Nikolas Karalis

We are seeking a passionate and dedicated research technician to join our team Neuronal Circuits & Brain Dynamics at the Paris Brain Institute (ICM). Our work focuses on unraveling the fascinating mysteries of how the brain generates internal states and how neuromodulators, such as dopamine and serotonin, influence neuronal activity during behavior. To achieve our goals, we employ state-of-the-art techniques, including behavioral, optogenetic, imaging, electrophysiological, and genetic approaches in mice. Main Responsibilities • As a research technician, you are at the epicenter of our research activities and you will serve as a point of reference of the lab know-how across generations of lab members. • As a hands-on research technician, your primary responsibilities will include organizing the laboratory, maintaining basic lab infrastructure, performing routine tasks, regularly updating lab databases, ensuring the lab runs efficiently, and contributing to the team's research efforts. • Collaborating closely with the team, you will contribute to ongoing research projects and you will conduct behavioral and optogenetic experiments, carry out stereotaxic surgeries, and handle histological processing, including tissue slicing, immunostaining, and fluorescent microscopy. • You will be responsible for learning, developing, and passing on Standard Operating Procedures (SOPs) for the techniques utilized in our lab. • Additionally, in coordination with the head of the animal facility, you will supervise and ensure adherence to animal welfare guidelines, as well as maintain project permits and annual reports. • This role provides the opportunity to lead and participate in research projects to the extent of your desire. We offer competitive compensation and benefits within an interactive, interdisciplinary working environment, where cutting-edge science thrives and a dynamic, international research community awaits. As part of your role, you will receive extensive training in traditional and cutting-edge neuroscience techniques related to mice. If you are eager to join our vibrant research community and contribute to groundbreaking discoveries, we warmly welcome your application. The position is available immediately, with the potential for a permanent contract based on performance. If you would like to know more, visit our website: neuronaldynamics.eu and read about our team's mission and values. Why join our team • We are a young and vibrant group of scientists, fueled by curiosity and passion for understanding the brain. • We work as a team and use or invent cutting-edge neurotechnologies to answer fundamental questions in neuroscience. • Our team is committed to the training, mentorship, and career development of the next generation of neuroscientists. To achieve that, we foster an inclusive and supportive environment, where we can learn and advance science while having fun in the process. • Our work is multi-disciplinary, and so is our team. Irrespective of your background and project, our research environment will expose you to a diverse range of experimental and computational aspects of systems and circuits neuroscience. We thus encourage everyone to apply, especially those from underrepresented minorities. • Our team is affiliated with Inserm and is located in the Paris Brain Institute (ICM), where we have access to state-of-the-art facilities and resources. • Our vibrant community at the ICM and throughout Paris promotes broad collaboration and learning opportunities. <b>How to apply</b> If you are eager to join our vibrant research community and contribute to groundbreaking discoveries, we warmly welcome your application. The position is available immediately, with the potential for a permanent contract based on performance. Please send a statement of your past work and interests, your CV, and contact information for 1-3 references to the address: contact@neuronaldynamics.eu

Nikolas Karalis

We invite applications for postdoctoral researchers to join our team Neuronal Circuits & Brain Dynamics at the Paris Brain Institute (ICM) to study the principles of neuronal circuit organization and brain dynamics. If you are an ambitious and driven researcher, interested in experimental or computational systems and circuits neuroscience, and seeking an environment that fosters intellectual and professional growth, we invite you to consider joining our team. Together, we'll make a lasting impact on science and pave the way for your successful research career. Our team values diversity and welcomes researchers from all backgrounds and profiles. If your project ideas align with our research focus, we encourage you to get in touch with us. Research Topics We are interested in how neuronal circuits are organized and how the collective action of neurons gives rise to the emergent complex brain dynamics and behavior. We focus on how neurochemicals and bodily signals influence the brain. * We study how the simultaneous release of neuromodulators influences the activity of neurons and the coordination of brain regions * We also study how bodily signals, such as breathing, serve as fundamental elements of the oscillatory circuit architecture * We employ our approach to study the brain dynamics during behavior and sleep and their involvement in the transformation of fleeting experiences into long-term memories To answer these fundamental questions about the nature and function of the brain, we combine a range of cutting-edge neurotechnologies that enable us to observe and control the activity of the brain. We aim to identify and explore the fundamental principles of neural circuit organization and apply our understanding for the improvement of the human condition. Pure experimental, as well as computational/theoretical, or hybrid projects are available, depending on your interest and skills. Opportunities As a postdoctoral researcher in our group: • You will be an integral part of shaping our research direction and team culture. You will engage in exciting and meaningful research and will have access to all the tools necessary to push the boundaries of scientific exploration, with our cutting-edge techniques and state-of-the-art facilities. • You will have the opportunity to mentor graduate and master's students. This role enhances your leadership and communication skills while you contribute to the growth of the next generation of scientists. By guiding and collaborating with these aspiring researchers, you contribute to the collective knowledge and expertise of the team. Mentoring fosters a supportive and enriching atmosphere that reduces the mental strain of working alone on a project, as you can share ideas, problem-solve together, and gain fresh perspectives. • You will have ample opportunities to develop vital skills for your future academic career, such as mentoring, grant writing, presenting your work, publishing papers, and leading projects to completion. In parallel, you will gain invaluable first-hand experience in setting up and managing a young research team. • We encourage participation in conferences and workshops, where you can present your research findings to the wider scientific community. Why join our team • We are a young and vibrant group of scientists, fueled by curiosity and passion for understanding the brain. We work as a team and use or invent cutting-edge neurotechnologies to answer fundamental questions in neuroscience. • Our team is committed to the training, mentorship, and career development of the next generation of neuroscientists. To achieve that, we foster an inclusive and supportive environment, where we can learn and advance science while having fun in the process. • Our work is multi-disciplinary, and so is our team. Irrespective of your background and project, our research environment will expose you to a diverse range of experimental and computational aspects of systems and circuits neuroscience. We thus encourage everyone to apply, especially those from underrepresented minorities. • Working in our team will provide you with invaluable experience across all stages of research and you will have the opportunity to engage in experiment design and execution, method development, software design, and data analysis, as well as publishing and communicating research results. • Our team is affiliated with Inserm and is located in the Paris Brain Institute (ICM), where we have access to state-of-the-art facilities and resources. • Our vibrant community at the ICM and throughout Paris promotes broad collaboration and learning opportunities.

