Vertebrate
vertebrate
Developmental and evolutionary perspectives on thalamic function
Brain organization and function is a complex topic. We are good at establishing correlates of perception and behavior across forebrain circuits, as well as manipulating activity in these circuits to affect behavior. However, we still lack good models for the large-scale organization and function of the forebrain. What are the contributions of the cortex, basal ganglia, and thalamus to behavior? In addressing these questions, we often ascribe function to each area as if it were an independent processing unit. However, we know from the anatomy that the cortex, basal ganglia, and thalamus, are massively interconnected in a large network. One way to generate insight into these questions is to consider the evolution and development of forebrain systems. In this talk, I will discuss the developmental and evolutionary (comparative anatomy) data on the thalamus, and how it fits within forebrain networks. I will address questions including, when did the thalamus appear in evolution, how is the thalamus organized across the vertebrate lineage, and how can the change in the organization of forebrain networks affect behavioral repertoires.
Of glia and macrophages, signaling hubs in development and homeostasis
We are interested in the biology of macrophages, which represent the first line of defense against pathogens. In Drosophila, the embryonic hemocytes arise from the mesoderm whereas glial cells arise from multipotent precursors in the neurogenic region. These cell types represent, respectively, the macrophages located outside and within the nervous system (similar to vertebrate microglia). Thus, despite their different origin, hemocytes and glia display common functions. In addition, both cell types express the Glide/Gcm transcription factor, which plays an evolutionarily conserved role as an anti-inflammatory factor. Moreover, embryonic hemocytes play an evolutionarily conserved and fundamental role in development. The ability to migrate and to contact different tissues/organs most likely allow macrophages to function as signaling hubs. The function of macrophages beyond the recognition of the non-self calls for revisiting the biology of these heterogeneous and plastic cells in physiological and pathological conditions across evolution.
A bottom up approach for analyzing circuits underlying navigation in vertebrates
Sex hormone regulation of neural gene expression
Gonadal steroid hormones are the principal drivers of sex-variable biology in vertebrates. In the brain, estrogen (17β-estradiol) establishes neural sex differences in many species and modulates mood, behavior, and energy balance in adulthood. To understand the diverse effects of estradiol on the brain, we profiled the genomic binding of estrogen receptor alpha (ERα), providing the first picture of the neural actions of any gonadal hormone receptor. To relate ERα target genes to brain sex differences we assessed gene expression and chromatin accessibility in the posterior bed nucleus of the stria terminalis (BNSTp), a sexually dimorphic node in limbic circuitry that underlies sex-differential social behaviors such as aggression and parenting. In adult animals we observe that levels of ERα are predictive of the extent of sex-variable gene expression, and that these sex differences are a dynamic readout of acute hormonal state. In neonates we find that transient ERα recruitment at birth leads to persistent chromatin opening and male-biased gene expression, demonstrating a true epigenetic mechanism for brain sexual differentiation. Collectively, our findings demonstrate that sex differences in gene expression in the brain are a readout of state-dependent hormone receptor actions, rather than other factors such as sex chromosomes. We anticipate that the ERα targets we have found will contribute to established sex differences in the incidence and etiology of neurological and psychiatric disorders.
Spatial matching tasks for insect minds: relational similarity in bumblebees
Understanding what makes human unique is a fundamental research drive for comparative psychologists. Cognitive abilities such as theory of mind, cooperation or mental time travel have been considered uniquely human. Despite empirical evidence showing that animals other than humans are able (to some extent) of these cognitive achievements, findings are still heavily contested. In this context, being able to abstract relations of similarity has also been considered one of the hallmarks of human cognition. While previous research has shown that other animals (e.g., primates) can attend to relational similarity, less is known about what invertebrates can do. In this talk, I will present a series of spatial matching tasks that previously were used with children and great apes and that I adapted for use with wild-caught bumblebees. The findings from these studies suggest striking similarities between vertebrates and invertebrates in their abilities to attend to relational similarity.
What shapes the transcriptional identity of a neuron?
Within the vertebrate neocortex and other telencephalic structures, molecularly-defined neurons tend to segregate at first order into GABAergic types and glutamatergic types. Two fundamental questions arise: (1) do non-telencephalic neurons similarly segregate by neurotransmitter status, and (2) do GABAergic (or glutamatergic) types sampled in different structures share many molecular features in common, beyond the few genes directly responsible for neurotransmitter synthesis and release? To address these questions, we used single-nucleus RNA sequencing, analyzing over 2.4 million brain cells sampled from 16 locations in a primate (the common marmoset). Unexpectedly, we find the answer to both is “no”. I will discuss implications for generalizing associations between neurotransmitter utilization and other phenotypes, and share ongoing efforts to map the biodistributions of cell types in the primate brain.
Development and evolution of neuronal connectivity
In most animal species including humans, commissural axons connect neurons on the left and right side of the nervous system. In humans, abnormal axon midline crossing during development causes a whole range of neurological disorders ranging from congenital mirror movements, horizontal gaze palsy, scoliosis or binocular vision deficits. The mechanisms which guide axons across the CNS midline were thought to be evolutionary conserved but our recent results suggesting that they differ across vertebrates. I will discuss the evolution of visual projection laterality during vertebrate evolution. In most vertebrates, camera-style eyes contain retinal ganglion cell (RGC) neurons projecting to visual centers on both sides of the brain. However, in fish, RGCs are thought to only innervate the contralateral side. Using 3D imaging and tissue clearing we found that bilateral visual projections exist in non-teleost fishes. We also found that the developmental program specifying visual system laterality differs between fishes and mammals. We are currently using various strategies to discover genes controlling the development of visual projections. I will also present ongoing work using 3D imaging techniques to study the development of the visual system in human embryo.
Seeing the world through moving photoreceptors - binocular photomechanical microsaccades give fruit fly hyperacute 3D-vision
To move efficiently, animals must continuously work out their x,y,z positions with respect to real-world objects, and many animals have a pair of eyes to achieve this. How photoreceptors actively sample the eyes’ optical image disparity is not understood because this fundamental information-limiting step has not been investigated in vivo over the eyes’ whole sampling matrix. This integrative multiscale study will advance our current understanding of stereopsis from static image disparity comparison to a morphodynamic active sampling theory. It shows how photomechanical photoreceptor microsaccades enable Drosophila superresolution three-dimensional vision and proposes neural computations for accurately predicting these flies’ depth-perception dynamics, limits, and visual behaviors.
