Lamin
Lamin
Modeling human brain development and disease: the role of primary cilia
Neurodevelopmental disorders (NDDs) impose a global burden, affecting an increasing number of individuals. While some causative genes have been identified, understanding the human-specific mechanisms involved in these disorders remains limited. Traditional gene-driven approaches for modeling brain diseases have failed to capture the diverse and convergent mechanisms at play. Centrosomes and cilia act as intermediaries between environmental and intrinsic signals, regulating cellular behavior. Mutations or dosage variations disrupting their function have been linked to brain formation deficits, highlighting their importance, yet their precise contributions remain largely unknown. Hence, we aim to investigate whether the centrosome/cilia axis is crucial for brain development and serves as a hub for human-specific mechanisms disrupted in NDDs. Towards this direction, we first demonstrated species-specific and cell-type-specific differences in the cilia-genes expression during mouse and human corticogenesis. Then, to dissect their role, we provoked their ectopic overexpression or silencing in the developing mouse cortex or in human brain organoids. Our findings suggest that cilia genes manipulation alters both the numbers and the position of NPCs and neurons in the developing cortex. Interestingly, primary cilium morphology is disrupted, as we find changes in their length, orientation and number that lead to disruption of the apical belt and altered delamination profiles during development. Our results give insight into the role of primary cilia in human cortical development and address fundamental questions regarding the diversity and convergence of gene function in development and disease manifestation. It has the potential to uncover novel pharmacological targets, facilitate personalized medicine, and improve the lives of individuals affected by NDDs through targeted cilia-based therapies.
Food, taste, and the role of the cortical laminar in action and imagination
Chemistry of the adaptive mind: lessons from dopamine
The human brain faces a variety of computational dilemmas, including the flexibility/stability, the speed/accuracy and the labor/leisure tradeoff. I will argue that striatal dopamine is particularly well suited to dynamically regulate these computational tradeoffs depending on constantly changing task demands. This working hypothesis is grounded in evidence from recent studies on learning, motivation and cognitive control in human volunteers, using chemical PET, psychopharmacology, and/or fMRI. These studies also begin to elucidate the mechanisms underlying the huge variability in catecholaminergic drug effects across different individuals and across different task contexts. For example, I will demonstrate how effects of the most commonly used psychostimulant methylphenidate on learning, Pavlovian and effortful instrumental control depend on fluctuations in current environmental volatility, on individual differences in working memory capacity and on opportunity cost respectively.
Retinal neurogenesis and lamination: What to become, where to become it and how to move from there!
The vertebrate retina is an important outpost of the central nervous system, responsible for the perception and transmission of visual information. It consists of five different types of neurons that reproducibly laminate into three layers, a process of crucial importance for the organ’s function. Unsurprisingly, impaired fate decisions as well as impaired neuronal migrations and lamination lead to impaired retinal function. However, how processes are coordinated at the cellular and tissue level and how variable or robust retinal formation is, is currently still underexplored. In my lab, we aim to shed light on these questions from different angles, studying on the one hand differentiation phenomena and their variability and on the other hand the downstream migration and lamination phenomena. We use zebrafish as our main model system due to its excellent possibilities for live imaging and quantitative developmental biology. More recently we also started to use human retinal organoids as a comparative system. We further employ cross disciplinary approaches to address these issues combining work of cell and developmental biology, biomechanics, theory and computer science. Together, this allows us to integrate cell with tissue-wide phenomena and generate an appreciation of the reproducibility and variability of events.
The circadian clock and neural circuits maintaining body fluid homeostasis
Neurons in the suprachiasmatic nucleus (SCN, the brain’s master circadian clock) display a 24 hour cycle in the their rate of action potential discharge whereby firing rates are high during the light phase and lower during the dark phase. Although it is generally agreed that this cycle of activity is a key mediator of the clock’s neural and humoral output, surprisingly little is known about how changes in clock electrical activity can mediate scheduled physiological changes at different times of day. Using opto- and chemogenetic approaches in mice we have shown that the onset of electrical activity in vasopressin releasing SCN neurons near Zeitgeber time 22 (ZT22) activates glutamatergic thirst-promoting neurons in the OVLT (organum vasculosum lamina terminalis) to promote water intake prior to sleep. This effect is mediated by activity-dependent release of vasopressin from the axon terminals of SCN neurons which acts as a neurotransmitter on OVLT neurons. More recently we found that the clock receives excitatory input from a different subset of sodium sensing neurons in the OVLT. Activation of these neurons by a systemic salt load delivered at ZT19 stimulated the electrical activity of SCN neurons which are normally silent at this time. Remarkably, this effect induced an acute reduction in non-shivering thermogenesis and body temperature, which is an adaptive response to the salt load. These findings provide information regarding the mechanisms by which the SCN promotes scheduled physiological rhythms and indicates that the clock’s output circuitry can also be recruited to mediate an unscheduled homeostatic response.
