A 3-year postdoctoral position in functional neurogenetics is available within the Language & Genetics Department at the Max Planck Institute, Nijmegen, the Netherlands. Within this Department, the Imaging Genomics group performs large-scale studies to identify genes involved in left-right asymmetry of the human brain – a trait which can be altered in various neurodevelopmental disorders. A challenge then remains to understand the roles of the implicated genes in brain development and function. Mice show evidence for functional and neurophysiological asymmetries in their brains, and are therefore a promising model for investigating the functions of genes implicated through our studies in humans. Your role will be to investigate asymmetry in developing and adult mouse brain tissue using transcriptomics, immunohistochemistry and histology. This research will be carried out within a dedicated molecular biology laboratory at the Max Planck Institute, and in partnership with labs and facilities of the Radboud University Medical Center, Nijmegen. You will also be keen to learn and involve yourself in the ongoing research of the department more generally, which is focused on genetics of the neuron, brain, behaviour and cognition.

Job description A 3-year postdoctoral position in functional neurogenetics is available within the Language & Genetics Department at the Max Planck Institute, Nijmegen, the Netherlands. Within this Department, the Imaging Genomics group performs large-scale studies to identify genes involved in left-right asymmetry of the human brain – a trait which can be altered in various neurodevelopmental disorders. A challenge then remains to understand the roles of the implicated genes in brain development and function. Mice show evidence for functional and neurophysiological asymmetries in their brains, and are therefore a promising model for investigating the functions of genes implicated through our studies in humans. Your role will be to investigate asymmetry in developing and adult mouse brain tissue using transcriptomics, immunohistochemistry and histology. This research will be carried out within a dedicated molecular biology laboratory at the Max Planck Institute, and in partnership with labs and facilities of the Radboud University Medical Center, Nijmegen. You will also be keen to learn and involve yourself in the ongoing research of the department more generally, which is focused on genetics of the neuron, brain, behaviour and cognition.

A postdoctoral position (2 years duration) on brain imaging genomics is available at the Language and Genetics Department of the Max Planck Institute, Nijmegen, the Netherlands. We seek a postdoctoral researcher to investigate links between gene expression in the human cerebral cortex and inter-individual variations in brain and behaviour. The position will be embedded within the Imaging Genomics group of the host department, and will be carried out in collaboration with leading researchers at the Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen. The successful candidate will join an innovative research program that is seeking to characterize the brain’s molecular infrastructure for language, and integrate this with data on individual differences in brain and behaviour. This is an initiative of the Language in Interaction (LiI) consortium, sponsored by a major grant from the Netherlands Organisation for Scientific Research. We recently generated a unique gene expression dataset using spatial transcriptomics from regions of the human cerebral cortex that are important for language. The postdoctoral scientist will take the lead on integrative analyses linking gene expression to genetic association, making use of large-scale resources such as the UK Biobank (currently data from over 30,000 individuals with brain image and genetic data – including common single nucleotide polymorphisms and rare genetic variants) and the international GenLang Consortium (data from up to 34,000 individuals on reading- and language-related abilities together with genetic data). One major goal is to apply a recently-optimized pipeline for measuring white matter tracts in biobank-scale diffusion tensor imaging data, and subsequently to apply genetic techniques such as genome-wide association analysis, partitioned heritability analysis, and polygenic score analysis. The project therefore offers the possibility to learn state-of-the-art techniques in both brain image analysis and genetic analysis.

Understanding brain circuit evolution at single-cell resolution using comparative connectomics and transcriptomics A position for a postdoc is available in the Kebschull Lab at the Department of Biomedical Engineering at the Johns Hopkins School of Medicine in Baltimore, MD. We develop and apply cutting edge molecular and neuroanatomical tools to study how primordial circuits expanded in evolution to form the complex brains that exist today. We have a special focus on barcode sequencing-based high-throughput connectomics (BRICseq, MAPseq) and in situ sequencing, which we apply in the cerebellar nuclei and brain-wide in different vertebrates. Recent relevant papers include Kebschull et al. 2020 Science, Huang et al. 2020 Cell, Han et al. 2018 Nature, and Kebschull et al. 2016 Neuron. Our lab is located on the School of Medicine Campus of Johns Hopkins University, surrounded by world-class neuroscience and biomedical engineering labs. We are committed to establishing a first-class, stimulating, diverse, and equitable environment in our new lab to allow you to flourish, achieve your goals, and further your career. Qualified applicants should send a letter describing their current and future research interests, their CV, and names and contact details for three references to kebschull@jhu.edu. More information is available on https://www.kebschull-lab.org/.