The evolution of computation in the brain: Insights from studying the retina
The retina is probably the most accessible part of the vertebrate central nervous system. Its computational logic can be interrogated in a dish, from patterns of lights as the natural input, to spike trains on the optic nerve as the natural output. Consequently, retinal circuits include some of the best understood computational networks in neuroscience. The retina is also ancient, and central to the emergence of neurally complex life on our planet. Alongside new locomotor strategies, the parallel evolution of image forming vision in vertebrate and invertebrate lineages is thought to have driven speciation during the Cambrian. This early investment in sophisticated vision is evident in the fossil record and from comparing the retina’s structural make up in extant species. Animals as diverse as eagles and lampreys share the same retinal make up of five classes of neurons, arranged into three nuclear layers flanking two synaptic layers. Some retina neuron types can be linked across the entire vertebrate tree of life. And yet, the functions that homologous neurons serve in different species, and the circuits that they innervate to do so, are often distinct to acknowledge the vast differences in species-specific visuo-behavioural demands. In the lab, we aim to leverage the vertebrate retina as a discovery platform for understanding the evolution of computation in the nervous system. Working on zebrafish alongside birds, frogs and sharks, we ask: How do synapses, neurons and networks enable ‘function’, and how can they rearrange to meet new sensory and behavioural demands on evolutionary timescales?
What the fly’s eye tells the fly’s brain…and beyond
Fly Escape Behaviors: Flexible and Modular We have identified a set of escape maneuvers performed by a fly when confronted by a looming object. These escape responses can be divided into distinct behavioral modules. Some of the modules are very stereotyped, as when the fly rapidly extends its middle legs to jump off the ground. Other modules are more complex and require the fly to combine information about both the location of the threat and its own body posture. In response to an approaching object, a fly chooses some varying subset of these behaviors to perform. We would like to understand the neural process by which a fly chooses when to perform a given escape behavior. Beyond an appealing set of behaviors, this system has two other distinct advantages for probing neural circuitry. First, the fly will perform escape behaviors even when tethered such that its head is fixed and neural activity can be imaged or monitored using electrophysiology. Second, using Drosophila as an experimental animal makes available a rich suite of genetic tools to activate, silence, or image small numbers of cells potentially involved in the behaviors. Neural Circuits for Escape Until recently, visually induced escape responses have been considered a hardwired reflex in Drosophila. White-eyed flies with deficient visual pigment will perform a stereotyped middle-leg jump in response to a light-off stimulus, and this reflexive response is known to be coordinated by the well-studied giant fiber (GF) pathway. The GFs are a pair of electrically connected, large-diameter interneurons that traverse the cervical connective. A single GF spike results in a stereotyped pattern of muscle potentials on both sides of the body that extends the fly's middle pair of legs and starts the flight motor. Recently, we have found that a fly escaping a looming object displays many more behaviors than just leg extension. Most of these behaviors could not possibly be coordinated by the known anatomy of the GF pathway. Response to a looming threat thus appears to involve activation of numerous different neural pathways, which the fly may decide if and when to employ. Our goal is to identify the descending pathways involved in coordinating these escape behaviors as well as the central brain circuits, if any, that govern their activation. Automated Single-Fly Screening We have developed a new kind of high-throughput genetic screen to automatically capture fly escape sequences and quantify individual behaviors. We use this system to perform a high-throughput genetic silencing screen to identify cell types of interest. Automation permits analysis at the level of individual fly movements, while retaining the capacity to screen through thousands of GAL4 promoter lines. Single-fly behavioral analysis is essential to detect more subtle changes in behavior during the silencing screen, and thus to identify more specific components of the contributing circuits than previously possible when screening populations of flies. Our goal is to identify candidate neurons involved in coordination and choice of escape behaviors. Measuring Neural Activity During Behavior We use whole-cell patch-clamp electrophysiology to determine the functional roles of any identified candidate neurons. Flies perform escape behaviors even when their head and thorax are immobilized for physiological recording. This allows us to link a neuron's responses directly to an action.
The Synaptome Architecture of the Brain: Lifespan, disease, evolution and behavior
The overall aim of my research is to understand how the organisation of the synapse, with particular reference to the postsynaptic proteome (PSP) of excitatory synapses in the brain, informs the fundamental mechanisms of learning, memory and behaviour and how these mechanisms go awry in neurological dysfunction. The PSP indeed bears a remarkable burden of disease, with components being disrupted in disorders (synaptopathies) including schizophrenia, depression, autism and intellectual disability. Our work has been fundamental in revealing and then characterising the unprecedented complexity (>1000 highly conserved proteins) of the PSP in terms of the subsynaptic architecture of postsynaptic proteins such as PSD95 and how these proteins assemble into complexes and supercomplexes in different neurons and regions of the brain. Characterising the PSPs in multiple species, including human and mouse, has revealed differences in key sets of functionally important proteins, correlates with brain imaging and connectome data, and a differential distribution of disease-relevant proteins and pathways. Such studies have also provided important insight into synapse evolution, establishing that vertebrate behavioural complexity is a product of the evolutionary expansion in synapse proteomes that occurred ~500 million years ago. My lab has identified many mutations causing cognitive impairments in mice before they were found to cause human disorders. Our proteomic studies revealed that >130 brain diseases are caused by mutations affecting postsynaptic proteins. We uncovered mechanisms that explain the polygenic basis and age of onset of schizophrenia, with postsynaptic proteins, including PSD95 supercomplexes, carrying much of the polygenic burden. We discovered the “Genetic Lifespan Calendar”, a genomic programme controlling when genes are regulated. We showed that this could explain how schizophrenia susceptibility genes are timed to exert their effects in young adults. The Genes to Cognition programme is the largest genetic study so far undertaken into the synaptic molecular mechanisms underlying behaviour and physiology. We made important conceptual advances that inform how the repertoire of both innate and learned behaviours is built from unique combinations of postsynaptic proteins that either amplify or attenuate the behavioural response. This constitutes a key advance in understanding how the brain decodes information inherent in patterns of nerve impulses, and provides insight into why the PSP has evolved to be so complex, and consequently why the phenotypes of synaptopathies are so diverse. Our most recent work has opened a new phase, and scale, in understanding synapses with the first synaptome maps of the brain. We have developed next-generation methods (SYNMAP) that enable single-synapse resolution molecular mapping across the whole mouse brain and extensive regions of the human brain, revealing the molecular and morphological features of a billion synapses. This has already uncovered unprecedented spatiotemporal synapse diversity organised into an architecture that correlates with the structural and functional connectomes, and shown how mutations that cause cognitive disorders reorganise these synaptome maps; for example, by detecting vulnerable synapse subtypes and synapse loss in Alzheimer’s disease. This innovative synaptome mapping technology has huge potential to help characterise how the brain changes during normal development, including in specific cell types, and with degeneration, facilitating novel pathways to diagnosis and therapy.
