Neurotrophins (NGF, BDNF, NT-3) are endogenous growth factors that exert neuroprotective effects by preventing neuronal death and promoting neurogenesis. They act by binding to their respective high-affinity, pro-survival receptors TrkA, TrkB or TrkC, as well as to p75NTR death receptor. While these molecules have been shown to significantly slow or prevent neurodegeneration, their reduced bioavailability and inability to penetrate the blood-brain-barrier limit their use as potential therapeutics. To bypass these limitations, our research team has developed and patented small-sized, lipophilic compounds which selectively resemble neurotrophins’ effects, presenting preferable pharmacological properties and promoting neuroprotection and repair against neurodegeneration. In addition, the combination of these molecules with 3D cultured human neuronal cells, and their targeted delivery in the brain ventricles through soft robotic systems, could offer novel therapeutic approaches against neurodegenerative diseases and brain trauma.

Subsecond timing underlies nearly all sensory and motor activities across species and is critical to survival. While subsecond temporal information has been found across cortical and subcortical regions, it is unclear if it is generated locally and intrinsically or if it is a read out of a centralized clock-like mechanism. Indeed, mechanisms of subsecond timing at the circuit level are largely obscure. Primary sensory areas are well-suited to address these question as they have early access to sensory information and provide minimal processing to it: if temporal information is found in these regions, it is likely to be generated intrinsically and locally. We test this hypothesis by training mice to perform an audio-visual temporal pattern sensory discrimination task as we use 2-photon calcium imaging, a technique capable of recording population level activity at single cell resolution, to record activity in primary visual cortex (V1). We have found significant changes in network dynamics through mice’s learning of the task from naive to middle to expert levels. Changes in network dynamics and behavioral performance are well accounted for by an intrinsic model of timing in which the trajectory of q network through high dimensional state space represents temporal sensory information. Conversely, while we found evidence of other temporal encoding models, such as oscillatory activity, we did not find that they accounted for increased performance but were in fact correlated with the intrinsic model itself. These results provide insight into how subsecond temporal information is encoded mechanistically at the circuit level.

Detecting the direction of image motion is important for visual navigation, predator avoidance and prey capture, and thus essential for the survival of all animals that have eyes. However, the direction of motion is not explicitly represented at the level of the photoreceptors: it rather needs to be computed by subsequent neural circuits, involving a comparison of the signals from neighboring photoreceptors over time. The exact nature of this process represents a classic example of neural computation and has been a longstanding question in the field. Much progress has been made in recent years in the fruit fly Drosophila melanogaster by genetically targeting individual neuron types to block, activate or record from them. Our results obtained this way demonstrate that the local direction of motion is computed in two parallel ON and OFF pathways. Within each pathway, a retinotopic array of four direction-selective T4 (ON) and T5 (OFF) cells represents the four Cartesian components of local motion vectors (leftward, rightward, upward, downward). Since none of the presynaptic neurons is directionally selective, direction selectivity first emerges within T4 and T5 cells. Our present research focuses on the cellular and biophysical mechanisms by which the direction of image motion is computed in these neurons.

Precisely estimating event timing is essential for survival, yet temporal distortions are ubiquitous in our daily sensory experience. Here, we tested whether the relative position, duration, and distance in time of two sequentially-organized events—standard S, with constant duration, and comparison C, with duration varying trial-by-trial—are causal factors in generating temporal distortions. We found that temporal distortions emerge when the first event is shorter than the second event. Importantly, a significant interaction suggests that a longer inter-stimulus interval (ISI) helps to counteract such serial distortion effect only when the constant S is in the first position, but not if the unpredictable C is in the first position. These results imply the existence of a perceptual bias in perceiving ordered event durations, mechanistically contributing to distortion in time perception. Our results clarify the mechanisms generating time distortions by identifying a hitherto unknown duration-dependent encoding inefficiency in human serial temporal perception, something akin to a strong prior that can be overridden for highly predictable sensory events but unfolds for unpredictable ones.

The transit of food through the gastrointestinal tract is critical for nutrient absorption and survival, and the gastrointestinal tract has the ability to initiate motility reflexes triggered by luminal distention. This complex function depends on the crosstalk between extrinsic and intrinsic neuronal innervation within the intestine, as well as local specialized enteroendocrine cells. However, the molecular mechanisms and the subset of sensory neurons underlying the initiation and regulation of intestinal motility remain largely unknown. Here, we show that humans lacking PIEZO2 exhibit impaired bowel sensation and motility. Piezo2 in mouse dorsal root but not nodose ganglia is required to sense gut content, and this activity slows down food transit rates in the stomach, small intestine, and colon. Indeed, Piezo2 is directly required to detect colon distension in vivo. Our study unveils the mechanosensory mechanisms that regulate the transit of luminal contents throughout the gut, which is a critical process to ensure proper digestion, nutrient absorption, and waste removal. These findings set the foundation of future work to identify the highly regulated interactions between sensory neurons, enteric neurons and non- neuronal cells that control gastrointestinal motility.

