Cardiac vagal motor drive originates in the brainstem's cardiac vagal motor neurons (CVNs). Despite well-established cardioinhibitory functions in health, our understanding of CVNs in disease is limited. There is a clear connection of cardiovascular regulation with metabolic and energy expenditure systems. Using high fat diet as a model, this talk will explore how metabolic dysfunction impacts the regulation of cardiac tissue through robust inhibition of CVNs. Specifically, it will present an often overlooked modality of inhibition, tonic gamma-aminobuytric acid (GABA) A-type neurotransmission using an array of techniques from single cell patch clamp electrophysiology to transgenic in vivo whole animal physiology. It also will highlight a unique interaction with the delta isoform of protein kinase C to facilitate GABA A-type receptor expression.

One of the most prominent features of the human brain is the fabulous size of the cerebral cortex and its intricate folding, both of which emerge during development. Over the last few years, work from my lab has shown that specific cellular and genetic mechanisms play central roles in cortex folding, particularly linked to neural stem and progenitor cells. Key mechanisms include high rates of neurogenesis, high abundance of basal Radial Glia Cells (bRGCs), and neuron migration, all of which are intertwined during development. We have also shown that primary cortical folds follow highly stereotyped patterns, defined by a spatial-temporal protomap of gene expression within germinal layers of the developing cortex. I will present recent findings from my laboratory revealing novel cellular and genetic mechanisms that regulate cortex expansion and folding. We have uncovered the contribution of epigenetic regulation to the establishment of the cortex folding protomap, modulating the expression levels of key transcription factors that control progenitor cell proliferation and cortex folding. At the single cell level, we have identified an unprecedented diversity of cortical progenitor cell classes in the ferret and human embryonic cortex. These are differentially enriched in gyrus versus sulcus regions and establish parallel cell lineages, not observed in mouse. Our findings show that genetic and epigenetic mechanisms in gyrencephalic species diversify cortical progenitor cell types and implement parallel cell linages, driving the expansion of neurogenesis and patterning cerebral cortex folds.

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.

The advent of next generation sequencing ushered in a ten-year period of exuberant technology development, enabling the quantification of gene expression and epigenetic features within individual cells, and within intact tissue sections.  In this seminar, I will outline our technological contributions, beginning with the development of Drop-seq, a method for high-throughput single cell analysis, followed by the development of Slide-seq, a technique for measuring genome-wide expression at 10 micron spatial resolution.  Using a combination of these techniques, we recently constructed a comprehensive cell type atlas of the adult mouse brain, positioning cell types within individual brain structures.  I will discuss the major findings from this dataset, including emerging principles of neurotransmission, and the localization of disease gene signatures to specific cell types.  Finally, I will introduce a new spatial technology, Slide-tags, that unifies single cell and spatial genomics into a single, highly scalable assay.

The size and structure of the dendritic arbor play important roles in determining how synaptic inputs of neurons are converted to action potential output and how neurons are integrated in the surrounding neuronal network. Accordingly, neurons with aberrant morphology have been associated with neurological disorders. Dysmorphic, enlarged neurons are, for example, a hallmark of focal epileptogenic lesions like focal cortical dysplasia (FCDIIb) and gangliogliomas (GG). However, the regulatory mechanisms governing the development of dendrites are insufficiently understood. The evolutionary conserved Ste20/Hippo kinase pathway has been proposed to play an important role in regulating the formation and maintenance of dendritic architecture. A key element of this pathway, Ste20-like kinase (SLK), regulates cytoskeletal dynamics in non-neuronal cells and is strongly expressed throughout neuronal development. Nevertheless, its function in neurons is unknown. We found that during development of mouse cortical neurons, SLK has a surprisingly specific role for proper elaboration of higher, ≥ 3rd, order dendrites both in cultured neurons and living mice. Moreover, SLK is required to maintain excitation-inhibition balance. Specifically, SLK knockdown causes a selective loss of inhibitory synapses and functional inhibition after postnatal day 15, while excitatory neurotransmission is unaffected. This mechanism may be relevant for human disease, as dysmorphic neurons within human cortical malformations exhibit significant loss of SLK expression. To uncover the signaling cascades underlying the action of SLK, we combined phosphoproteomics, protein interaction screens and single cell RNA seq. Overall, our data identifies SLK as a key regulator of both dendritic complexity during development and of inhibitory synapse maintenance.