Retinal neurogenesis and lamination: What to become, where to become it and how to move from there!
The vertebrate retina is an important outpost of the central nervous system, responsible for the perception and transmission of visual information. It consists of five different types of neurons that reproducibly laminate into three layers, a process of crucial importance for the organ’s function. Unsurprisingly, impaired fate decisions as well as impaired neuronal migrations and lamination lead to impaired retinal function. However, how processes are coordinated at the cellular and tissue level and how variable or robust retinal formation is, is currently still underexplored. In my lab, we aim to shed light on these questions from different angles, studying on the one hand differentiation phenomena and their variability and on the other hand the downstream migration and lamination phenomena. We use zebrafish as our main model system due to its excellent possibilities for live imaging and quantitative developmental biology. More recently we also started to use human retinal organoids as a comparative system. We further employ cross disciplinary approaches to address these issues combining work of cell and developmental biology, biomechanics, theory and computer science. Together, this allows us to integrate cell with tissue-wide phenomena and generate an appreciation of the reproducibility and variability of events.
Untitled Seminar
Rachel Moore- Microtubules are not required to generate a nascent axon in embryonic spinal neurons in vivo Michael Notaras-TBA Rachel Wong- Circuit assembly in the vertebrate retina
Opponent processing in the expanded retinal mosaic of Nymphalid butterflies
In many butterflies, the ancestral trichromatic insect colour vision, based on UV-, blue- and green-sensitive photoreceptors, is extended with red-sensitive cells. Physiological evidence for red receptors has been missing in nymphalid butterflies, although some species can discriminate red hues well. In eight species from genera Archaeoprepona, Argynnis, Charaxes, Danaus, Melitaea, Morpho, Heliconius and Speyeria, we found a novel class of green-sensitive photoreceptors that have hyperpolarizing responses to stimulation with red light. These green-positive, red-negative (G+R–) cells are allocated to positions R1/2, normally occupied by UV and blue-sensitive cells. Spectral sensitivity, polarization sensitivity and temporal dynamics suggest that the red opponent units (R–) are the basal photoreceptors R9, interacting with R1/2 in the same ommatidia via direct inhibitory synapses. We found the G+R– cells exclusively in butterflies with red-shining ommatidia, which contain longitudinal screening pigments. The implementation of the red colour channel with R9 is different from pierid and papilionid butterflies, where cells R5–8 are the red receptors. The nymphalid red-green opponent channel and the potential for tetrachromacy seem to have been switched on several times during evolution, balancing between the cost of neural processing and the value of extended colour information.
Neural representations of space in the hippocampus of a food-caching bird
Spatial memory in vertebrates requires brain regions homologous to the mammalian hippocampus. Between vertebrate clades, however, these regions are anatomically distinct and appear to produce different spatial patterns of neural activity. We asked whether hippocampal activity is fundamentally different even between distant vertebrates that share a strong dependence on spatial memory. We studied tufted titmice – food-caching birds capable of remembering many concealed food locations. We found mammalian-like neural activity in the titmouse hippocampus, including sharp-wave ripples and anatomically organized place cells. In a non-food-caching bird species, spatial firing was less informative and was exhibited by fewer neurons. These findings suggest that hippocampal circuit mechanisms are similar between birds and mammals, but that the resulting patterns of activity may vary quantitatively with species-specific ethological needs.
Chapter 2. The Origin of Vertebrates: Invertebrate Chordates and Cyclostomes
What transcriptomics tells us about retinal development, disease and evolution
Classification of neurons, long viewed as a fairly boring enterprise, has emerged as a major bottleneck in analysis of neural circuits. High throughput single cell RNA-seq has provided a new way to improve the situation. We initially applied this method to mouse retina, showing that its five neuronal classes (photoreceptors, three groups of interneurons, and retinal ganglion cells) can be divided into 130 discrete types. We then applied the method to other species including human, macaque, zebrafish and chick. With the atlases in hand, we are now using them to address questions about how retinal cell types diversify, how they differ in their responses to injury and disease, and the extent to which cell classes and types are conserved among vertebrates.
Target detection in the natural world
Animal sensory systems are optimally adapted to those features typically encountered in natural surrounds, thus allowing neurons that have a limited bandwidth to encode almost impossibly large input ranges. Importantly, natural scenes are not random, and peripheral visual systems have therefore evolved to reduce the predictable redundancy. The vertebrate visual cortex is also optimally tuned to the spatial statistics of natural scenes, but much less is known about how the insect brain responds to these. We are redressing this deficiency using several techniques. Olga Dyakova uses exquisite image manipulation to give natural images unnatural image statistics, or vice versa. Marissa Holden then uses these images as stimuli in electrophysiological recordings of neurons in the fly optic lobes, to see how the brain codes for the statistics typically encountered in natural scenes, and Olga Dyakova measures the behavioral optomotor response on our trackball set-up.