Nikolas Karalis

If you are a data scientist, programmer, or engineer, with a keen interest in helping to understand the brain, consider joining our team Neuronal Circuits & Brain Dynamics at the Paris Brain Institute (ICM). We study the principles of neuronal circuit organization and brain dynamics. Our work focuses on unraveling the fascinating mysteries of how the brain generates internal states and how neuromodulators, such as dopamine and serotonin, influence neuronal activity and communication between brain regions during behavior. To achieve our goals, we perform large-scale recordings from thousands of neurons simultaneously using multimodal recordings, including electrophysiological or optical imaging approaches. We employ state-of-the-art techniques, including behavioral, optogenetic, imaging, electrophysiological, and genetic approaches in mice to record and manipulate the brain activity during behavior. Using this unprecedented data, we will be able to understand information flow in the brain in ways that would be unimaginable only a few years ago. However, the scale and complexity of this data provide major challenges and unique opportunities. We are looking for computationally-orientated researchers to join our team as temporary or permanent staff members, to help us develop methods to interact and analyze our multi-dimensional neurophysiological and behavioral data, and to develop innovative analysis approaches and efficient processing pipelines, to accelerate the progress of our research on our path to understanding the brain. As a data analyst in our group, you will interact closely with experimentalists and contribute crucially to the research. Our team values diversity and welcomes researchers from all backgrounds and profiles. If your profile aligns with our research needs, we encourage you to get in touch with us. Main responsibilities • Organize data management pipeline • Analyze neurophysiological and behavioral data • Develop analysis methods and software tools to facilitate the analysis of multi-modal and multi-dimensional neurophysiological data • Implement cutting-edge data science approaches (statistical, computational, and ML) for complex neuroscience problems • Create robust and efficient data pipelines to extract, transform, and visualize data • Develop, test, and implement scientific software (e.g., for reproducible analysis pipelines and data storage) • Interact with experimentalists to design experiments and implement analyses • Analyze current technologies, algorithms, models, and methods • As part of your role, you will have the opportunity to collaborate with other teams, attend trainings, mentor students, have independent projects, and present at major relevant conferences (Cosyne, NeurIPS). We offer competitive compensation and benefits within an interactive, interdisciplinary working environment, where cutting-edge science thrives and a dynamic, international research community awaits.

Dr. Yoav Livneh

We are looking for enthusiastic students and researchers from diverse backgrounds, including (but not limited to) biology, physics, medicine, physiology, psychology, engineering, and more. We have several ERC-funded positions at different levels.