Detecting the direction of image motion is important for visual navigation, predator avoidance and prey capture, and thus essential for the survival of all animals that have eyes. However, the direction of motion is not explicitly represented at the level of the photoreceptors: it rather needs to be computed by subsequent neural circuits. The exact nature of this process represents a classic example of neural computation and has been a longstanding question in the field. Our results obtained in the fruit fly Drosophila demonstrate that the local direction of motion is computed in two parallel ON and OFF pathways. Within each pathway, a retinotopic array of four direction-selective T4 (ON) and T5 (OFF) cells represents the four Cartesian components of local motion vectors (leftward, rightward, upward, downward). Since none of the presynaptic neurons is directionally selective, direction selectivity first emerges within T4 and T5 cells. Our present research focuses on the cellular and biophysical mechanisms by which the direction of image motion is computed in these neurons.

Pediatric high-grade gliomas (pHGG) are a devastating group of diseases that urgently require novel therapeutic options. We have previously demonstrated that pHGGs directly synapse onto neurons and the subsequent tumor cell depolarization, mediated by calcium-permeable AMPA channels, promotes their proliferation. The regulatory mechanisms governing these postsynaptic connections are unknown. Here, we investigated the role of BDNF-TrkB signaling in modulating the plasticity of the malignant synapse. BDNF ligand activation of its canonical receptor, TrkB (which is encoded for by the gene NTRK2), has been shown to be one important modulator of synaptic regulation in the normal setting. Electrophysiological recordings of glioma cell membrane properties, in response to acute neurotransmitter stimulation, demonstrate in an inward current resembling AMPA receptor (AMPAR) mediated excitatory neurotransmission. Extracellular BDNF increases the amplitude of this glutamate-induced tumor cell depolarization and this effect is abrogated in NTRK2 knockout glioma cells. Upon examining tumor cell excitability using in situ calcium imaging, we found that BDNF increases the intensity of glutamate-evoked calcium transients in GCaMP6s expressing glioma cells. Western blot analysis indicates the tumors AMPAR properties are altered downstream of BDNF induced TrkB activation in glioma. Cell membrane protein capture (via biotinylation) and live imaging of pH sensitive GFP-tagged AMPAR subunits demonstrate an increase of calcium permeable channels at the tumors postsynaptic membrane in response to BDNF. We find that BDNF-TrkB signaling promotes neuron-to-glioma synaptogenesis as measured by high-resolution confocal and electron microscopy in culture and tumor xenografts. Our analysis of published pHGG transcriptomic datasets, together with brain slice conditioned medium experiments in culture, indicates the tumor microenvironment as the chief source of BDNF ligand. Disruption of the BDNF-TrkB pathway in patient-derived orthotopic glioma xenograft models, both genetically and pharmacologically, results in an increased overall survival and reduced tumor proliferation rate. These findings suggest that gliomas leverage normal mechanisms of plasticity to modulate the excitatory channels involved in synaptic neurotransmission and they reveal the potential to target the regulatory components of glioma circuit dynamics as a therapeutic strategy for these lethal cancers.

If the mind controls the brain, then there is free will and its corollaries, dignity and responsibility. You are king in your skull-sized kingdom and the architect of your destiny. If, on the other hand, the brain controls the mind, an incendiary conclusion follows: There can be no free will, no praise, no punishment and no purgatory. In this webinar, Professor George Paxinos will discuss his highly respected work on the construction of human and experimental animal brain atlases. He has discovered 94 brain regions, 64 homologies and published 58 books. His first book, The Rat Brain in Stereotaxic Coordinates, is the most cited publication in neuroscience and, for three decades, the third most cited book in science. Professor Paxinos will also present his recently published novel, A River Divided, which was 21 years in the making. Neuroscience principles were used in the formation of charters, such as those related to the mind, soul, free will and consciousness. Environmental issues are at the heart of the novel, including the question of whether the brain is the right ‘size’ for survival. Professor Paxinos studied at Berkeley, McGill and Yale and is now Scientia Professor of Medical Sciences at Neuroscience Research Australia and The University of New South Wales in Sydney.