The Geometry of Decision-Making
Choosing among spatially distributed options is a central challenge for animals, from deciding among alternative potential food sources or refuges, to choosing with whom to associate. Here, using an integrated theoretical and experimental approach (employing immersive Virtual Reality), with both invertebrate and vertebrate models—the fruit fly, desert locust and zebrafish—we consider the recursive interplay between movement and collective vectorial integration in the brain during decision-making regarding options (potential ‘targets’) in space. We reveal that the brain repeatedly breaks multi-choice decisions into a series of abrupt (critical) binary decisions in space-time where organisms switch, spontaneously, from averaging vectorial information among, to suddenly excluding one of, the remaining options. This bifurcation process repeats until only one option—the one ultimately selected—remains. Close to each bifurcation the ‘susceptibility’ of the system exhibits a sharp increase, inevitably causing small differences among the remaining options to become amplified; a property that both comes ‘for free’ and is highly desirable for decision-making. This mechanism facilitates highly effective decision-making, and is shown to be robust both to the number of options available, and to context, such as whether options are static (e.g. refuges) or mobile (e.g. other animals). In addition, we find evidence that the same geometric principles of decision-making occur across scales of biological organisation, from neural dynamics to animal collectives, suggesting they are fundamental features of spatiotemporal computation.
Analyzing Retinal Disease Using Electron Microscopic Connectomics
John DowlingJohn E. Dowling received his AB and PhD from Harvard University. He taught in the Biology Department at Harvard from 1961 to 1964, first as an Instructor, then as assistant professor. In 1964 he moved to Johns Hopkins University, where he held an appointment as associate professor of Ophthalmology and Biophysics. He returned to Harvard as professor of Biology in 1971, was the Maria Moors Cabot Professor of Natural Sciences from 1971-2001, Harvard College professor from 1999-2004 and is presently the Gordon and Llura Gund Professor of Neurosciences. Dowling was chairman of the Biology Department at Harvard from 1975 to 1978 and served as associate dean of the faculty of Arts and Sciences from 1980 to 1984. He was Master of Leverett House at Harvard from 1981-1998 and currently serves as president of the Corporation of The Marine Biological Laboratory in Woods Hole. He is a Fellow of the American Academy of Arts and Sciences, a member of the National Academy of Sciences and a member of the American Philosophical Society. Awards that Dowling received include the Friedenwald Medal from the Association of Research in Ophthalmology and Vision in 1970, the Annual Award of the New England Ophthalmological Society in 1979, the Retinal Research Foundation Award for Retinal Research in 1981, an Alcon Vision Research Recognition Award in 1986, a National Eye Institute's MERIT award in 1987, the Von Sallman Prize in 1992, The Helen Keller Prize for Vision Research in 2000 and the Llura Ligget Gund Award for Lifetime Achievement and Recognition of Contribution to the Foundation Fighting Blindness in 2001. He was granted an honorary MD degree by the University of Lund (Sweden) in 1982 and an honorary Doctor of Laws degree from Dalhousie University (Canada) in 2012. Dowling's research interests have focused on the vertebrate retina as a model piece of the brain. He and his collaborators have long been interested in the functional organization of the retina, studying its synaptic organization, the electrical responses of the retinal neurons, and the mechanisms underlying neurotransmission and neuromodulation in the retina. Dowling became interested in zebrafish as a system in which one could explore the development and genetics of the vertebrate retina about 20 years ago. Part of his research team has focused on retinal development in zebrafish and the role of retinoic acid in early eye and photoreceptor development. A second group has developed behavioral tests to isolate mutations, both recessive and dominant, specific to the visual system.
A fresh look at the bird retina
I am working on the vertebrate retina, with a main focus on the mouse and bird retina. Currently my work is focused on three major topics: Functional and molecular analysis of electrical synapses in the retina Circuitry and functional role of retinal interneurons: horizontal cells Circuitry for light-dependent magnetoreception in the bird retina Electrical synapses Electrical synapses (gap junctions) permit fast transmission of electrical signals and passage of metabolites by means of channels, which directly connect the cytoplasm of adjoining cells. A functional gap junction channel consists of two hemichannels (one provided by each of the cells), each comprised of a set of six protein subunits, termed connexins. These building blocks exist in a variety of different subtypes, and the connexin composition determines permeability and gating properties of a gap junction channel, thereby enabling electrical synapses to meet a diversity of physiological requirements. In the retina, various connexins are expressed in different cell types. We study the cellular distribution of different connexins as well as the modulation induced by transmitter action or change of ambient light levels, which leads to altered electrical coupling properties. We are also interested in exploiting them as therapeutic avenue for retinal degeneration diseases. Horizontal cells Horizontal cells receive excitatory input from photoreceptors and provide feedback inhibition to photoreceptors and feedforward inhibition to bipolar cells. Because of strong electrical coupling horizontal cells integrate the photoreceptor input over a wide area and are thought to contribute to the antagonistic organization of bipolar cell and ganglion cell receptive fields and to tune the photoreceptor–bipolar cell synapse with respect to the ambient light conditions. However, the extent to which this influence shapes retinal output is unclear, and we aim to elucidate the functional importance of horizontal cells for retinal signal processing by studying various transgenic mouse models. Retinal circuitry for light-dependent magnetoreception in the bird We are studying which neuronal cell types and pathways in the bird retina are involved in the processing of magnetic signals. Likely, magnetic information is detected in cryptochrome-expressing photoreceptors and leaves the retina through ganglion cell axons that project via the thalamofugal pathway to Cluster N, a part of the visual wulst essential for the avian magnetic compass. Thus, we aim to elucidate the synaptic connections and retinal signaling pathways from putatively magnetosensitive photoreceptors to thalamus-projecting ganglion cells in migratory birds using neuroanatomical and electrophysiological techniques.
Optogenetic silencing of synaptic transmission with a mosquito rhodopsin
Long-range projections link distant circuits in the brain, allowing efficient transfer of information between regions and synchronization of distributed patterns of neural activity. Understanding the functional roles of defined neuronal projection pathways requires temporally precise manipulation of their activity, and optogenetic tools appear to be an obvious choice for such experiments. However, we and others have previously shown that commonly-used inhibitory optogenetic tools have low efficacy and off-target effects when applied to presynaptic terminals. In my talk, I will present a new solution to this problem: a targeting-enhanced mosquito homologue of the vertebrate encephalopsin (eOPN3), which upon activation can effectively suppress synaptic transmission through the Gi/o signaling pathway. Brief illumination of presynaptic terminals expressing eOPN3 triggers a lasting suppression of synaptic output that recovers spontaneously within minutes in vitro and in vivo. The efficacy of eOPN3 in suppressing presynaptic release opens new avenues for functional interrogation of long-range neuronal circuits in vivo.