Professor Maria Geffen

The Geffen laboratory at the University of Pennsylvania has multiple postdoctoral positions open in systems neuroscience with the broad goal of understanding the neuronal circuits for auditory perception and learning. We are looking for energetic and talented scientists interested in studying the function of the brain. The postdoctoral fellow will have the opportunity to learn and apply a host of systems neuroscience techniques, including two-photon imaging of population activity, optogenetic manipulations, large-scale electrophysiology and behavior in mice. Prior experience with some of these methods is preferred, but not required. Depending on the candidate’s interests, all projects provide an opportunity to learn and apply advanced computational methods, including dynamic systems analysis of neuronal population activity; Bayesian approaches for understanding the relation between neuronal activity and behavior; machine learning methods to understand large-scale neuronal activity. We currently have openings for postdoctoral fellows for three projects: (1) Neuronal mechanisms for predictive coding: Auditory perception relies on predicting statistics of incoming signals, be it identifying the speech of a conversation partner in a crowded room or recognizing the sound of a babbling brook in a forest. The human brain detects statistical regularities in sounds as a fundamental aspect of prediction, evidenced by reduced responses to repeated sound patterns and enhanced responses to unexpected sounds. Multiple studies demonstrate that the neuronal responses to regular signals are reduced through adaptation, which can contribute to prediction. However, adaptation alone is not sufficient to account for prediction and studies at cellular and neuronal population levels in animals thus far lend only partial support to existing theories of predictive coding. The goal of the project is to close this gap in knowledge and to determine the circuits that predict signals and detect statistical regularity and its violation in auditory behavior. Funded by NIH NIDCD. (2) Neuronal circuits for learning-driven changes in auditory perception: Everyday auditory behavior depends critically on learning-driven changes in auditory perception that rely on neuronal plasticity within the auditory pathway. By combining state-of-the-art optogenetic, electrophysiological, behavioral and computational approaches, the project seeks to identify the function of specific circuit elements in auditory learning. Funded by NIH NIDCD. (3) Neuronal mechanisms for hearing under uncertainty: In everyday life, because both sensory signals and neuronal responses are noisy, important cognitive tasks, such as auditory categorization, are based on uncertain information. To overcome this limitation, listeners incorporate other types of signals, such as the statistics of sounds over short and long time scales and signals from other sensory modalities into their categorization decision processes. This project will identify the contribution of specific cell types to categorization and the neuronal mechanisms for how contextual signals bias auditory categorization. In collaboration with Dr. Yale Cohen and Dr. Konrad Kording, funded by NIH BRAIN Initiative. Our laboratory is a close community of fun-loving scientists, striving to help each other while exploring the mysteries of the brain. Our trainees have won numerous awards and have been awarded government and private foundation grants. We value diversity and promote equity in the scientific community and beyond. The systems neuroscience community at the University of Pennsylvania is top-notch and highly collaborative, and postdoctoral fellows will have opportunities to engage in interdepartmental initiatives, including MindCore, MINS and CNI. Penn has a gorgeous campus and offers many cultural activities. Philadelphia is a beautiful city with world-class music, food and entertainment. To apply, please email Dr. Geffen at mgeffen@pennmedicine.upenn.edu : a cover letter (summarize your prior research experience, why you are interested in the position, and your future plans) and your CV.

Dr Sylvia Schröder

The successful candidate will study information processing in the early visual system of mice using two-photon imaging, electrophysiology (Neuropixels probes), and opto- and chemogenetic manipulations. The lab’s goal is to determine how behavioural and internal states like arousal are integrated with visual responses in the retina and superior colliculus. We want to discover the underlying mechanisms and the purpose of this integration in terms of visual processing and the animal’s behavioural demands. This paper describes our previous findings. Start date: January 2021 or later Contract: for 2 years initially, funding available for 5 years (through Sir Henry Dale Fellowship, Wellcome Trust) Location: campus is just outside Brighton at the coast of South East England, surrounded by South Downs National Park, 1 h from London See the job advertisement for details on how to apply: https://www.sussex.ac.uk/about/jobs/research-fellow-in-neuroscience-4726 Informal enquiries are highly encouraged and should be made to Sylvia Schröder (sylvia.schroeder@ucl.ac.uk).

Dr Adil Khan

Applications are invited for a postdoctoral researcher position funded by the Wellcome Trust. The successful applicant will pursue a research project with the goal of understanding how brain-wide neural circuits lead to flexible cognitive behaviours in mice. The techniques employed will include chronic in-vivo two photon calcium imaging of multiple cell classes, targeted optogenetic manipulations, viral vector based functional circuit mapping, and quantitative mouse behaviour. The successful applicant will benefit from the collaborative culture of the Centre for Developmental Neurobiology at King’s College London and will have the opportunity to develop collaborations with groups studying animal models of brain disorders. Candidates must have a strong research track record. Experience with in-vivo two photon imaging, rodent behaviour and analysis of complex datasets will be highly valued. Candidates with programming skills are encouraged to apply.

Unpacking the role of the medial septum in spatial coding in the medial entorhinal cortex

Fear learning induces synaptic potentiation between engram neurons in the rat lateral amygdala

Fear learning induces synaptic potentiation between engram neurons in the rat lateral amygdala. This study by Marios Abatis et al. demonstrates how fear conditioning strengthens synaptic connections between engram cells in the lateral amygdala, revealed through optogenetic identification of neuronal ensembles and electrophysiological measurements. The work provides crucial insights into memory formation mechanisms at the synaptic level, with implications for understanding anxiety disorders and developing targeted interventions. Presented by Dr. Kenneth Hayworth, this journal club will explore the paper's methodology linking engram cell reactivation with synaptic plasticity measurements, and discuss implications for memory decoding research.