Discriminating distinct objects and concepts from sensory stimuli is essential for survival. Our brains accomplish this feat by forming meaningful internal representations in deep sensory networks with plastic synaptic connections. Experience-dependent plasticity presumably exploits temporal contingencies between sensory inputs to build these internal representations. However, the precise mechanisms underlying plasticity remain elusive. We derive a local synaptic plasticity model inspired by self-supervised machine learning techniques that shares a deep conceptual connection to Bienenstock-Cooper-Munro (BCM) theory and is consistent with experimentally observed plasticity rules. We show that our plasticity model yields disentangled object representations in deep neural networks without the need for supervision and implausible negative examples. In response to altered visual experience, our model qualitatively captures neuronal selectivity changes observed in the monkey inferotemporal cortex in-vivo. Our work suggests a plausible learning rule to drive learning in sensory networks while making concrete testable predictions.

Bioluminescence, which is rare on land, is extremely common in the deep sea, being found in 80% of the animals living between 200 and 1000 m. These animals rely on bioluminescence for communication, feeding, and/or defense, so the generation and detection of light is essential to their survival. Our present knowledge of this phenomenon has been limited due to the difficulty in bringing up live deep-sea animals to the surface, and the lack of proper techniques needed to study this complex system. However, new genomic techniques are now available, and a team with extensive experience in deep-sea biology, vision, and genomics has been assembled to lead this project. This project is aimed to study three questions 1) What are the evolutionary patterns of different types of bioluminescence in deep-sea shrimp? 2) How are deep-sea organisms’ eyes adapted to detect bioluminescence? 3) Can bioluminescent organs (called photophores) detect light in addition to emitting light? Findings from this study will provide valuable insight into a complex system vital to communication, defense, camouflage, and species recognition. This study will bring monumental contributions to the fields of deep sea and evolutionary biology, and immediately improve our understanding of bioluminescence and light detection in the marine environment. In addition to scientific advancement, this project will reach K-college aged students through the development and dissemination of educational tools, a series of molecular and organismal-based workshops, museum exhibits, public seminars, and biodiversity initiatives.

Learning is known to induce the formation of new dendritic spines, but despite decades of effort, the functional properties of new spines in vivo remain unknown. Here, using a combination of longitudinal in vivo 2-photon imaging of the glutamate reporter, iGluSnFR, and correlated electron microscopy (CLEM) of dendritic spines on the apical dendrites of L2/3 excitatory neurons in the motor cortex during motor learning, we describe a framework of new spines' formation, survival, and resulting function. Specifically, our data indicate that the potentiation of a subset of clustered, pre-existing spines showing task-related activity in early sessions of learning creates a micro-environment of plasticity within dendrites, wherein multiple filopodia sample the nearby neuropil, form connections with pre-existing boutons connected to allodendritic spines, and are then selected for survival based on co-activity with nearby task-related spines. Thus, the formation and survival of new spines is determined by the functional micro-environment of dendrites. After formation, new spines show preferential co-activation with nearby task-related spines. This synchronous activity is more specific to movements than activation of the individual spines in isolation, and further, is coincident with movements that are more similar to the learned pattern. Thus, new spines functionally engage with their parent clusters to signal the learned movement. Finally, by reconstructing the axons associated with new spines, we found that they synapse with axons previously unrepresented in these dendritic domains, suggesting that the strong local co-activity structure exhibited by new spines is likely not due to axon sharing. Thus, learning involves the binding of new information streams into functional synaptic clusters to subserve the learned behavior.

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.

Conventionally, neurons are thought to be cellular units that process synaptic inputs into synaptic spikes. However, it is well known that neurons can also spike spontaneously and display a rich repertoire of firing properties with no apparent functional relevance e.g. in in vitro cortical slice preparations. In this talk, I will propose a hypothesis according to which intrinsic excitability in neurons may be a survival mechanism to minimize toxic byproducts of the cell’s energy metabolism. In neurons, this toxicity can arise when mitochondrial ATP production stalls due to limited ADP. Under these conditions, electrons deviate from the electron transport chain to produce reactive oxygen species, disrupting many cellular processes and challenging cell survival. To mitigate this, neurons may engage in ADP-producing metabolic spikes. I will explore the validity of this hypothesis using computational models that illustrate the implications of synaptic and metabolic spiking, especially in the context of substantia nigra pars compacta dopaminergic neurons and their degeneration in Parkinson's disease.