Untitled Seminar
Sean Miller will present "From brain wiring to synaptic physiology - reuse of a cell recognition molecule to carry out higher order nervous system functions". Then, Patricia Jusuf will talk about " Visual vertebrate pipeline for assessing novel human GWAS gene candidates". Victor Borrell with deal with the "Genetic evolution of cerebral cortex size determinants" and Louise Cheng will present
The Brain’s Constraints on Human Number Concepts
Although animals can estimate numerical quantities, true counting and arithmetic abilities are unique to humans and are inextricably linked to symbolic competence. However, our unprecedented numerical skills are deeply rooted in our neuronal heritage as primates and vertebrates. I argue that numerical competence in humans is the result of three neural constraints. First, I propose that the neuronal mechanisms of quantity estimation are part of our evolutionary heritage and can be witnessed across primate and vertebrate phylogeny. Second, I suggest that a basic understanding of number, what numerical quantity means, is innately wired into the brain and gives rise to an intuitive number sense, or number instinct. Third and finally, I argue that symbolic counting and arithmetic in humans is rooted in an evolutionarily and ontogenetically primeval neural system for non-symbolic number representations. These three neural constraints jointly determine the basic processing of number concepts in the human mind.
Vision outside of the visual system (in Drosophila)
We seek to understand the control of behavior – by animals, their brains, and their neurons. Reiser and his team are focused on the fly visual system, using modern methods from the Drosophila toolkit to understand how visual pathways are involved in specific behaviors. Due to the recent connectomics explosion, they now study the brain-wide networks organizing visual information for behavior control. The team combines explorations of visually guided behaviors with functional investigations of specific cell types throughout the fly brain. The Reiser lab actively develops and disseminates new methods and instruments enabling increasingly precise quantification of animal behavior.
Stereo vision in humans and insects
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.
Australian Bogong moths use a true stellar compass for long-distance navigation at night
Each spring, billions of Bogong moths escape hot conditions in different regions of southeast Australia by migrating over 1000 km to a limited number of cool caves in the Australian Alps, historically used for aestivating over the summer. At the beginning of autumn the same individuals make a return migration to their breeding grounds to reproduce and die. To steer migration Bogong moths sense the Earth’s magnetic field and correlate its directional information with visual cues. In this presentation, we will show that a critically important visual cue is the distribution of starlight within the austral night sky. By tethering spring and autumn migratory moths in a flight simulator, we found that under natural dorsally-projected night skies, and in a nulled magnetic field (disabling the magnetic sense), moths flew in their seasonally appropriate migratory directions, turning in the opposite direction when the night sky was rotated 180°. Visual interneurons in the moth’s optic lobe and central brain responded vigorously to identical sky rotations. Migrating Bogong moths thus use the starry night sky as a true compass to distinguish geographic cardinal directions, the first invertebrate known to do so. These stellar cues are likely reinforced by the Earth’s magnetic field to create a robust compass mechanism for long-distance nocturnal navigation.
Fish Feelings: Emotional states in larval zebrafish
I’ll give an overview of internal - or motivational - states in larval zebrafish. Specifically we will focus on the role of the Oxytocin system in regulating the detection of, and behavioral responses to, conspecifics. The appeal here is that Oxytocin has likely conserved roles across all vertebrates, including humans, and that the larval zebrafish allows us to study some of the general principles across the brain but nonetheless at cellular resolution. This allows us to propose mechanistic models of emotional states.
Neural control of motor actions: from whole-brain landscape to millisecond dynamics
Animals control motor actions at multiple timescales. We use larval zebrafish and advanced optical microscopy to understand the underlying neural mechanisms. First, we examined the mechanisms of short-term motor learning by using whole-brain neural activity imaging. We found that the 5-HT system integrates the sensory outcome of actions and determines future motor patterns. Second, we established a method for recording spiking activity and membrane potential from a population of neurons during behavior. We identified putative motor command signals and internal copy signals that encode millisecond-scale details of the swimming dynamics. These results demonstrate that zebrafish provide a holistic and mechanistic understanding of the neural basis of motor control in vertebrate brains.
Young IBRO NextInNeuro Webinar - The retinal basis of colour vision: from fish to humans
Colour vision is based on circuit-level comparison of the signals from spectral distinct types of photoreceptors. In our own eyes, the presence of three types of cones enable trichromatic colour vision. However, many phylogenetically ‘older’ vertebrates have four or more cone types, and in almost all their cases the circuits that enable tetra- or possibly even pentachromatic colour vision are not known. This includes the majority of birds, reptiles, amphibians, and bony fish. In the lab we study neuronal circuits for colour vision in non-mammalian vertebrates, with a focus on zebrafish, a tetrachromatic surface dwelling species of teleost. I will discuss how in the case of zebrafish, retinal colour computations are implemented in a fundamentally different, and probably much more efficient way compared to how they are thought to work in humans. I will then highlight how these fish circuits might be linked with those in mammals, possibly providing a new way of thinking about how circuits for colour vision are organized in vertebrates.
Emergence of long time scales in data-driven network models of zebrafish activity
How can neural networks exhibit persistent activity on time scales much larger than allowed by cellular properties? We address this question in the context of larval zebrafish, a model vertebrate that is accessible to brain-scale neuronal recording and high-throughput behavioral studies. We study in particular the dynamics of a bilaterally distributed circuit, the so-called ARTR, including hundreds neurons. ARTR exhibits slow antiphasic alternations between its left and right subpopulations, which can be modulated by the water temperature, and drive the coordinated orientation of swim bouts, thus organizing the fish spatial exploration. To elucidate the mechanism leading to the slow self-oscillation, we train a network graphical model (Ising) on neural recordings. Sampling the inferred model allows us to generate synthetic oscillatory activity, whose features correctly capture the observed dynamics. A mean-field analysis of the inferred model reveals the existence several phases; activated crossing of the barriers in between those phases controls the long time scales present in the network oscillations. We show in particular how the barrier heights and the nature of the phases vary with the water temperature.