The nervous system is fundamentally a closed loop control device: the output of actions continually influences the internal state and subsequent actions. This is true at the single cell and even the molecular level, where “actions” take the form of signals that are fed back to achieve a variety of functions, including homeostasis, excitability and various kinds of multistability that allow switching and storage of memory. It is also true at the behavioural level, where an animal’s motor actions directly influence sensory input on short timescales, and higher level information about goals and intended actions are continually updated on the basis of current and past actions. Studying the brain in a closed loop setting requires a multidisciplinary approach, leveraging engineering and theory as well as advances in measuring and manipulating the nervous system. I will describe our recent attempts to achieve this fusion of approaches at multiple levels in the nervous system, from synaptic signalling to closed loop brain machine interfaces.

Schizophrenia is a neuropsychiatric disorder characterized by positive symptoms (such as hallucinations and delusions), negative symptoms (such as avolition and withdrawal) and cognitive dysfunction1. Schizophrenia is highly heritable, and genetic studies are playing a pivotal role in identifying potential biomarkers and causal disease mechanisms with the hope of informing new treatments. Genome-wide association studies (GWAS) identified nearly 270 loci with a high statistical association with schizophrenia risk; however each locus confers only a small increase in risk therefore it is difficult to translate these findings into understanding disease biology that can lead to treatments. Induced pluripotent stem cell (iPSC) models are a tractable system to translate genetic findings and interrogate mechanisms of pathogenesis. Mounting research with patient-derived iPSCs has proposed several neurodevelopmental pathways altered in SCZ, such as neural progenitor cell (NPC) proliferation, imbalanced differentiation of excitatory and inhibitory cortical neurons. However, it is unclear what exactly these iPS models recapitulate, how potential perturbations of early brain development translates into illness in adults and how iPS models that represent fetal stages can be utilized to further drug development efforts to treat adult illness. I will present the largest transcriptome analysis of post-mortem caudate nucleus in schizophrenia where we discovered that decreased presynaptic DRD2 autoregulation is the causal dopamine risk factor for schizophrenia (Benjamin et al, Nature Neuroscience 2022 https://doi.org/10.1038/s41593-022-01182-7). We developed stem cell models from a subset of the postmortem cohort to better understand the molecular underpinnings of human psychiatric disorders (Sawada et al, Stem Cell Research 2020). We established a method for the differentiation of iPS cells into ventral forebrain organoids and performed single cell RNAseq and cellular phenotyping. To our knowledge, this is the first study to evaluate iPSC models of SZ from the same individuals with postmortem tissue. Our study establishes that striatal neurons in the patients with SCZ carry abnormalities that originated during early brain development. Differentiation of inhibitory neurons is accelerated whereas excitatory neuronal development is delayed, implicating an excitation and inhibition (E-I) imbalance during early brain development in SCZ. We found a significant overlap of genes upregulated in the inhibitory neurons in SCZ organoids with upregulated genes in postmortem caudate tissues from patients with SCZ compared with control individuals, including the donors of our iPS cell cohort. Altogether, we demonstrate that ventral forebrain organoids derived from postmortem tissue of individuals with schizophrenia recapitulate perturbed striatal gene expression dynamics of the donors’ brains (Sawada et al, biorxiv 2022 https://doi.org/10.1101/2022.05.26.493589).