Survival is predicated on the ability of an organism to respond to stress. The reliability of this response is ensured by a synaptic architecture that is relatively inflexible (i.e. hard-wired). Our work has shown that in naive animals, synapses on CRH neurons in the paraventricular nucleus of the hypothalamus are very reluctant to modification. If animals are stressed, however, these synapses become willing to learn. This seminar will focus on mechanisms linking acute stress to metaplastic changes at glutamate synapses, and also show how stress, and these synaptic changes can be transmitted from one individual to another.

In this talk I will discuss our recent findings that sensory signals from the brain adjust the physiology and behavior of the nematode C. elegans, enabling this animal to deal with the lethal threat of hydrogen peroxide. Hydrogen peroxide (H2O2) is the most common chemical threat in the microbial battlefield. Prevention and repair of the damage that hydrogen peroxide inflicts on macromolecules are critical for health and survival. In the first part of the talk, I will discuss our findings that C. elegans represses their own H2O2 defenses in response to sensory perception of Escherichia coli, the nematode’s food source, because E. coli can deplete H2O2 from the local environment and thereby protect the nematodes. Thus, the E. coli self-defense mechanisms create a public good, an environment safe from the threat of H2O2, that benefits C. elegans. In the second part of the talk, I will discuss how the modulation of C. elegans’ sensory perception by the interplay of hydrogen peroxide and bacteria adjusts the nematode’s behavior to improve the nematode’s chances of finding a niche that provides both food and protection from hydrogen peroxide.

Activation of pro-degenerative protein SARM1 in response to diverse physical and disease-relevant injuries triggers programmed axon death. Original studies indicated substantially decreased levels of SARM1 were required for neuroprotection. However, we demonstrate that lowering SARM1 levels by 50% in Sarm1 haploinsufficient mice delays axon degeneration in vivo (after sciatic nerve transection), in vitro (in response to diverse traumatic, neurotoxic, and genetic triggers), and partially prevents neurite outgrowth defects in mice lacking pro-survival factor NMNAT2. We also demonstrate the capacity for Sarm1 antisense oligonucleotides to decrease SARM1 levels by more than 50% which delays or prevents programmed axon degeneration in vitro. Combining Sarm1 haploinsufficiency with antisense oligonucleotides further decreases SARM1 levels and prolongs protection after neurotoxic injuries. These data demonstrate that axon protection occurs in a Sarm1 gene-dose responsive manner and that SARM1 lowering agents have therapeutic potential. Thus, antisense oligonucleotide targeting of Sarm1 is a promising therapeutic strategy against diverse triggers of axon degeneration.

Microbes have shaped the evolution of eukaryotes and contribute significantly to the physiology and behavior of animals. Some of these traits are inherited by the progenies. Despite the vast importance of microbe-host communication, we still do not know how bacteria change short term traits or long-term decisions in individuals or communities. In this seminar I will present our work on how commensal and pathogenic bacteria impact specific neuronal phenotypes and decision making. The traits we specifically study are the degeneration and regeneration of neurons and survival behaviors in animals. We use the nematode Caenorhabditis elegans and its dietary bacteria as model organisms. Both nematode and bacteria are genetically tractable, simplifying the detection of specific molecules and their effect on measurable characteristics. To identify these molecules we analyze their genomes, transcriptomes and metabolomes, followed by functional in vivo validation. We found that specific bacterial RNAs and bacterially produced neurotransmitters are key to trigger a survival behavioral and neuronal protection respectively. While RNAs cause responses that lasts for many generations we are still investigating whether bacterial metabolites are capable of inducing long lasting phenotypic changes.

In an ever-changing environment, uncertainty is omnipresent. To deal with this, organisms have evolved mechanisms that allow them to take advantage of environmental regularities in order to make decisions robustly and adjust their behavior efficiently, thus maximizing their chances of survival. In this talk, I will present behavioral evidence that animals perform model-based state inference to predict environmental state changes and adjust their behavior rapidly, rather than slowly updating choice values. This model-based inference process can be described using Bayesian change-point models. Furthermore, I will show that neural populations in the prefrontal cortex accurately predict behavioral switches, and that the activity of these populations is associated with Bayesian estimates. In addition, we will see that learning leads to the emergence of a high-dimensional representational subspace that can be reused when the animals re-learn a previously learned set of action-value associations. Altogether, these findings highlight the role of the PFC in representing a belief about the current state of the world.