Virus-like intercellular communication in the nervous system
The neuronal gene Arc is essential for long-lasting information storage in the mammalian brain and mediates various forms of synaptic plasticity. We recently discovered that Arc self-assembles into virus-like capsids that encapsulate RNA. Endogenous Arc protein is released from neurons in extracellular vesicles that mediate the transfer of Arc mRNA into new target cells. Evolutionary analysis indicates that Arc is derived from a vertebrate lineage of Ty3/gypsy retrotransposons, which are also ancestral to retroviruses such as HIV. These findings suggest that Gag retroelements have been repurposed during evolution to mediate intercellular communication in the nervous system that may underlie cognition and memory.
Cones with character: An in vivo circuit implementation of efficient coding
In this talk I will summarize some of our recent unpublished work on spectral coding in the larval zebrafish retina. Combining 2p imaging, hyperspectral stimulation, computational modeling and connectomics, we take a renewed look at the spectral tuning of cone photoreceptors in the live eye. We find that already cones optimally rotate natural colour space in a PCA-like fashion to disambiguate greyscale from "colour" information. We then follow this signal through the retinal layers and ultimately into the brain to explore the major spectral computations performed by the visual system at its consecutive stages. We find that by and large, zebrafish colour vision can be broken into three major spectral zones: long wavelength grey-scale-like vision, short-wavelength prey capture circuits, and spectrally diverse mid-wavelength circuits which possibly support the bulk of "true colour vision" in this tetrachromate vertebrate.
About time: the temporal control of cell fate in the developing vertebrate nervous system
Food Mind Control: Regulation of Sensory Behaviors by Gut-Brain Signaling
How does the presence or absence of food shape and prioritize behavioral decisions? When is food more than just food? As in other animals, prolonged food deprivation dramatically alters sensory behaviors in C. elegans. For instance, it has been known since the mid-1970s that hungry worms no longer respond to temperature changes in their environment, but the underlying mechanisms have been unclear. I will describe unpublished work showing that insulin signaling from the gut regulates thermosensory behaviors as a function of feeding state by engaging a modulatory sensorimotor circuit that gates the output of the core thermosensory network. C. elegans is associated with, and consumes, diverse bacteria in the wild. I will also discuss a recent story in which we find that in addition to providing nutrition, a bacterial strain in the worm gut alters the hosts’ olfactory behavior and drives food choice decisions by producing a neurotransmitter that targets the hosts’ sensory neurons. These results add to our growing body of knowledge of how signaling from the gut modulates peripheral and central neuron properties and drives sensory behavioral plasticity.
A robust neural code for human odor in the Aedes aegpyti mosquito brain
A globally invasive form of the mosquito Aedes aegypti has evolved to specialize in biting humans, making it an efficient vector of dengue, yellow fever, Zika, and chikungunya. Host-seeking females identify humans primarily by smell, strongly preferring human odour over the odor of non-human animals. Exactly how they discriminate, however, is unclear. Human and animal odors are complex blends that share most of the same chemical components, presenting an interesting challenge in sensory coding. I will talk about recent work from the lab showing that (1) human and animal blends can be distinguished by the relative concentration of a diverse array of compounds and that (2) these complex chemical differences translate into a neural code for human odor that involves as few as two to three olfactory glomeruli in the mosquito brain. Our work demonstrates how organisms may evolve to discriminate complex odor stimuli of special biological relevance with a surprisingly simple combinatorial code and reveals novel targets for the design of next-generation mosquito control strategies.
Untangling the web of behaviours used to produce spider orb webs
Many innate behaviours are the result of multiple sensorimotor programs that are dynamically coordinated to produce higher-order behaviours such as courtship or architecture construction. Extendend phenotypes such as architecture are especially useful for ethological study because the structure itself is a physical record of behavioural intent. A particularly elegant and easily quantifiable structure is the spider orb-web. The geometric symmetry and regularity of these webs have long generated interest in their behavioural origin. However, quantitative analyses of this behaviour have been sparse due to the difficulty of recording web-making in real-time. To address this, we have developed a novel assay enabling real-time, high-resolution tracking of limb movements and web structure produced by the hackled orb-weaver Uloborus diversus. With its small brain size of approximately 100,000 neurons, the spider U. diversus offers a tractable model organism for the study of complex behaviours. Using deep learning frameworks for limb tracking, and unsupervised behavioural clustering methods, we have developed an atlas of stereotyped movement motifs and are investigating the behavioural state transitions of which the geometry of the web is an emergent property. In addition to tracking limb movements, we have developed algorithms to track the web’s dynamic graph structure. We aim to model the relationship between the spider’s sensory experience on the web and its motor decisions, thereby identifying the sensory and internal states contributing to this sensorimotor transformation. Parallel efforts in our group are establishing 2-photon in vivo calcium imaging protocols in this spider, eventually facilitating a search for neural correlates underlying the internal and sensory state variables identified by our behavioural models. In addition, we have assembled a genome, and are developing genetic perturbation methods to investigate the genetic underpinnings of orb-weaving behaviour. Together, we aim to understand how complex innate behaviours are coordinated by underlying neuronal and genetic mechanisms.
How the brain comes to balance: Development of postural stability and its neural architecture in larval zebrafish
Maintaining posture is a vital challenge for all freely-moving organisms. As animals grow, their relationship to destabilizing physical forces changes. How does the nervous system deal with this ongoing challenge? Vertebrates use highly conserved vestibular reflexes to stabilize the body. We established the larval zebrafish as a new model system to understand the development of the vestibular reflexes responsible for balance. In this talk, I will begin with the biophysical challenges facing baby fish as they learn to swim. I’ll briefly review published work by David Ehrlich, Ph.D., establishing a fundamental relationship between postural stability and locomotion. The bulk of the talk will highlight unpublished work by Kyla Hamling. She discovered that a small (~50) population of molecularly-defined brainstem neurons called vestibulo-spinal cells act as a nexus for postural development. Her loss-of-function experiments show that these neurons contribute more to postural stability as animals grow older. I’ll end with brief highlights from her ongoing work examining tilt-evoked responses of these neurons using 2-photon imaging and the consequences of downstream activity in the spinal cord using single-objective light-sheet (SCAPE) microscopy
Theme and variations: circuit mechanisms of behavioural evolution
Animals exhibit extraordinary variation in their behaviour, yet little is known about the neural mechanisms that generate this diversity. My lab has been taking advantage of the rapid diversification of male courtship behaviours in Drosophila to gain insight into how evolution shapes the nervous system to generate species-specific behaviours. By translating neurogenetic tools from D. melanogaster to closely related Drosophila species, we have begun to directly compare the homologous neural circuits and pinpoint sites of adaptive change. Across species, P1 interneurons serve as a conserved and key node in regulating male courtship: these neurons are selectively activated by the sensory cues carried by an appropriate mate and their activation triggers enduring courtship displays. We have been examining how different sensory pathways converge onto P1 neurons to regulate a male’s state of arousal, honing his pursuit of a prospective partner. Moreover, by performing cross-species comparison of these circuits, we have begun to gain insight into how reweighting of sensory inputs to P1 neurons underlies species-specific mate recognition. Our results suggest how variation at flexible nodes within the nervous system can serve as a substrate for behavioural evolution, shedding light on the types of changes that are possible and preferable within brain circuits.