Combined electrophysiological and optical recording of multi-scale neural circuit dynamics

This webinar will showcase new approaches for electrophysiological recordings using our silicon neural probes and surface arrays combined with diverse optical methods such as wide-field or 2-photon imaging, fiber photometry, and optogenetic perturbations in awake, behaving mice. Multi-modal recording of single units and local field potentials across cortex, hippocampus and thalamus alongside calcium activity via GCaMP6F in cortical neurons in triple-transgenic animals or in hippocampal astrocytes via viral transduction are brought to bear to reveal hitherto inaccessible and under-appreciated aspects of coordinated dynamics in the brain.

Roles of inhibition in stabilizing and shaping the response of cortical networks

Inhibition has long been thought to stabilize the activity of cortical networks at low rates, and to shape significantly their response to sensory inputs. In this talk, I will describe three recent collaborative projects that shed light on these issues. (1) I will show how optogenetic excitation of inhibition neurons is consistent with cortex being inhibition stabilized even in the absence of sensory inputs, and how this data can constrain the coupling strengths of E-I cortical network models. (2) Recent analysis of the effects of optogenetic excitation of pyramidal cells in V1 of mice and monkeys shows that in some cases this optogenetic input reshuffles the firing rates of neurons of the network, leaving the distribution of rates unaffected. I will show how this surprising effect can be reproduced in sufficiently strongly coupled E-I networks. (3) Another puzzle has been to understand the respective roles of different inhibitory subtypes in network stabilization. Recent data reveal a novel, state dependent, paradoxical effect of weakening AMPAR mediated synaptic currents onto SST cells. Mathematical analysis of a network model with multiple inhibitory cell types shows that this effect tells us in which conditions SST cells are required for network stabilization.

Consolidation of remote contextual memory in the neocortical memory engram

Recent studies identified memory engram neurons, a neuronal population that is recruited by initial learning and is reactivated during memory recall.  Memory engram neurons are connected to one another through memory engram synapses in a distributed network of brain areas.  Our central hypothesis is that an associative memory is encoded and consolidated by selective strengthening of engram synapses.  We are testing this hypothesis, using a combination of engram cell labeling, optogenetic/chemogenetic, electrophysiological, and virus tracing approaches in rodent models of contextual fear conditioning.  In this talk, I will discuss our findings on how synaptic plasticity in memory engram synapses contributes to the acquisition and consolidation of contextual fear memory in a distributed network of the amygdala, hippocampus, and neocortex.

Manipulating single-unit theta phase-locking with PhaSER: An open-source tool for real-time phase estimation and manipulation

Zoe has developed an open-source tool PhaSER, which allows her to perform real-time oscillatory phase estimation and apply optogenetic manipulations at precise phases of hippocampal theta during high-density electrophysiological recordings in head-fixed mice while they navigate a virtual environment. The precise timing of single-unit spiking relative to network-wide oscillations (i.e., phase locking) has long been thought to maintain excitatory-inhibitory homeostasis and coordinate cognitive processes, but due to intense experimental demands, the causal influence of this phenomenon has never been determined. Thus, we developed PhaSER (Phase-locked Stimulation to Endogenous Rhythms), a tool which allows the user to explore the temporal relationship between single-unit spiking and ongoing oscillatory activity.

Wave-front shaping and circuit optogenetics

Hypothalamic episode generators underlying the neural control of fertility

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

Pynapple: a light-weight python package for neural data analysis - webinar + tutorial

In systems neuroscience, datasets are multimodal and include data-streams of various origins: multichannel electrophysiology, 1- or 2-p calcium imaging, behavior, etc. Often, the exact nature of data streams are unique to each lab, if not each project. Analyzing these datasets in an efficient and open way is crucial for collaboration and reproducibility. In this combined webinar and tutorial, Adrien Peyrache and Guillaume Viejo will present Pynapple, a Python-based data analysis pipeline for systems neuroscience. Designed for flexibility and versatility, Pynapple allows users to perform cross-modal neural data analysis via a common programming approach which facilitates easy sharing of both analysis code and data.

Pynapple: a light-weight python package for neural data analysis - webinar + tutorial

In systems neuroscience, datasets are multimodal and include data-streams of various origins: multichannel electrophysiology, 1- or 2-p calcium imaging, behavior, etc. Often, the exact nature of data streams are unique to each lab, if not each project. Analyzing these datasets in an efficient and open way is crucial for collaboration and reproducibility. In this combined webinar and tutorial, Adrien Peyrache and Guillaume Viejo will present Pynapple, a Python-based data analysis pipeline for systems neuroscience. Designed for flexibility and versatility, Pynapple allows users to perform cross-modal neural data analysis via a common programming approach which facilitates easy sharing of both analysis code and data.