An in-silico framework to study the cholinergic modulation of the neocortex
Neuromodulators control information processing in cortical microcircuits by regulating the cellular and synaptic physiology of neurons. Computational models and detailed simulations of neocortical microcircuitry offer a unifying framework to analyze the role of neuromodulators on network activity. In the present study, to get a deeper insight in the organization of the cortical neuropil for modeling purposes, we quantify the fiber length per cortical volume and the density of varicosities for catecholaminergic, serotonergic and cholinergic systems using immunocytochemical staining and stereological techniques. The data obtained are integrated into a biologically detailed digital reconstruction of the rodent neocortex (Markram et al, 2015) in order to model the influence of modulatory systems on the activity of the somatosensory cortex neocortical column. Simulations of ascending modulation of network activity in our model predict the effects of increasing levels of neuromodulators on diverse neuron types and synapses and reveal a spectrum of activity states. Low levels of neuromodulation drive microcircuit activity into slow oscillations and network synchrony, whereas high neuromodulator concentrations govern fast oscillations and network asynchrony. The models and simulations thus provide a unifying in silico framework to study the role of neuromodulators in reconfiguring network activity.
Malformation of cortical development: the genesis of epileptogenic networks
Malformations of cortical development (MCDs) result from alterations of one or combined developmental steps, including progenitors proliferation, neuronal migration and differentiation. They are important cause of childhood epilepsy and frequently associate cognitive deficits and behavioral alterations. Though the genetic basis of MCDs have known prominent progress during the past decade, including the identification of somatic, mosaic mutations responsible for focal MCDs, the pathophysiological mechanisms linking malformations to epileptogenesis remain elusive. In this seminar I will present data from my team and from the literature addressing this topic in two different MCDs types, the subcortical band heterotopia as a model of cortical migration defect and mTOR- dependent MCDs , that characterize by cortical dyslamination and neuronal differentiation defects.
Toxic effect of pathogenic tau on the nucleus
The nuclear envelope is a lipid bilayer that encases the genome and provides a physical boundary between the cytoplasm and the nucleoplasm. While the nucleus is typically depicted as a sphere encircled by a smooth surface of nuclear envelope, the smooth exterior can be interrupted by tubular invaginations of the nuclear envelope into the deep nuclear interior. Such structures are termed the "nucleoplasmic reticulum." Increased frequency of nuclear envelope invagination occurs in disease states including various cancers, viral infections, and laminopathies, a group of heterogeneous disorders that arise due to mutations in the gene encoding lamin A. A significant increase in the frequency of nuclear envelope invaginations in the human Alzheimer's disease brain has recently been reported. Nuclear envelope invaginations are caused by pathogenic tau, one of the two major pathological hallmarks of Alzheimer's disease. Pathogenic tau-induced dysfunction of the lamin nucleoskeleton drives nuclear envelope invagination and consequent accumulation of polyadenylated RNA within invaginations, both of which drive neuronal death. Our ongoing studies suggest that maintaining proper cytoskeletal, nucleoskeletal, and genomic architecture are critical for survival and function of adult neurons.