Three intimately related dimensions of the mammalian genome—linear DNA sequence, gene transcription, and 3D genome architecture—are crucial for the development of nervous systems. Changes in the linear genome (e.g., de novo mutations), transcriptome, and 3D genome structure lead to debilitating neurodevelopmental disorders, such as autism and schizophrenia. However, current technologies and data are severely limited: (1) 3D genome structures of single brain cells have not been solved; (2) little is known about the dynamics of single-cell transcriptome and 3D genome after birth; (3) true de novo mutations are extremely difficult to distinguish from false positives (DNA damage and/or amplification errors). Here, I filled in this longstanding technological and knowledge gap. I recently developed a high-resolution method—diploid chromatin conformation capture (Dip-C)—which resolved the first 3D structure of the human genome, tackling a longstanding problem dating back to the 1880s. Using Dip-C, I obtained the first 3D genome structure of a single brain cell, and created the first transcriptome and 3D genome atlas of the mouse brain during postnatal development. I found that in adults, 3D genome “structure types” delineate all major cell types, with high correlation between chromatin A/B compartments and gene expression. During development, both transcriptome and 3D genome are extensively transformed in the first month of life. In neurons, 3D genome is rewired across scales, correlated with gene expression modules, and independent of sensory experience. Finally, I examined allele-specific structure of imprinted genes, revealing local and chromosome-wide differences. More recently, I expanded my 3D genome atlas to the human and mouse cerebellum—the most consistently affected brain region in autism. I uncovered unique 3D genome rewiring throughout life, providing a structural basis for the cerebellum’s unique mode of development and aging. In addition, to accurately measure de novo mutations in a single cell, I developed a new method—multiplex end-tagging amplification of complementary strands (META-CS), which eliminates nearly all false positives by virtue of DNA complementarity. Using META-CS, I determined the true mutation spectrum of single human brain cells, free from chemical artifacts. Together, my findings uncovered an unknown dimension of neurodevelopment, and open up opportunities for new treatments for autism and other developmental disorders.

Nearly all motivated behaviors require the ability to associate outcomes with specific actions and make adaptive decisions about future behavior. The nucleus accumbens (NAc) is integrally involved in these processes. The NAc is a heterogeneous population primarily composed of D1 and D2 medium spiny projection (MSN) neurons that are thought to have opposed roles in behavior, with D1 MSNs promoting reward and D2 MSNs promoting aversion. Here we examined what types of information are encoded by the D1 and D2 MSNs using optogenetics, fiber photometry, and cellular resolution calcium imaging. First, we showed that mice responded for optical self-stimulation of both cell types, suggesting D2-MSN activation is not inherently aversive. Next, we recorded population and single cell activity patterns of D1 and D2 MSNs during reinforcement as well as Pavlovian learning paradigms that allow dissociation of stimulus value, outcome, cue learning, and action. We demonstrated that D1 MSNs respond to the presence and intensity of unconditioned stimuli – regardless of value. Conversely, D2 MSNs responded to the prediction of these outcomes during specific cues. Overall, these results provide foundational evidence for the discrete aspects of information that are encoded within the NAc D1 and D2 MSN populations. These results will significantly enhance our understanding of the involvement of the NAc MSNs in learning and memory as well as how these neurons contribute to the development and maintenance of substance use disorders.

Learning entails self-modification of a system under closed-loop dynamics with its environment. Not only the system's components may change, but also the way they interact with one another - like synapses during learning in the brain, that modify interactions between neurons. Such processes, however, are not limited to the brain but can be found also in other areas of biology. I will describe a framework for a primitive form of learning that takes place within the single cell. This type of learning is composed of random modifications guided by global feedback. The capacity to utilize exploratory dynamics, improvisational in nature, provide cells with the plasticity required to overcome extreme challenges and to develop novel phenotypes.

Recent advances of single cell techniques catalyzed quantitative studies on the dynamics of cell phenotypic transitions (CPT) emerging as a new field. However, fixed cell-based approaches have fundamental limits on revealing temporal information, and fluorescence-based live cell imaging approaches are technically challenging for multiplex long-term imaging. To tackle the challenges, we developed an integrated experimental/computational platform for reconstructing single cell phenotypic transition dynamics. Experimentally, we developed a live-cell imaging platform to record the phenotypic transition path of A549 VIM-RFP reporter cell line and unveil parallel paths of epithelial-to-mesenchymal transition (EMT). Computationally, we modified a finite temperature string method to reconstruct the reaction coordinate from the paths, and reconstruct a corresponding quasi-potential, which reveals that the EMT process resembles a barrier-less relaxation process. Our work demonstrates the necessity of extracting dynamical information of phenotypic transitions and the existence of a unified theoretical framework describing transition and relaxation dynamics in systems with and without detailed balance.