Neural Representations of Social Homeostasis

How does our brain rapidly determine if something is good or bad? How do we know our place within a social group? How do we know how to behave appropriately in dynamic environments with ever-changing conditions? The Tye Lab is interested in understanding how neural circuits important for driving positive and negative motivational valence (seeking pleasure or avoiding punishment) are anatomically, genetically and functionally arranged. We study the neural mechanisms that underlie a wide range of behaviors ranging from learned to innate, including social, feeding, reward-seeking and anxiety-related behaviors. We have also become interested in “social homeostasis” -- how our brains establish a preferred set-point for social contact, and how this maintains stability within a social group. How are these circuits interconnected with one another, and how are competing mechanisms orchestrated on a neural population level? We employ optogenetic, electrophysiological, electrochemical, pharmacological and imaging approaches to probe these circuits during behavior.

Building a Simple and Versatile Illumination System for Optogenetic Experiments

Controlling biological processes using light has increased the accuracy and speed with which researchers can manipulate many biological processes. Optical control allows for an unprecedented ability to dissect function and holds the potential for enabling novel genetic therapies. However, optogenetic experiments require adequate light sources with spatial, temporal, or intensity control, often a bottleneck for researchers. Here we detail how to build a low-cost and versatile LED illumination system that is easily customizable for different available optogenetic tools. This system is configurable for manual or computer control with adjustable LED intensity. We provide an illustrated step-by-step guide for building the circuit, making it computer-controlled, and constructing the LEDs. To facilitate the assembly of this device, we also discuss some basic soldering techniques and explain the circuitry used to control the LEDs. Using our open-source user interface, users can automate precise timing and pulsing of light on a personal computer (PC) or an inexpensive tablet. This automation makes the system useful for experiments that use LEDs to control genes, signaling pathways, and other cellular activities that span large time scales. For this protocol, no prior expertise in electronics is required to build all the parts needed or to use the illumination system to perform optogenetic experiments.

Dynamic dopaminergic signaling probabilistically controls the timing of self-timed movements

Human movement disorders and pharmacological studies have long suggested molecular dopamine modulates the pace of the internal clock. But how does the endogenous dopaminergic system influence the timing of our movements? We examined the relationship between dopaminergic signaling and the timing of reward-related, self-timed movements in mice. Animals were trained to initiate licking after a self-timed interval following a start cue; reward was delivered if the animal’s first lick fell within a rewarded window (3.3-7 s). The first-lick timing distributions exhibited the scalar property, and we leveraged the considerable variability in these distributions to determine how the activity of the dopaminergic system related to the animals’ timing. Surprisingly, dopaminergic signals ramped-up over seconds between the start-timing cue and the self-timed movement, with variable dynamics that predicted the movement/reward time, even on single trials. Steeply rising signals preceded early initiation, whereas slowly rising signals preceded later initiation. Higher baseline signals also predicted earlier self-timed movement. Optogenetic activation of dopamine neurons during self-timing did not trigger immediate movements, but rather caused systematic early-shifting of the timing distribution, whereas inhibition caused late-shifting, as if dopaminergic manipulation modulated the moment-to-moment probability of unleashing the planned movement. Consistent with this view, the dynamics of the endogenous dopaminergic signals quantitatively predicted the moment-by-moment probability of movement initiation. We conclude that ramping dopaminergic signals, potentially encoding dynamic reward expectation, probabilistically modulate the moment-by-moment decision of when to move. (Based on work from Hamilos et al., eLife, 2021).

Optical manipulation of neuronal circuits using holographic optogenetics

The Open-Source UCLA Miniscope Project

The Miniscope Project -- an open-source collaborative effort—was created to accelerate innovation of miniature microscope technology and to increase global access to this technology. Currently, we are working on advancements ranging from optogenetic stimulation and wire-free operation to simultaneous optical and electrophysiological recording. Using these systems, we have uncovered mechanisms underlying temporal memory linking and investigated causes of cognitive deficits in temporal lobe epilepsy. Through innovation and optimization, this work aims to extend the reach of neuroscience research and create new avenues of scientific inquiry.

Visual restoration from prosthesis to optogenetic therapy

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.

A metabolic function of the hippocampal sharp wave-ripple

The hippocampal formation has been implicated in both cognitive functions as well as the sensing and control of endocrine states. To identify a candidate activity pattern which may link such disparate functions, we simultaneously measured electrophysiological activity from the hippocampus and interstitial glucose concentrations in the body of freely behaving rats. We found that clusters of sharp wave-ripples (SPW-Rs) recorded from both dorsal and ventral hippocampus reliably predicted a decrease in peripheral glucose concentrations within ~10 minutes. This correlation was less dependent on circadian, ultradian, and meal-triggered fluctuations, it could be mimicked with optogenetically induced ripples, and was attenuated by pharmacogenetically suppressing activity of the lateral septum, the major conduit between the hippocampus and subcortical structures. Our findings demonstrate that a novel function of the SPW-R is to modulate peripheral glucose homeostasis and offer a mechanism for the link between sleep disruption and blood glucose dysregulation seen in type 2 diabetes and obesity.