The cortex comprises many neuronal types, which can be distinguished by their transcriptomes: the sets of genes they express. Little is known about the in vivo activity of these cell types, particularly as regards the structure of their spike trains, which might provide clues to cortical circuit function. To address this question, we used Neuropixels electrodes to record layer 5 excitatory populations in mouse V1, then transcriptomically identified the recorded cell types. To do so, we performed a subsequent recording of the same cells using 2-photon (2p) calcium imaging, identifying neurons between the two recording modalities by fingerprinting their responses to a “zebra noise” stimulus and estimating the path of the electrode through the 2p stack with a probabilistic method. We then cut brain slices and performed in situ transcriptomics to localize ~300 genes using coppaFISH3d, a new open source method, and aligned the transcriptomic data to the 2p stack. Analysis of the data is ongoing, and suggests substantial differences in spike time coordination between ET and IT neurons, as well as between transcriptomic subtypes of both these excitatory types.

Exploration of genome organization and function in the HIV infected brain is critical to aid in the understanding and development of treatments for HIV-associated neurocognitive disorder (HAND). Here, we applied a multiomic approach, including single nuclei transcriptomics, cell-type specific Hi-C 3D genome mapping, and viral integration site sequencing (IS-seq) to frontal lobe tissue from HIV-infected individuals with encephalitis (HIVE) and without encephalitis (HIV+). We observed reorganization of open/repressive (A/B) compartment structures in HIVE microglia encompassing 6.4% of the genome with enrichment for regions containing interferon (IFN) pathway genes. 3D genome remodeling was associated with transcriptomic reprogramming, including down-regulation of cell adhesion and synapse-related functions and robust activation of IFN signaling and cell migratory pathways, and was recapitulated by IFN-g stimulation of cultured microglial cells. Microglia from HIV+ brains showed, to a lesser extent, similar transcriptional alterations. IS-seq recovered 1,221 integration sites in the brain that were enriched for chromosomal domains newly mobilized into a permissive chromatin environment in HIVE microglia. Viral transcription, which was detected in 0.003% of all nuclei in HIVE brain, occurred in a subset of highly activated microglia that drove differential expression in HIVE. Thus, we observed a dynamic interrelationship of interferon-associated 3D genome and transcriptome remodeling with HIV integration and transcription in the brain.

Transcriptomics has revealed that cortical inhibitory neurons exhibit a great diversity of fine molecular subtypes, but it is not known whether these subtypes have correspondingly diverse activity patterns in the living brain. We show that inhibitory subtypes in primary visual cortex (V1) have diverse correlates with brain state, but that this diversity is organized by a single factor: position along their main axis of transcriptomic variation. We combined in vivo 2-photon calcium imaging of mouse V1 with a novel transcriptomic method to identify mRNAs for 72 selected genes in ex vivo slices. We classified inhibitory neurons imaged in layers 1-3 into a three-level hierarchy of 5 Subclasses, 11 Types, and 35 Subtypes using previously-defined transcriptomic clusters. Responses to visual stimuli differed significantly only across Subclasses, suppressing cells in the Sncg Subclass while driving cells in the other Subclasses. Modulation by brain state differed at all hierarchical levels but could be largely predicted from the first transcriptomic principal component, which also predicted correlations with simultaneously recorded cells. Inhibitory Subtypes that fired more in resting, oscillatory brain states have less axon in layer 1, narrower spikes, lower input resistance and weaker adaptation as determined in vitro and express more inhibitory cholinergic receptors. Subtypes firing more during arousal had the opposite properties. Thus, a simple principle may largely explain how diverse inhibitory V1 Subtypes shape state-dependent cortical processing.