Many animals are highly visual. They view their world through photoreceptors sensitive to different wavelengths of light. Animal survival and optimal behavioral performance may select for varying photoreceptor sensitivities depending on animal habitat or visual tasks. Our goal is to understand what drives visual diversity from both an evolutionary and molecular perspective. The group of more than 2000 cichlid fish species are an ideal system for examining such diversity. Cichlid are a colorful group of fresh water fishes. They have undergone adaptive radiation throughout Africa and the new world and occur in rivers and lakes that vary in water clarity. They are also behaviorally complex, having diverse behaviors for foraging, mate choice and even parental care. As a result, cichlids have highly diverse visual systems with cone sensitivities shifting by 30-90 nm between species. Although this group has seven cone opsin genes, individual species differ in which subset of the cone opsins they express. Some species show developmental shifts in opsin expression, switching from shorter to longer wavelength opsins through ontogeny. Other species modify that developmental program to express just one of the sets, causing the large sensitivity differences. Cichlids are therefore natural mutants for opsin expression. We have used cichlid diversity to explore the relationship between visual sensitivities and ecology. We have also exploited the genomic power of the cichlid system to identify genes and mutations that cause opsin expression shifts. Ultimately, our goal is to learn how different cichlid species see the world and whether differences matter. Behavioral experiments suggest they do indeed use color vision to survive and thrive. Cichlids therefore are a unique model for exploring how visual systems evolve in a changing world.

Motivational drives are internal states that can be different even in similar interactions with external stimuli. Curiosity as the motivational drive for novelty-seeking and investigating the surrounding environment is for survival as essential and intrinsic as hunger. Curiosity, hunger, and appetitive aggression drive three different goal-directed behaviors—novelty seeking, food eating, and hunting— but these behaviors are composed of similar actions in animals. This similarity of actions has made it challenging to study novelty seeking and distinguish it from eating and hunting in nonarticulating animals. The brain mechanisms underlying this basic survival drive, curiosity, and novelty-seeking behavior have remained unclear. In spite of having well-developed techniques to study mouse brain circuits, there are many controversial and different results in the field of motivational behavior. This has left the functions of motivational brain regions such as the zona incerta (ZI) still uncertain. Not having a transparent, nonreinforced, and easily replicable paradigm is one of the main causes of this uncertainty. Therefore, we chose a simple solution to conduct our research: giving the mouse freedom to choose what it wants—double freeaccess choice. By examining mice in an experimental battery of object free-access double-choice (FADC) and social interaction tests—using optogenetics, chemogenetics, calcium fiber photometry, multichannel recording electrophysiology, and multicolor mRNA in situ hybridization—we uncovered a cell type–specific cortico-subcortical brain circuit of the curiosity and novelty-seeking behavior. We found in mice that inhibitory neurons in the medial ZI (ZIm) are essential for the decision to investigate an object or a conspecific. These neurons receive excitatory input from the prelimbic cortex to signal the initiation of exploration. This signal is modulated in the ZIm by the level of investigatory motivation. Increased activity in the ZIm instigates deep investigative action by inhibiting the periaqueductal gray region. A subpopulation of inhibitory ZIm neurons expressing tachykinin 1 (TAC1) modulates the investigatory behavior.

Detection of motion is essential for survival, but how the visual system processes moving stimuli is not fully understood. Here, based on a detailed analysis of glutamate release from bipolar cells, we outline the rules that govern the representation of object motion in the early processing stages. Our main findings are as follows: (1) Motion processing begins already at the first retinal synapse. (2) The shape and the amplitude of motion responses cannot be reliably predicted from bipolar cell responses to stationary objects. (3) Enhanced representation of novel objects - particularly in bipolar cells with transient dynamics. (4) Response amplitude in bipolar cells matches visual salience reported in humans: suddenly appearing objects > novel motion > existing motion. These findings can be explained by antagonistic interactions in the center-surround receptive field, demonstrate that despite their simple operational concepts, classical center-surround receptive fields enable sophisticated visual computations.

Organisms face challenges to survival throughout life. When we freeze or flee in danger, we often feel fear. Tracing the deep history of danger gives a different perspective. The first cells living billions of years ago had to detect and respond to danger in order to survive. Life is about not being dead, and behavior is a major way that organisms hold death off. Although behavior does not require a nervous system, complex organisms have brain circuits for detecting and responding to danger, the deep roots of which go back to the first cells. But these circuits do not make fear, and fear is not the cause of why we freeze or flee. Fear a human invention; a construct we use to account for what happens in our minds when we become aware that we are in harm’s way. This requires a brain that can personally know that it existed in the past, that it is the entity that might be harmed in the present, and that it will cease to exist it the future. If other animals have conscious experiences, they cannot have the kinds of conscious experiences we have because they do not have the kinds of brains we have. This is not meant as a denial of animal consciousness; it is simply a statement about the fact that every species has a different brain. Nor is it a declaration about the wonders of the human brain, since we have done some wonderful, but also horrific, things with our brains. In fact, we are on the way to a climatic disaster that will not, as some suggest, destroy the Earth. But it will make it inhabitable for our kind, and other organisms with high energy demands. Bacteria have made it for billions of years and will likely be fine. The rest is up for grabs, and, in a very real sense, up to us.