A distinct subcircuit in medial entorhinal cortex mediates learning of interval timing behavior during immobility

Over 60 years of research has established that medial temporal lobe structures, including the hippocampus and entorhinal cortex, are necessary for the formation of episodic memories (i.e. memories of specific personal events that occur in spatial and temporal context). While prior work to establish the neural mechanisms underlying episodic memory has largely focused on questions related spatial context, recently we have begun to investigate how these brain structures could be involved in encoding aspects of temporal context. In particular, we have focused on how medial entorhinal cortex, a structure well known for its role in spatial memory, may also be involved in encoding interval time. To answer this question we have developed an instrumental paradigm for head-fixed mice that requires both immobile interval timing and locomotion-dependent navigation behavior. By combining this behavioral paradigm with large-scale cellular resolution functional imaging and optogenetic-mediated inactivation, our results suggest that MEC is required for learning of interval timing behavior and that interval timing could be mediated through regular, sequential neural activity of a distinct subpopulation of neurons in MEC that encode elapsed time during periods of immobility (Heys and Dombeck, 2018; Heys et al, 2020; Issa et al., 2020). In this talk, I will discuss these findings and discuss our on-going work to investigate the principles underlying the role of medial temporal lobe structures in timing behavior and episodic memory.

Sensory and metasensory responses during sequence learning in the mouse somatosensory cortex

Sequential temporal ordering and patterning are key features of natural signals, used by the brain to decode stimuli and perceive them as sensory objects. Touch is one sensory modality where temporal patterning carries key information, and the rodent whisker system is a prominent model for understanding neuronal coding and plasticity underlying touch sensation. Neurons in this system are precise encoders of fluctuations in whisker dynamics down to a timescale of milliseconds, but it is not clear whether they can refine their encoding abilities as a result of learning patterned stimuli. For example, can they enhance temporal integration to become better at distinguishing sequences? To explore how cortical coding plasticity underpins sequence discrimination, we developed a task in which mice distinguished between tactile ‘word’ sequences constructed from distinct vibrations delivered to the whiskers, assembled in different orders. Animals licked to report the presence of the target sequence. Optogenetic inactivation showed that the somatosensory cortex was necessary for sequence discrimination. Two-photon imaging in layer 2/3 of the primary somatosensory “barrel” cortex (S1bf) revealed that, in well-trained animals, neurons had heterogeneous selectivity to multiple task variables including not just sensory input but also the animal’s action decision and the trial outcome (presence or absence of the predicted reward). Many neurons were activated preceding goal-directed licking, thus reflecting the animal’s learnt action in response to the target sequence; these neurons were found as soon as mice learned to associate the rewarded sequence with licking. In contrast, learning evoked smaller changes in sensory response tuning: neurons responding to stimulus features were already found in naïve mice, and training did not generate neurons with enhanced temporal integration or categorical responses. Therefore, in S1bf sequence learning results in neurons whose activity reflects the learnt association between target sequence and licking, rather than a refined representation of sensory features. Taken together with results from other laboratories, our findings suggest that neurons in sensory cortex are involved in task-specific processing and that an animal does not sense the world independently of what it needs to feel in order to guide behaviour.

Bridging scales – combining functional ultrasound imaging, optogenetics, and electrophysiology to study neuronal networks underlying behavior

Contextual modulation of cortical processing by a higher-order thalamic input

Higher-order thalamic nuclei have extensive connections with various cortical areas. Yet their functionals roles remain not well understood. In our recent studies, using optogenetic and chemogenetic tools we manipulated the activity of a higher-order thalamic nucleus, the lateral posterior nucleus (LP, analogous to the primate pulvinar nucleus) and its projections and examined the effects on sensory discrimination and information processing functions in the cortex. We found an overall suppressive effect on layer 2/3 pyramidal neurons in the cortex, resulting in enhancements of sensory feature selectivities. These mechanisms are in place in contextual modulation of cortical processing, as well as in cross-modality modulation of sensory processing.

Circuits optogenetics and wave front shaping

Tools for Analyzing and Repairing the Brain. (Simultaneous translation to Spanish)

