnRH pulse generator network” and current understanding of its operation to drive pulsatile hormone secretion.

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, bodywide system of nerves, hormones and other signals that we will 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.

Night shift work is associated with adverse health effects and leads to misalignment between timing cues from the environment and the endogenous circadian clock. In this presentation, I will discuss the effect of circadian misalignment induced by night shift work on peripheral 24-h rhythms on the transcriptome and metabolome in humans, presenting findings from both controlled laboratory studies and field studies. Furthermore, I will highlight the importance of taking into account interindividual differences in the response to circadian misalignment.

A critical function of sensory systems is to reliably extract ethologically relevant features from the complex natural environment. A classic model to study feature detection is the direction-selective circuit of the mammalian retina. In this talk, I will discuss our recent work on how visual contexts dynamically influence the neural processing of motion signals in the direction-selective circuit in the mouse retina.

Brain aging leads to cognitive decline and is the main risk factor for sporadic forms of neurodegenerative diseases including Alzheimer’s disease. While brain cell- and tissue-intrinsic factors are likely key determinants of the aging process recent studies document a remarkable susceptibility of the brain to circulatory factors. Thus, blood borne factors from young mice or humans are sufficient to slow aspects of brain aging and improve cognitive function in old mice and, vice versa, factors from old mice are detrimental for young mice and impair cognition. We found evidence that the cerebrovasculature is an important target of circulatory factors and that brain endothelial cells show prominent age-related transcriptional changes in response to plasma. Furthermore, plasma proteins are taken up broadly into the young brain through receptor mediated transport which declines with aging. At the same time, brain derived proteins are detectable in plasma allowing us to measure physiological changes linked to brain aging in plasma. We are exploring the relevance of these findings for neurodegeneration and potential applications towards therapies.

Laboratory studies have shown that meaningful changes in light exposure lead to phase shifts in melatonin rhythm. In natural settings, however, light is a very complex signal. How melatonin responds to weekly- and seasonal-dependent variations in light exposure is still poorly understood. In this talk I will present results from a series of observational and intervention studies on the relationship between melatonin and light exposure in the field.

Liset M de la Prida is a Physicist (1994) and PhD in Neuroscience (1998), who leads the Laboratorio de Circuitos Neuronales at the Instituto Cajal, Madrid, Spain (http://www.hippo-circuitlab.es). The main focus of her lab is to understand the function of the hippocampal circuits in the normal and the diseased brain, in particular oscillations and neuronal representations. She is a leading international expert in the study of the basic mechanisms of physiological ripples and epileptic fast ripples, with strong visibility as developer of novel groundbreaking electrophysiological tools. Dr. de la Prida serves as an Editor for prestigious journals including eLife, Journal of Neuroscience Methods and eNeuro, and has commissioning duties in the American Epilepsy Society, FENS and the Spanish Society for Neurosciences.

The research in my lab focuses on sensory signal processing, particularly in cases where sensory systems perform at or near the limits imposed by physics. Photon counting in the visual system is a beautiful example. At its peak sensitivity, the performance of the visual system is limited largely by the division of light into discrete photons. This observation has several implications for phototransduction and signal processing in the retina: rod photoreceptors must transduce single photon absorptions with high fidelity, single photon signals in photoreceptors, which are only 0.03 – 0.1 mV, must be reliably transmitted to second-order cells in the retina, and absorption of a single photon by a single rod must produce a noticeable change in the pattern of action potentials sent from the eye to the brain. My approach is to combine quantitative physiological experiments and theory to understand photon counting in terms of basic biophysical mechanisms. Fortunately there is more to visual perception than counting photons. The visual system is very adept at operating over a wide range of light intensities (about 12 orders of magnitude). Over most of this range, vision is mediated by cone photoreceptors. Thus adaptation is paramount to cone vision. Again one would like to understand quantitatively how the biophysical mechanisms involved in phototransduction, synaptic transmission, and neural coding contribute to adaptation.

The arousal construct underlies a spectrum of behaviors that include sleep, exploration, feeding, sexual activity and adaptive stress. Pathological arousal conditions include stress, anxiety disorders, and addiction. The dynamics between arousal state transitions are modulated by norepinephrine neurons in the locus coeruleus, histaminergic neurons in the hypothalamus, dopaminergic neurons in the mesencephalon and cholinergic neurons in the basal forebrain. The hypocretin/orexin system in the lateral hypothalamus I will also present a new mechanism underlying sleep fragmentation during aging. Hcrt neurons are hyperexcitable in aged mice. We identify a potassium conductance known as the M-current, as a critical player in maintaining excitability of Hcrt neurons. Genetic disruption of KCNQ channels in Hcrt neurons of young animals results in sleep fragmentation. In contrast, treatment of aged animals with a KCNQ channel opener restores sleep/wake architecture. These data point to multiple circuits modulating sleep integrity across lifespan.

Information processing is energetically expensive. In the mammalian brain, it is unclear how information coding and energy usage are regulated during food scarcity. I addressed this in the visual cortex of awake mice using whole-cell recordings and two-photon imaging to monitor layer 2/3 neuronal activity and ATP usage. I found that food restriction reduced synaptic ATP usage by 29% through a decrease in AMPA receptor conductance. Neuronal excitability was nonetheless preserved by a compensatory increase in input resistance and a depolarized resting membrane potential. Consequently, neurons spiked at similar rates as controls, but spent less ATP on underlying excitatory currents. This energy-saving strategy had a cost since it amplified the variability of visually-evoked subthreshold responses, leading to a 32% broadening in orientation tuning and impaired fine visual discrimination. This reduction in coding precision was associated with reduced levels of the fat mass-regulated hormone leptin and was restored by exogenous leptin supplementation. These findings reveal novel mechanisms that dynamically regulate energy usage and coding precision in neocortex.

Leonard Maler will focus on a specialized caudal portion of the cerebellum of teleost fish whose structure and physiology has been especially well studies to the point that we now have detailed computational analyses of its function. Idoia Quintana-Urzainqui will talk about what sharks can tell us about the evolution of the telencephalon, mainly focusing on the evolutionary expansion of the pallium and how shark embryos can hold key information to interpret the origin of the developmental processes that triggered this phenomenon.

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.

Neurons in the suprachiasmatic nucleus (SCN, the brain’s master circadian clock) display a 24 hour cycle in the their rate of action potential discharge whereby firing rates are high during the light phase and lower during the dark phase. Although it is generally agreed that this cycle of activity is a key mediator of the clock’s neural and humoral output, surprisingly little is known about how changes in clock electrical activity can mediate scheduled physiological changes at different times of day. Using opto- and chemogenetic approaches in mice we have shown that the onset of electrical activity in vasopressin releasing SCN neurons near Zeitgeber time 22 (ZT22) activates glutamatergic thirst-promoting neurons in the OVLT (organum vasculosum lamina terminalis) to promote water intake prior to sleep. This effect is mediated by activity-dependent release of vasopressin from the axon terminals of SCN neurons which acts as a neurotransmitter on OVLT neurons. More recently we found that the clock receives excitatory input from a different subset of sodium sensing neurons in the OVLT. Activation of these neurons by a systemic salt load delivered at ZT19 stimulated the electrical activity of SCN neurons which are normally silent at this time. Remarkably, this effect induced an acute reduction in non-shivering thermogenesis and body temperature, which is an adaptive response to the salt load. These findings provide information regarding the mechanisms by which the SCN promotes scheduled physiological rhythms and indicates that the clock’s output circuitry can also be recruited to mediate an unscheduled homeostatic response.

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.