Classification of neurons, long viewed as a fairly boring enterprise, has emerged as a major bottleneck in analysis of neural circuits. High throughput single cell RNA-seq has provided a new way to improve the situation. We initially applied this method to mouse retina, showing that its five neuronal classes (photoreceptors, three groups of interneurons, and retinal ganglion cells) can be divided into 130 discrete types. We then applied the method to other species including human, macaque, zebrafish and chick. With the atlases in hand, we are now using them to address questions about how retinal cell types diversify, how they differ in their responses to injury and disease, and the extent to which cell classes and types are conserved among vertebrates.

Laura Fenlon (Australia): Time shapes all brains: timing of a conserved transcriptional network underlies divergent cortical connectivity routes in mammalian brain development and evolution; Laurent Nguyen (Belgium): Regulation of cerebral cortex morphogenesis by migrating cells; Carol Ann Mason (USA): Wiring the eye to brain for binocular vision: lessons from the albino visual system. Thomas Perlmann (Sweden): Interrogating dopamine neuron development at the single cell level

The symposium will start with Prof Song-Hai Shi who will present “Assembly of the neocortex”. Then, Dr Lynette Lim will talk about “Shared and Unique Developmental Trajectories of Cortical Inhibitory Neurons”. Dr Alfredo Molina will deal with the “Tuneable progenitor cells to build the cerebral cortex”, and Prof Tomasz Nowakowski will present “Charting the molecular 'protomap' of the human cerebral cortex using single cell genomic”.

The precise spatial localization of molecular signals within tissues richly informs the mechanisms of tissue formation and function. Here, we’ll introduce Slide-seq, a technology which enables transcriptome-wide measurements with near-single cell spatial resolution. We’ll describe recent experimental and computational advances to enable Slide-seq in biological contexts in biological contexts where high detection sensitivity is important. More broadly, we’ll discuss the promise and challenges of spatial transcriptomics for tissue genomics. Lastly, we’ll touch upon novel molecular recording technologies, which allows recording of the absolute time dynamics of gene expression in live systems into DNA sequences.

Genetic targeting of neuronal cells with activity reporters (calcium or voltage indicators) has initiated the paradigmatic transition whereby photons have replaced electrons for reading large-scale brain activities at cellular resolution. This has alleviated the limitations of single cell or extracellular electrophysiological probing, which only give access to the activity of at best a few neurons simultaneously and to population activity of unresolved cellular origin, respectively. In parallel, optogenetics has demonstrated that targeting neuronal cells with photosensitive microbial opsins, enables the transduction of photons into electrical currents of opposite polarities thus writing, through activation or inhibition, neuronal signals in a non-invasive way. These progresses have in turn stimulated the development of sophisticated optical methods to increase spatial and temporal resolution, light penetration depth and imaging volume. Today, nonlinear microscopy, combined with spatio-temporal wave front shaping, endoscopic probes engineering or multi scan heads design, enable in vivo in depth, simultaneous recording of thousands of cells in mm 3 volumes at single-spike precision and single-cell resolution. Joint progress in opsin engineering, wave front shaping and laser development have provided the methodology, that we named circuits optogenetics, to control single or multiple target activity independently in space and time with single- neuron and single-spike precision, at large depths. Here, we will review the most significant breakthroughs of the past years, which enable reading and writing neuronal activity at the relevant spatiotemporal scale for brain circuits manipulation, with particular emphasis on the most recent advances in circuit optogenetics.