Inaugural Simons-Emory Symposium On Motor Control: "What tools are we missing to understand motor control? What could we learn if we had them
This is the inaugural symposium of the Simons-Emory International Consortium on Motor Control, and speakers will deliver 10 minute talks (each followed by 10 minutes of discussion) addressing this question: "What tools are we missing to understand motor control, and what could we learn if we had them?”
Functional and structural loci of individuality in the Drosophila olfactory circuit
behaviour varies even among genetically identical animals raised in the same environment. However, little is known about the circuit or anatomical underpinnings of this individuality, though previous work implicates sensory periphery. Drosophila olfaction presents an ideal model to study the biological basis of behavioural individuality, because while the neural circuit underlying olfactory behaviour is well-described and highly stereotyped, persistent idiosyncrasy in behaviour, neural coding, and neural wiring have also been described. Projection neurons (PNs), which relay odor signals sensed by olfactory receptor neurons (ORNs) to deeper brain structures, exhibit variable calcium responses to identical odor stimuli across individuals, but how these idiosyncrasies relate to individual behavioural responses remains unknown. Here, using paired behaviour and two-photon imaging measurements, we show that idiosyncratic calcium dynamics in both ORNs and PNs predict individual preferences for an aversive monomolecular odorant versus air, suggesting that variation at the periphery of the olfactory system determines individual preference for an odor’s presence. In contrast, PN, but not ORN, calcium responses predict individual preferences in a two-odor choice assay. Furthermore, paired behaviour and immunohistochemistry measurements reveal that variation in ORN presynaptic density also predicts two-odor preference, suggesting this site is a locus of individuality where microscale circuit variation gives rise to idiosyncrasy in behaviour. Our results demonstrate how a neural circuit may vary functionally and structurally to produce variable behaviour among individuals.
The active modulation of sound and vibration perception
The dominant view of perception right now is that information travels from the environment to the sensory system, then to the nervous systems which processes it to generate a percept and behaviour. Ongoing behaviour is thought to occur largely through simple iterations of this process. However, this linear view, where information flows only in one direction and the properties of the environment and the sensory system remain static and unaffected by behaviour, is slowly fading. Many of us are beginning to appreciate that perception is largely active, i.e. that information flows back and forth between the three systems modulating their respective properties. In other words, in the real world, the environment and sensorimotor loop is pretty much always closed. I study the loop; in particular I study how the reverse arm of the loop affects sound and vibration perception. I will present two examples of motor modulation of perception at two very different temporal and spatial scales. First, in crickets, I will present data on how high-speed molecular motor activity enhances hearing via the well-studied phenomenon of active amplification. Second, in spiders I will present data on how body posture, a slow macroscopic feature, which can barely be called ‘active’, can nonetheless modulate vibration perception. I hope these results will motivate a conversation about whether ‘active’ perception is an optional feature observed in some sensory systems, or something that is ultimately necessitated by both evolution and physics.
The ecology of collective behaviour
Collective behaviour operates without central control, through interactions among individuals. The collective behaviour of ant colonies is based on simple olfactory interactions. Ant species differ enormously in the algorithms that regulate collective behaviour, reflecting diversity in ecology. I will contrast two species in very different ecological situations. Harvester ant colonies in the desert, where water is scarce but conditions are stable, regulate foraging to conserve water. Response to positive feedback from olfactory interactions depends on the risk of water loss, mediated by dopamine neurophysiology. For arboreal turtle ants in the tropical forest, life is easy but unpredictable, and a highly modular system uses negative feedback to sustain activity. In all natural systems, from ant colonies to brains, collective behaviour evolves in relation with changing conditions. Similar dynamics in environmental conditions may lead to the evolution of similar processes to regulate collective behaviour.
The evolutionary origins of cortical cell types
In the last 500 million years, the dorsal telencephalon changed like no other region of the vertebrate brain. Differences range from the six-layered neocortex of mammals, to the small three-layered cortex of reptiles, and the complete absence of lamination in birds. These anatomical differences have prompted endless discussions on the origins and evolution of the cerebral cortex. We have approached this problem from a cell type and transcriptomics perspective. This reveals a more granular picture, where different cell types and classes have followed independent trajectories of evolutionary change. In this presentation, I will discuss how the molecular analysis of cell types in the brains of turtles, lizards and amphibians is updating our views on the evolution of the cerebral cortex, and the new questions emerging from these results.
Motion vision in Drosophila: from single neuron computation to behaviour
How nervous systems control behaviour is the main question we seek to answer in neuroscience. Although visual systems have been a popular entry point into the brain, we don’t understand—in any deep sense—how visual perception guides navigation in flies (or any organism). I will present recent progress towards this goal from our lab. We are using anatomical insights from connectomics, genetic methods for labelling and manipulating identified cell types, neurophysiology, behaviour, and computational modeling to explain how the fly brain processes visual motion to regulate behaviour.