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

The nuclear envelope is a lipid bilayer that encases the genome and provides a physical boundary between the cytoplasm and the nucleoplasm. While the nucleus is typically depicted as a sphere encircled by a smooth surface of nuclear envelope, the smooth exterior can be interrupted by tubular invaginations of the nuclear envelope into the deep nuclear interior. Such structures are termed the "nucleoplasmic reticulum." Increased frequency of nuclear envelope invagination occurs in disease states including various cancers, viral infections, and laminopathies, a group of heterogeneous disorders that arise due to mutations in the gene encoding lamin A. A significant increase in the frequency of nuclear envelope invaginations in the human Alzheimer's disease brain has recently been reported. Nuclear envelope invaginations are caused by pathogenic tau, one of the two major pathological hallmarks of Alzheimer's disease. Pathogenic tau-induced dysfunction of the lamin nucleoskeleton drives nuclear envelope invagination and consequent accumulation of polyadenylated RNA within invaginations, both of which drive neuronal death. Our ongoing studies suggest that maintaining proper cytoskeletal, nucleoskeletal, and genomic architecture are critical for survival and function of adult neurons.

Odor memories are exceptionally robust and essential for the survival of many species. In rodents, the olfactory cortex shows features of an autoassociative memory network and plays a key role in the retrieval of olfactory memories (Meissner-Bernard et al., 2019). Interestingly, the telencephalic area Dp, the zebrafish homolog of olfactory cortex, transiently enters a state of precise balance during the presentation of an odor (Rupprecht and Friedrich, 2018). This state is characterized by large synaptic conductances (relative to the resting conductance) and by co-tuning of excitation and inhibition in odor space and in time at the level of individual neurons. Our aim is to understand how this precise synaptic balance affects memory function. For this purpose, we build a simplified, yet biologically plausible spiking neural network model of Dp using experimental observations as constraints: besides precise balance, key features of Dp dynamics include low firing rates, odor-specific population activity and a dominance of recurrent inputs from Dp neurons relative to afferent inputs from neurons in the olfactory bulb. To achieve co-tuning of excitation and inhibition, we introduce structured connectivity by increasing connection probabilities and/or strength among ensembles of excitatory and inhibitory neurons. These ensembles are therefore structural memories of activity patterns representing specific odors. They form functional inhibitory-stabilized subnetworks, as identified by the “paradoxical effect” signature (Tsodyks et al., 1997): inhibition of inhibitory “memory” neurons leads to an increase of their activity. We investigate the benefits of co-tuning for olfactory and memory processing, by comparing inhibitory-stabilized networks with and without co-tuning. We find that co-tuned excitation and inhibition improves robustness to noise, pattern completion and pattern separation. In other words, retrieval of stored information from partial or degraded sensory inputs is enhanced, which is relevant in light of the instability of the olfactory environment. Furthermore, in co-tuned networks, odor-evoked activation of stored patterns does not persist after removal of the stimulus and may therefore subserve fast pattern classification. These findings provide valuable insights into the computations performed by the olfactory cortex, and into general effects of balanced state dynamics in associative memory networks.

It has generally been presumed that sensory information encoded by a nervous system should be as accurate as its biological limitations allow. However, perhaps counter intuitively, accurate representations of sensory signals do not necessarily maximize the organism’s chances of survival. We show that neural codes that maximize reward expectation—and not accurate sensory representations—account for retinal responses in insects, and retinotopically-specific adaptive codes in humans. Thus, our results provide evidence that fitness-maximizing rules imposed by the environment are applied at the earliest stages of sensory processing.

Constipation is a common but not a universal feature in early PD, suggesting that gut involvement is heterogeneous and may be part of a distinct PD subtype with prognostic implications. We analysed data from the Parkinson’s Incidence Cohorts Collaboration, composed of incident community-based cohorts of PD patients assessed longitudinally over 8 years. Constipation was assessed with the MDS-UPDRS constipation item or a comparable categorical scale. Primary PD outcomes of interest were dementia, postural instability and death. PD patients were stratified according to constipation severity at diagnosis: none (n=313, 67.3%), minor (n=97, 20.9%) and major (n=55, 11.8%). Clinical progression to all 3 outcomes was more rapid in those with more severe constipation at baseline (Kaplan Meier survival analysis). Cox regression analysis, adjusting for relevant confounders, confirmed a significant relationship between constipation severity and progression to dementia, but not postural instability or death. Early constipation may predict an accelerated progression of neurodegenerative pathology. Conclusions: We show widespread cortical and subcortical grey matter micro-structure associations with schizophrenia PRS. Across all investigated phenotypes NDI, a measure of the density of myelinated axons and dendrites, showed the most robust associations with schizophrenia PRS. We interpret these results as indicative of reduced density of myelinated axons and dendritic arborization in large-scale cortico-subcortical networks mediating the genetic risk for schizophrenia.