After an injury in the adult mammalian central nervous system, lesioned axons fail to regenerate. This failure to regenerate contrasts with the remarkable potential of axons to grow during embryonic development and after an injury in the peripheral nervous system. Peripheral sensory neurons with cell soma in dorsal root ganglia (DRG) switch to a regenerative state after nerve injury to enable axon regeneration and functional recovery. Decades of research have focused on the signaling pathways elicited by injury in sensory neurons and in Schwann cells that insulate axons as central mechanisms regulating nerve repair. However, neuronal microenvironment is far more complex and is composed of multiple cell types including endothelial, immune and glial cells. Whether the microenvironment surrounding neuronal soma contribute to the poor regenerative outcomes following central injuries remains largely unexplored. To answer this question, we performed a single cell transcriptional profiling of the DRG neuronal microenvironment response to peripheral and central injuries. In dissecting the roles of the microenvironment contribution, we have focused on a poorly studied population of Satellite Glial Cells (SGC) surrounding the neuronal cell soma. This study has uncovered a previously unknown role for SGC in nerve regeneration and defined SGC as transcriptionally distinct from Schwann cells while sharing similarities with astrocytes. Upon a peripheral injury, SGC contribute to axon regeneration via Fatty acid synthase (Fasn)-PPARα signaling pathway. Through repurposing fenofibrate, an FDA- approved PPARα agonist used for dyslipidemia treatment, we were able to rescue the impaired regeneration in mice lacking Fasn in SGC. Our analysis reveals that in response to central injuries, SGC do not activate the PPAR signaling pathway. However, induction of this pathway with fenofibrate treatment, rescued axon regeneration following an injury to the central nerves. Collectively, our results uncovered a previously unappreciated role of the neuronal microenvironment differential response in central and peripheral injuries.

The amyloid cascade hypothesis for Alzheimer disease ((Hardy and Selkoe, 2002; Hardy and Higgins, 1992; Selkoe, 1991), updated in (Karran et al., 2011) provides a linear model for the pathogenesis of AD with Aβ accumulation upstream and Tau pathology, inflammation, synaptic dysfunction, neuronal loss and dementia downstream, all interlinked, initiated and driven by Aβ42 peptides or oligomers. The genetic mutations causing familial Alzheimer disease seem to support this model. The nagging problem remains however that the postulated causal, and especially the ’driving’ role of abnormal Aβ aggregation or Aβ oligomer formation could not be convincingly demonstrated until now. Indeed, many questions (e.g. what causes Aβ toxicity, what is the relation between Aβ and Tau pathology, what causes neuronal death, why is amyloid deposition not correlated with dementia etc…) were already raised when the amyloid hypothesis was conceived 25 years ago. These questions remain in essence unanswered. It seems that the old paradigm is not tenable: the amyloid cascade is too linear, too neurocentric, and does not take into account the long time lag between the biochemical phase i.e. the appearance of amyloid plaques and neuronal tangles and the ultimate clinical phase, i.e. the manifestation of dementia. The pathways linking these two phases must be complex and tortuous. We have called this the cellular phase of AD (De Strooper and Karran, 2016) to suggest that a long period of action and reaction involving neurons, neuronal circuitry but also microglia, astroglia, oligodendrocytes, and the vasculature underlies the disease. In fact it is this long disease process that should be studied in the coming years. While microglia are part of this process, they should not be considered as the only component of the cellular phase. We expect that further clinical investigations and novel tools will allow to diagnose the effects of the cellular changes in the brain and provide clinical signs for this so called preclinical or prodromal AD. Furthermore the better understanding of this phase will lead to completely novel drug targets and treatments and will lead to an era where patients will receive an appropriate therapy according to their clinical stage. In this view anti-amyloid therapy is probably only effective and useful in the very early stage of the disease and AD does no longer equal to dementia. We will discuss in our talk how single cell technology and transplantation of human iPS cells into mouse brain allow to start to map in a systematic way the cellular phase of Alzheimer’s Disease.

Social interactions are central to the human experience, yet it is also one of the faculty of the brain that is the most impaired by mental illness. Similarly, social interactions are essential for animals to survive, reproduce, and raise their young. Over the years, my lab has attempted to decipher the unique characteristics of social recognition: what are the unique cues that trigger distinct social behaviors, what is the nature and identity of social behavior circuits, how is the function of these circuits different in males and females and how are they modulated by the animal physiological status? In this lecture, I will describe our recent progress in using genetic, imaging, molecular and behavioral approaches to understand how the brain controls specific social behaviors in both males and females, and how areas throughout the brain participate in the positive and negative controls of specific social interactions. I will also describe how new approaches of single cell transcriptomics have enabled us to uncover specific cell populations involved in distinct social behaviors and the basis of their activity modulation according to the animal state.