To enable the understanding and repair of complex biological systems, such as the brain, we are creating novel optical tools that enable molecular-resolution maps of such systems, as well as technologies for observing and controlling high-speed physiological dynamics in such systems. First, we have developed a method for imaging specimens with nanoscale precision, by embedding them in a swellable polymer, homogenizing their mechanical properties, and exposing them to water – which causes them to expand manyfold isotropically. This method, which we call expansion microscopy (ExM), enables ordinary microscopes to do nanoscale imaging, in a multiplexed fashion – important, for example, for brain mapping. Second, we have developed a set of genetically-encoded reagents, known as optogenetic tools, that when expressed in specific neurons, enable their electrical activities to be precisely driven or silenced in response to millisecond timescale pulses of light. Finally, we are designing, and evolving, novel reagents, such as fluorescent voltage indicators and somatically targeted calcium indicators, to enable the imaging of fast physiological processes in 3-D with millisecond precision. In this way we aim to enable the systematic mapping, control, and dynamical observation of complex biological systems like the brain. The talk will be simultaneously interpreted English-Spanish) by the Interpreter, Mg. Lourdes Martino. Para permitir la comprensión y reparación de sistemas biológicos complejos, como el cerebro, estamos creando herramientas ópticas novedosas que permiten crear mapas de resolución molecular de dichos sistemas, así como tecnologías para observar y controlar la dinámica fisiológica de alta velocidad en dichos sistemas. Primero, hemos desarrollado un método para obtener imágenes de muestras con precisión a nanoescala, incrustándolas en un polímero hinchable, homogeneizando sus propiedades mecánicas y exponiéndolas al agua, lo que hace que se expandan muchas veces isotrópicamente. Este método, que llamamos microscopía de expansión (ExM), permite que los microscopios ordinarios obtengan imágenes a nanoescala, de forma multiplexada, lo que es importante, por ejemplo, para el mapeo cerebral. En segundo lugar, hemos desarrollado un conjunto de reactivos codificados genéticamente, conocidos como herramientas optogenéticas, que cuando se expresan en neuronas específicas, permiten que sus actividades eléctricas sean activadas o silenciadas con precisión en respuesta a pulsos de luz en una escala de tiempo de milisegundos. Finalmente, estamos diseñando y desarrollando reactivos novedosos, como indicadores de voltaje fluorescentes e indicadores de calcio dirigidos somáticamente, para permitir la obtención de imágenes de procesos fisiológicos rápidos en 3-D con precisión de milisegundos. De esta manera, nuestro objetivo es permitir el mapeo sistemático, el control y la observación dinámica de sistemas biológicos complejos como el cerebro. La conferencia será traducida simultáneamente al español por la intérprete Mg. Lourdes Martino.

An Algorithmic Barrier to Neural Circuit Understanding

Neuroscience is witnessing extraordinary progress in experimental techniques, especially at the neural circuit level. These advances are largely aimed at enabling us to understand precisely how neural circuit computations mechanistically cause behavior. Establishing this type of causal understanding will require multiple perturbational (e.g optogenetic) experiments. It has been unclear exactly how many such experiments are needed and how this number scales with the size of the nervous system in question. Here, using techniques from Theoretical Computer Science, we prove that establishing the most extensive notions of understanding need exponentially-many experiments in the number of neurons, in many cases, unless a widely-posited hypothesis about computation is false (i.e. unless P = NP). Furthermore, using data and estimates, we demonstrate that the feasible experimental regime is typically one where the number of experiments performable scales sub-linearly in the number of neurons in the nervous system. This remarkable gulf between the worst-case and the feasible suggests an algorithmic barrier to such an understanding. Determining which notions of understanding are algorithmically tractable to establish in what contexts, thus, becomes an important new direction for investigation. TL; DR: Non-existence of tractable algorithms for neural circuit interrogation could pose a barrier to comprehensively understanding how neural circuits cause behavior. Preprint: https://biorxiv.org/content/10.1101/639724v1/…

Neural Circuit Mechanisms of Emotional and Social Processing

How does our brain rapidly determine if something is good or bad? How do we know our place within a social group? How do we know how to behave appropriately in dynamic environments with ever-changing conditions? The Tye Lab is interested in understanding how neural circuits important for driving positive and negative motivational valence (seeking pleasure or avoiding punishment) are anatomically, genetically and functionally arranged. We study the neural mechanisms that underlie a wide range of behaviours ranging from learned to innate, including social, feeding, reward-seeking and anxiety-related behaviours. We have also become interested in “social homeostasis” -- how our brains establish a preferred set-point for social contact, and how this maintains stability within a social group. How are these circuits interconnected with one another, and how are competing mechanisms orchestrated on a neural population level? We employ optogenetic, electrophysiological, electrochemical, pharmacological and imaging approaches to probe these circuits during behaviour.

Playing the piano with the cortex: role of neuronal ensembles and pattern completion in perception