If only those behaviours evolve that increase the actor’s own survival and reproductive success, then it might come as a surprise that cooperative behaviours, i.e. providing benefits to others, are a widespread phenomenon. Many animals cooperate even with unrelated individuals in various contexts, like providing care or food. One possibility to explain these behaviours is reciprocity. Reciprocal cooperation, i.e. helping those that were helpful before, is a ubiquitous and important trait of human sociality. Still, the evolutionary origin of it is largely unclear, mainly because it is believed that other animals do not exchange help reciprocally. Consequently, reciprocity is suggested to have evolved in the human lineage only. In contrast to this, I propose that reciprocity is not necessarily cognitively demanding and likely to be widespread. In my talk, I will first shed light on the mechanisms of reciprocal cooperation in Norway rats (Rattus norvegicus). In a series of studies, my colleagues and I have demonstrated that Norway rats reciprocally exchange goods and services between and within different commodities and independent of kinship. Furthermore, to understand the evolutionary origins of human reciprocity, and whether it is shared with other animals, I will then discuss evidence for reciprocity in non-human primates, which are our closest living relatives. A thorough analysis of the findings showed that reciprocity is present and, for example, not confined to unrelated individuals, but that the choice of commodities can impact the likelihood of reciprocation. Based on my findings, I conclude that reciprocal cooperation in non-human animals is present but largely neglected and not restricted to humans. In order to deepen our understanding of the evolutionary origins of reciprocity in more general, future studies should investigate when and how reciprocity in non-human animals emerged and how it is maintained.

My lab is focused on how brain encodes and modulates social interactions. Intraspecific social interactions are integral for survival and maintenance of society among all mammalian species. Despite the importance of social interactions, we lack a complete understanding of the brain circuitry involved in processing social behaviour. My lab investigates how the hypothalamic orexin (hypocretin) neurons and their downstream circuits participate in social interaction behaviours. These neurons are located exclusively in the hypothalamus that regulates complex and goal-directed behaviours. We recently identified that orexin neurons differentially encode interaction between familiar and novel animals. We are currently investigating how chronic social isolation, a risk factor for the development of social-anxiety like behaviours, affects orexin neuron activity and how we can manipulate the activity of these neurons to mitigate isolation-induced social deficits.

For social animals, successfully communicating with others is essential for interactions and survival. My research aims to answer a central question on the neuronal basis of this ability, from the perspective of the listener: how do our brains enable us to communicate with each other? My work develops nonhuman animal models to study the behavioural and neuronal mechanisms underlying the perception of vocal patterns. I will start by providing an overview of my past research characterizing the neuronal-level substrates of voice processing along the primate temporal lobe. I will then focus on my current work on vocal perception in mice, in which I utilize natural male-female courtship behaviour to evaluate the acoustic dimensions extracted by listeners from ultrasonic sequences. I will then talk about ongoing work investigating the neuronal substrates supporting the perception of behaviourally relevant acoustic cues from mouse vocal sequences.

Maternal care is profoundly important for mammalian survival, and in many species requires the contribution of non-biological parents, or alloparents. In the absence of partum and post-partum related hormonal changes, alloparents acquire maternal skills from experience, by yet unknown mechanisms. One critical molecular signal for maternal behavior is oxytocin, a hormone centrally released by hypothalamic paraventricular nucleus (PVN). Do experiences that induce maternal behavior act by engaging PVN oxytocin neurons? To answer this, we used virgin female mice, animals that in the wild live in colonies with experienced mothers and their pups, helping with pup care. We replicated this setup in the lab, and we continuously monitored homecage behavior of virgin mice co-housed for days with a mother and litter, synchronized with recordings from virgin PVN cells, including from oxytocin neurons. Mothers engaged virgins in maternal care in part by shepherding virgins towards the nest, ensuring their proximity to pups, and in part by self-generating pup retrieval episodes, demonstrating maternal behavior to virgins. The frequency of shepherding and of dam retrievals correlates with virgin's subsequent ability to retrieve pups, a quintessential mouse maternal skill. These social interactions activated virgin PVN and gated behaviorally-relevant cortical plasticity for pup vocalizations. Thus, rodents can acquire maternal behavior by social transmission, and our results describe a mechanism for adapting brains of adult caregivers to infant needs via endogenous oxytocin.