Abuse, neglect, and other forms of uncontrollable stress during childhood and early adolescence can lead to adverse outcomes later in life, including especially perturbations in the regulation of mood and emotional states, and specifically anxiety disorders and depression. However, stress experiences vary from one individual to the next, meaning that causal relationships and mechanistic accounts are often difficult to establish in humans. This interdisciplinary talk considers the value of research in experimental animals where stressor experiences can be tightly controlled and detailed investigations of molecular, cellular, and circuit-level mechanisms can be carried out. The talk will focus on the widely used repeated maternal separation procedure in rats where rat offspring are repeatedly separated from maternal care during early postnatal life. This early life stress has remarkably persistent effects on behaviour with a general recognition that maternally-deprived animals are susceptible to depressive-like phenotypes. The validity of this conclusion will be critically appraised with convergent insights from a recent longitudinal study in maternally separated rats involving translational brain imaging, transcriptomics, and behavioural assessment.

To understand the function of the brain and how its dysfunction leads to brain diseases, it is essential to have a deep understanding of the cell type composition of the brain, how the cell types are connected with each other and what their roles are in circuit function. At the Allen Institute, we have built multiple platforms, including single-cell transcriptomics, single and multi-patching electrophysiology, 3D reconstruction of neuronal morphology, high throughput brain-wide connectivity mapping, and large-scale neuronal activity imaging, to characterize the transcriptomic, physiological, morphological, and connectional properties of different types of neurons in a standardized way, towards a taxonomy of cell types and a description of their wiring diagram for the mouse brain, with a focus on the visual cortico-thalamic system. Building such knowledge base lays the foundation towards the understanding of the computational mechanisms of brain circuit function.

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.

Emerging genetic studies of late-onset Alzheimer’s Disease implicate the brain’s resident macrophages in the pathogenesis of AD. More than half the risk genes associated with late-onset AD are selectively expressed in microglia and peripheral myeloid cells; yet we know little about the underlying biology or how myeloid cells contribute to AD pathogenesis. Using single-cell RNA sequencing and spatial transcriptomics we identified molecular signatures that can be used to localize and monitor distinct microglia functional states in the human and mouse brain. Our results show that microglia assume diverse functional states in development, aging and injury, including populations corresponding to known microglial functions including proliferation, migration, inflammation, and synaptic phagocytosis. We identified several innate immune pathways by which microglia recognize and prune synapses during development and in models of Alzheimer’s disease, including the classical complement cascade. Illuminating the mechanisms by which developing synaptic circuits are sculpted is providing important insight on understanding how to protect synapses in Alzheimer’s and other neurodegenerative diseases of synaptic dysfunction.

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.

I will introduce a web portal for the retinal neuroscience community to explore the catalog of mouse retinal ganglion cell (RGC) types, including data on light responses, correspondences with morphological types in EyeWire, and gene expression data from single-cell transcriptomics. Our current classification includes 43 types, accounting for 90% of the cells in EyeWire. Many of these cell types have new stories to tell, and I will cover two of them that represent opposite ends of the spectrum of levels of analysis in my lab. First, I will introduce the “Bursty Suppressed-by-Contrast” RGC and show how its intrinsic properties rather than its synaptic inputs differentiate its function from that of a different well-known RGC type. Second, I will present the histogram of cell types that project to the Olivary Pretectal Nucleus, focusing on the recently discovered M6 ipRGC.

In the last 500 million years, the dorsal telencephalon changed like no other region of the vertebrate brain. Differences range from the six-layered neocortex of mammals, to the small three-layered cortex of reptiles, and the complete absence of lamination in birds. These anatomical differences have prompted endless discussions on the origins and evolution of the cerebral cortex. We have approached this problem from a cell type and transcriptomics perspective. This reveals a more granular picture, where different cell types and classes have followed independent trajectories of evolutionary change. In this presentation, I will discuss how the molecular analysis of cell types in the brains of turtles, lizards and amphibians is updating our views on the evolution of the cerebral cortex, and the new questions emerging from these results.