The Ca2+ modulated pulsatile secretions of glucagon and insulin by pancreatic α and β cells play a key role in glucose metabolism and homeostasis. However, how different types of cells in the islet couple and coordinate to give rise to various Ca2+ oscillation patterns and how these patterns are being tuned by paracrine regulation are still elusive. Here we developed a microfluidic device to facilitate long-term recording of islet Ca2+ activity at single cell level and found that islets show heterogeneous but intrinsic oscillation patterns. The α and β cells in an islet oscillate in antiphase and are globally phase locked to display a variety of oscillation modes. A mathematical model of islet oscillation maps out the dependence of the oscillation modes on the paracrine interactions between α and β cells. Our study reveals the origin of the islet oscillation patterns and highlights the role of paracrine regulation in tuning them.

The vagus nerve contains a diversity of sensory neurons that detect peripheral stimuli such as blood pressure changes at the aortic arch, lung expansion during breathing, meal-induced stomach distension, and chemotherapeutics that induce nausea. Underlying vagal sensory mechanisms are largely unresolved at a molecular level, presenting tremendously important problems in sensory biology. We charted vagal sensory neurons by single cell RNA sequencing, identifying novel cell surface receptors and classifying a staggering diversity of sensory neuron types. We then generated a collection of ires-Cre knock-in mice to target each neuron type, and adapted genetic tools for Cre-based anatomical mapping, in vivo imaging, targeted ablation, and optogenetic control of vagal neuron activity. We found different sensory neuron types that innervate the lung and exert powerful effects on breathing, others that monitor and control the digestive system, and yet others that innervate that innervate the larynx and protect the airways. Together with Ardem Patapoutian, we also identified a critical role for Piezo mechanoreceptors in the sensation of airway stretch, which underlies a classical respiratory reflex termed the Hering-Breuer inspiratory reflex, as well as in the neuronal sensation of blood pressure and the baroreceptor reflex.

The concerted production of the correct number and diversity of neurons and glia by neural stem cells is essential for intricate neural circuit assembly. In the developing cerebral cortex, radial glia progenitors (RGPs) are responsible for producing all neocortical neurons and certain glia lineages. We recently performed a clonal analysis by exploiting the genetic MADM (Mosaic Analysis with Double Markers) technology and discovered a high degree of non-stochasticity and thus deterministic mode of RGP behaviour. However, the cellular and molecular mechanisms controlling RGP lineage progression remain unknown. To this end we use quantitative MADM-based genetic paradigms at single cell resolution to define the cell-autonomous functions of signaling pathways controlling cortical neuron/glia genesis and postnatal stem cell behaviour in health and disease. Here I will outline our current understanding of the mechanistic framework instructing neural stem cell lineage progression and discuss new data about the role of genomic imprinting – an epigenetic phenomenon - in cortical development.

Bursts in gamma and other frequency ranges are thought to contribute to the efficiency of working memory or communication tasks. Abnormalities in bursts have also been associated with motor and psychiatric disorders. The determinants of burst generation are not known, specifically how single cell and connectivity parameters influence burst statistics and the corresponding brain states. We first present a generic mathematical model for burst generation in an excitatory-inhibitory (EI) network with self-couplings. The resulting equations for the stochastic phase and envelope of the rhythm’s fluctuations are shown to depend on only two meta-parameters that combine all the network parameters. They allow us to identify different regimes of amplitude excursions, and to highlight the supportive role that network finite-size effects and noisy inputs to the EI network can have. We discuss how burst attributes, such as their durations and peak frequency content, depend on the network parameters. In practice, the problem above follows the a priori challenge of fitting such E-I spiking networks to single neuron or population data. Thus, the second part of the talk will discuss a novel method to fit mesoscale dynamics using single neuron data along with a low-dimensional, and hence statistically tractable, single neuron model. The mesoscopic representation is obtained by approximating a population of neurons as multiple homogeneous ‘pools’ of neurons, and modelling the dynamics of the aggregate population activity within each pool. We derive the likelihood of both single-neuron and connectivity parameters given this activity, which can then be used to either optimize parameters by gradient ascent on the log-likelihood, or to perform Bayesian inference using Markov Chain Monte Carlo (MCMC) sampling. We illustrate this approach using an E-I network of generalized integrate-and-fire neurons for which mesoscopic dynamics have been previously derived. We show that both single-neuron and connectivity parameters can be adequately recovered from simulated data.