Axons degenerate before the neuronal soma in many neurodegenerative diseases. Programmed axon death (Wallerian degeneration) is a widely-occurring mechanism of axon loss that is well understood and preventable in animals. Its aberrant activation by mutation of the pro-survival gene Nmnat2 directly causes axonopathy in mice with severity ranging from mild polyneuropathy to perinatal lethality. Rare biallelic mutations in the homologous human gene cause related phenotypes in patients. NMNAT2 is a negative regulator of the prodegenerative NADase SARM1. Constitutive activation of SARM1 is cytotoxic and the human SARM1 locus is significantly associated with sporadic ALS. Another negative regulator, STMN2, has also been implicated in ALS, where it is commonly depleted downstream of TDP-43. In mice, programmed axon death can be robustly blocked by deletion of Sarm1, or by overexpression, axonal targeting and/or stabilization of various NMNAT isoforms. This alleviates models of many human disorders including some forms of peripheral neuropathy, motor neuron diseases, glaucoma, Parkinson’s disease and traumatic brain injury, and it confers lifelong rescue on the lethal Nmnat2 null phenotype and other conditions. Drug discovery programs now aim to achieve similar outcomes in human disease. In order to optimize the use of such drugs, we have characterized a range of human NMNAT2 and SARM1 functional variants that underlie a spectrum of axon vulnerability in the human population. Individuals at the vulnerable end of this spectrum are those most likely to benefit from drugs blocking programmed axon death, and disorders associated with these genotypes are promising indications in which to apply them.

Human genes associated with brain-related diseases are being discovered at an accelerating pace. A major challenge is an identification of the mechanisms through which these genes act, and of potential therapeutic strategies. To elucidate such mechanisms in human cells, we established a CRISPR-based platform for genetic screening in human iPSC-derived neurons, astrocytes and microglia. Our approach relies on CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa), in which a catalytically dead version of the bacterial Cas9 protein recruits transcriptional repressors or activators, respectively, to endogenous genes to control their expression, as directed by a small guide RNA (sgRNA). Complex libraries of sgRNAs enable us to conduct genome-wide or focused loss-of-function and gain-of-function screens. Such screens uncover molecular players for phenotypes based on survival, stress resistance, fluorescent phenotypes, high-content imaging and single-cell RNA-Seq. To uncover disease mechanisms and therapeutic targets, we are conducting genetic modifier screens for disease-relevant cellular phenotypes in patient-derived neurons and glia with familial mutations and isogenic controls. In a genome-wide screen, we have uncovered genes that modulate the formation of disease-associated aggregates of tau in neurons with a tauopathy-linked mutation (MAPT V337M). CRISPRi/a can also be used to model and functionally evaluate disease-associated changes in gene expression, such as those caused by eQTLs, haploinsufficiency, or disease states of brain cells. We will discuss an application to Alzheimer’s Disease-associated genes in microglia.

Olfactory navigation is essential for the survival of living beings from unicellular organisms to mammals. In the wild, rodents combine odor information with an internal spatial representation of the environment for foraging and navigation. What are the neural circuits in the brain that implement these behaviours? My research addresses this question by examining the synaptic circuits and neural population activity in the olfactory cortex to understand the integration of olfactory and spatial information. Primary olfactory (piriform) cortex (PCx) has long been recognized as a highly associative brain structure. What is the behavioural and functional role of these associative synapses in PCx? We designed an odor-cued navigation task, where rats must use both olfactory and spatial information to obtain water rewards. We recorded from populations of posterior piriform cortex (pPCx) neurons during behaviour and found that individual neurons were not only odor-selective, but also fired differentially to the same odor sampled at different locations, forming an “olfactory place map”. Spatial locations can be decoded from simultaneously recorded pPCx population, and spatial selectivity is maintained in the absence of odors, across behavioural contexts. This novel olfactory place map is consistent with our finding for a dominant role of associative excitatory synapses in shaping PCx representations, and suggest a role for PCx spatial representations in supporting olfactory navigation. This work not only provides insight into the neural basis for how odors can be used for navigation, but also reveals PCx as a prime site for addressing the general question of how sensory information is anchored within memory systems and combined with cognitive maps to guide flexible behaviour.