Vision in dynamically changing environments
Many visual systems can process information in dynamically changing environments. In general, visual perception scales with changes in the visual stimulus, or contrast, irrespective of background illumination. This is achieved by adaptation. However, visual perception is challenged when adaptation is not fast enough to deal with sudden changes in overall illumination, for example when gaze follows a moving object from bright sunlight into a shaded area. We have recently shown that the visual system of the fly found a solution by propagating a corrective luminance-sensitive signal to higher processing stages. Using in vivo two-photon imaging and behavioural analyses we showed that distinct OFF-pathway inputs encode contrast and luminance. The luminance-sensitive pathway is particularly required when processing visual motion in contextual dim light, when pure contrast sensitivity underestimates the salience of a stimulus. Recent work in the lab has addressed the question how two visual pathways obtain such fundamentally different sensitivities, given common photoreceptor input. We are furthermore currently working out the network-based strategies by which luminance- and contrast-sensitive signals are combined to guide appropriate visual behaviour. Together, I will discuss the molecular, cellular, and circuit mechanisms that ensure contrast computation, and therefore robust vision, in fast changing visual scenes.
Neural mechanisms of proprioception and motor control in Drosophila
Animals rely on an internal sense of body position and movement to effectively control motor behaviour. This sense of proprioception is mediated by diverse populations of internal mechanosensory neurons distributed throughout the body. My lab is trying to understand how proprioceptive stimuli are detected by sensory neurons, integrated and transformed in central circuits, and used to guide motor output. We approach these questions using genetic tools, in vivo two-photon imaging, and patch-clamp electrophysiology in Drosophila. We recently found that the axons of fly leg proprioceptors are organized into distinct functional projections that contain topographic representations of specific kinematic features: one group of axons encodes tibia position, another encodes movement direction, and a third encodes bidirectional movement and vibration frequency. Whole-cell recordings from downstream neurons reveal that position, movement, and directional information remain segregated in central circuits. These feedback signals then converge upon motor neurons that control leg muscles during walking. Overall, our findings reveal how a low-dimensional stimulus – the angle of a single leg joint – is encoded by a diverse population of mechanosensory neurons. Specific proprioceptive parameters are initially processed by parallel pathways, but are ultimately integrated to influence motor output. This architecture may help to maximize information transmission, processing speed, and robustness, which are critical for feedback control of the limbs during adaptive locomotion.
Multi-layer network learning in an electric fish
The electrosensory lobe (ELL) in mormyrid electric fish is a cerebellar-like structure that cancels the sensory effects of self-generated electric fields, allowing prey to be detected. Like the cerebellum, the ELL involves two stages of processing, analogous to the Purkinje cells and cells of the deep cerebellar nuclei. Through the work of Curtis Bell and others, a model was previously developed to describe the output stage of the ELL, but the role of the Purkinje-cell analogs, the medium ganglion (MG) cells, in the circuit had remained mysterious. I will present a complete, multi-layer circuit description of the ELL, developed in collaboration with Nate Sawtell and Salomon Muller, that reveals a novel role for the MG cells. The resulting model provides an example of how a biological system solves well-known problems associated with learning in multi-layer networks, and it reveals that ELL circuitry is organization on the basis of learning rather than by the response properties of neurons.
Algorithms and circuits for olfactory navigation in walking Drosophila
Olfactory navigation provides a tractable model for studying the circuit basis of sensori-motor transformations and goal-directed behaviour. Macroscopic organisms typically navigate in odor plumes that provide a noisy and uncertain signal about the location of an odor source. Work in many species has suggested that animals accomplish this task by combining temporal processing of dynamic odor information with an estimate of wind direction. Our lab has been using adult walking Drosophila to understand both the computational algorithms and the neural circuits that support navigation in a plume of attractive food odor. We developed a high-throughput paradigm to study behavioural responses to temporally-controlled odor and wind stimuli. Using this paradigm we found that flies respond to a food odor (apple cider vinegar) with two behaviours: during the odor they run upwind, while after odor loss they perform a local search. A simple computational model based one these two responses is sufficient to replicate many aspects of fly behaviour in a natural turbulent plume. In on-going work, we are seeking to identify the neural circuits and biophysical mechanisms that perform the computations delineated by our model. Using electrophysiology, we have identified mechanosensory neurons that compute wind direction from movements of the two antennae and central mechanosensory neurons that encode wind direction are are involved in generating a stable downwind orientation. Using optogenetic activation, we have traced olfactory circuits capable of evoking upwind orientation and offset search from the periphery, through the mushroom body and lateral horn, to the central complex. Finally, we have used optogenetic activation, in combination with molecular manipulation of specific synapses, to localize temporal computations performed on the odor signal to olfactory transduction and transmission at specific synapses. Our work illustrates how the tools available in fruit fly can be applied to dissect the mechanisms underlying a complex goal-directed behaviour.
Cell Fate Determination in the Retina
The Cepko lab investigates the mechanisms that direct development of the central nervous system (CNS) of vertebrates, with a focus on the retina. These studies have revealed that the retina has distinct types of progenitor cells that are biased, or committed, to produce distinct types of daughter cells in terminal divisions. The gene regulatory networks that underlie these cell fate choices are being studied by analysis of both gene function and cis-regulatory networks. New methods that enable these studies have been developed, including high throughput enhancer assays and quantitative, inexpensive and sensitive multiplex in situ hybridization methods.
Computation Within and Beyond the Brain - Uncovering Brain-Body-Wide Communication Networks through Imaging Cellular Activity of All Cells in a Vertebrate
COSYNE 2025
Rapid predator learning in a developing vertebrate brain
COSYNE 2025
Thalamocortical-like circuits transform and integrate sensory information in the early vertebrate forebrain.
COSYNE 2025
Comparative analysis of the molecular, spatial, and functional domains of vertebrate habenula
FENS Forum 2024
Decoding transcriptional regulation in response to sunlight in vertebrates: Circadian clocks and beyond
FENS Forum 2024
Effects of alprazolam on anxiety-related behavior in an invertebrate model: Advancing translational neuroscience
FENS Forum 2024
Exploring gaze movements in lampreys: Insights into vertebrate neural mechanisms for stabilizing and goal-oriented eye movements
FENS Forum 2024
Histological, cellular, and molecular changes induced by chronic exposure to the (neuro)endocrine disruptor tributyltin in a widely used invertebrate model species
FENS Forum 2024
Locomotor maturation during early development in a small vertebrate
FENS Forum 2024
Single-cell volumetric transcriptomic atlas of the adult zebrafish forebrain reveals teleost homologues of cortical and subcortical structures from terrestrial vertebrates
FENS Forum 2024