The design of neural circuits, with large numbers of neurons interconnected in vast networks, strongly suggest that they are specifically build to generate emergent functional properties (1). To explore this hypothesis, we have developed two-photon holographic methods to selective image and manipulate the activity of neuronal populations in 3D in vivo (2). Using them we find that groups of synchronous neurons (neuronal ensembles) dominate the evoked and spontaneous activity of mouse primary visual cortex (3). Ensembles can be optogenetically imprinted for several days and some of their neurons trigger the entire ensemble (4). By activating these pattern completion cells in ensembles involved in visual discrimination paradigms, we can bi-directionally alter behavioural choices (5). Our results demonstrate that ensembles are necessary and sufficient for visual perception and are consistent with the possibility that neuronal ensembles are the functional building blocks of cortical circuits. 1. R. Yuste, From the neuron doctrine to neural networks. Nat Rev Neurosci 16, 487-497 (2015). 2. L. Carrillo-Reid, W. Yang, J. E. Kang Miller, D. S. Peterka, R. Yuste, Imaging and Optically Manipulating Neuronal Ensembles. Annu Rev Biophys, 46: 271-293 (2017). 3. J. E. Miller, I. Ayzenshtat, L. Carrillo-Reid, R. Yuste, Visual stimuli recruit intrinsically generated cortical ensembles. Proceedings of the National Academy of Sciences of the United States of America 111, E4053-4061 (2014). 4. L. Carrillo-Reid, W. Yang, Y. Bando, D. S. Peterka, R. Yuste, Imprinting and recalling cortical ensembles. Science 353, 691-694 (2016). 5. L. Carrillo-Reid, S. Han, W. Yang, A. Akrouh, R. Yuste, (2019). Controlling visually-guided behaviour by holographic recalling of cortical ensembles. Cell 178, 447-457. DOI:https://doi.org/10.1016/j.cell.2019.05.045.

The subcellular organization of excitation and inhibition underlying high-fidelity direction coding in the retina

Understanding how neural circuits in the brain compute information not only requires determining how individual inhibitory and excitatory elements of circuits are wired together, but also a detailed knowledge of their functional interactions. Recent advances in optogenetic techniques and mouse genetics now offer ways to specifically probe the functional properties of neural circuits with unprecedented specificity. Perhaps one of the most heavily interrogated circuits in the mouse brain is one in the retina that is involved in coding direction (reviewed by Mauss et al., 2017; Vaney et al., 2012). In this circuit, direction is encoded by specialized direction-selective (DS) ganglion cells (DSGCs), which respond robustly to objects moving in a ‘preferred’ direction but not in the opposite or ‘null’ direction (Barlow and Levick, 1965). We now know this computation relies on the coordination of three transmitter systems: glutamate, GABA and acetylcholine (ACh). In this talk, I will discuss the synaptic mechanisms that produce the spatiotemporal patterns of inhibition and excitation that are crucial for shaping directional selectivity. Special emphasis will be placed on the role of ACh, as it is unclear whether it is mediated by synaptic or non-synaptic mechanisms, which is in fact a central issue in the CNS. Barlow, H.B., and Levick, W.R. (1965). The mechanism of directionally selective units in rabbit's retina. J Physiol 178, 477-504. Mauss, A.S., Vlasits, A., Borst, A., and Feller, M. (2017). Visual Circuits for Direction Selectivity. Annu Rev Neurosci 40, 211-230. Vaney, D.I., Sivyer, B., and Taylor, W.R. (2012). Direction selectivity in the retina: symmetry and asymmetry in structure and function. Nat Rev Neurosci 13, 194-208

A paradoxical kind of sleep In Drosophila melanogaster

The dynamic nature of sleep in most animals suggests distinct stages which serve different functions. Genetic sleep induction methods in animal models provide a powerful way to disambiguate these stages and functions, although behavioural methods alone are insufficient to accurately identify what kind of sleep is being engaged. In Drosophila, activation of the dorsal fan-shaped body (dFB) promotes sleep, but it remains unclear what kind of sleep this is, how the rest of the fly brain is behaving, or if any specific sleep functions are being achieved. Here, we developed a method to record calcium activity from thousands of neurons across a volume of the fly brain during dFB-induced sleep, and we compared this to the effects of a sleep-promoting drug. We found that drug-induced spontaneous sleep decreased brain activity and connectivity, whereas dFB sleep was not different from wakefulness. Paradoxically, dFB-induced sleep was found to be even deeper than drug- induced sleep. When we probed the sleeping fly brain with salient visual stimuli, we found that the activity of visually-responsive neurons was blocked by dFB activation, confirming a disconnect from the external environment. Prolonged optogenetic dFB activation nevertheless achieved a significant sleep function, by correcting visual attention defects brought on by sleep deprivation. These results suggest that dFB activation promotes a distinct form of sleep in Drosophila, where brain activity and connectivity remain similar to wakefulness, but responsiveness to external sensory stimuli is profoundly suppressed.

Characterization of neuronal resonance and inter-areal transfer using optogenetics

COSYNE 2022

Balanced two-photon holographic bidirectional optogenetics defines the mechanism for stimulus quenching of neural variability

COSYNE 2025

InLOV: Optogenetics for light-controlled insulin signaling modulates neuronal plasticity and cerebellar-driven behavior

FENS Forum 2024

Probing neural circuit motifs in zebrafish using holographic optogenetics

FENS Forum 2024

Untangling the visuomotor circuit in intact and regenerating brains of the axolotl (Ambystoma mexicanum) using behavioral assays, calcium imaging, and optogenetics

FENS Forum 2024

Upconversion-mediated transcranial optogenetics: Juggling with photons to control fear in mice

FENS Forum 2024

Wireless headstage controlled via Bluetooth for closed-loop optogenetics experiments in rodents

FENS Forum 2024