Neural mechanisms of active vision in the marmoset monkey
Human vision relies on rapid eye movements (saccades) 2-3 times every second to bring peripheral targets to central foveal vision for high resolution inspection. This rapid sampling of the world defines the perception-action cycle of natural vision and profoundly impacts our perception. Marmosets have similar visual processing and eye movements as humans, including a fovea that supports high-acuity central vision. Here, I present a novel approach developed in my laboratory for investigating the neural mechanisms of visual processing using naturalistic free viewing and simple target foraging paradigms. First, we establish that it is possible to map receptive fields in the marmoset with high precision in visual areas V1 and MT without constraints on fixation of the eyes. Instead, we use an off-line correction for eye position during foraging combined with high resolution eye tracking. This approach allows us to simultaneously map receptive fields, even at the precision of foveal V1 neurons, while also assessing the impact of eye movements on the visual information encoded. We find that the visual information encoded by neurons varies dramatically across the saccade to fixation cycle, with most information localized to brief post-saccadic transients. In a second study we examined if target selection prior to saccades can predictively influence how foveal visual information is subsequently processed in post-saccadic transients. Because every saccade brings a target to the fovea for detailed inspection, we hypothesized that predictive mechanisms might prime foveal populations to process the target. Using neural decoding from laminar arrays placed in foveal regions of area MT, we find that the direction of motion for a fixated target can be predictively read out from foveal activity even before its post-saccadic arrival. These findings highlight the dynamic and predictive nature of visual processing during eye movements and the utility of the marmoset as a model of active vision. Funding sources: NIH EY030998 to JM, Life Sciences Fellowship to JY
Understanding and treating epilepsy in tuberous sclerosis complex
Tuberous sclerosis complex (TSC) and focal cortical dysplasia type II (FCDII) are caused by mutations in mTOR pathway genes leading to mTOR hyperactivity, focal malformations of cortical development (fMCD), and seizures in 80-90% of the patients. The current definitive treatments for epilepsy are surgical resection or treatment with everolimus, which inhibits mTOR activity (only approved for TSC). Because both options have severe limitations, there is a major need to better understand the mechanisms leading to seizures to improve life-long epilepsy treatment in TSC and FCDII. To investigate such mechanisms, we recently developed a murine model of fMCD-associated epilepsy that recapitulates the human TSC and FCDII disorders. fMCD are defined by the presence of misplaced, dysmorphic cortical neurons expressing hyperactive mTOR – for simplicity we will refer to these as “mutant” neurons. In our model and in human TSC tissue, we made a surprising finding that mutant neurons express HCN4 channels, which are not normally functionally expressed in cortical neurons, and increased levels of filamin A (FLNA). FLNA is an actin-crossing linking molecule that has also multiple binding partners inside cells. These data led us to ask several important questions: (1) As HCN4 channels are responsible for the pacemaking activity of the heart, can HCN4 channel expression lead to repetitive firing of mutant neurons resulting in seizures? (2) HCN4 is the most cAMP-sensitive of the four HCN isoforms. Does increase in cAMP lead to the firing of mutant neurons? (3) Does increase in FLNA contribute to neuronal alterations and seizures? (4) Is the abnormal HCN4 and FLNA expression in mutant neurons due to mTOR? These questions will be discussed and addressed in the lecture.
From oscillations to laminar responses - characterising the neural circuitry of autobiographical memories
Autobiographical memories are the ghosts of our past. Through them we visit places long departed, see faces once familiar, and hear voices now silent. These, often decades-old, personal experiences can be recalled on a whim or come unbidden into our everyday consciousness. Autobiographical memories are crucial to cognition because they facilitate almost everything we do, endow us with a sense of self and underwrite our capacity for autonomy. They are often compromised by common neurological and psychiatric pathologies with devastating effects. Despite autobiographical memories being central to everyday mental life, there is no agreed model of autobiographical memory retrieval, and we lack an understanding of the neural mechanisms involved. This precludes principled interventions to manage or alleviate memory deficits, and to test the efficacy of treatment regimens. This knowledge gap exists because autobiographical memories are challenging to study – they are immersive, multi-faceted, multi-modal, can stretch over long timescales and are grounded in the real world. One missing piece of the puzzle concerns the millisecond neural dynamics of autobiographical memory retrieval. Surprisingly, there are very few magnetoencephalography (MEG) studies examining such recall, despite the important insights this could offer into the activity and interactions of key brain regions such as the hippocampus and ventromedial prefrontal cortex. In this talk I will describe a series of MEG studies aimed at uncovering the neural circuitry underpinning the recollection of autobiographical memories, and how this changes as memories age. I will end by describing our progress on leveraging an exciting new technology – optically pumped MEG (OP-MEG) which, when combined with virtual reality, offers the opportunity to examine millisecond neural responses from the whole brain, including deep structures, while participants move within a virtual environment, with the attendant head motion and vestibular inputs.
The impact of elongation on transport in shear flow
I shall present two recent piece of work investigating how shape effects the transport of active particles in shear. Firstly we will consider the sedimentation of particles in 2D laminar flow fields of increasing complexity; and how insights from this can help explain why turbulence can enhance the sedimentation of negatively buoyant diatoms [1]. Secondly, we will consider the 3D transport of elongated active particles under the action of an aligning force (e.g. gyrotactic swimmers) in some simple flow fields; and will see how shape can influence the vertical distribution, for example changing the structure of thin layers [2]. [1] Enhanced sedimentation of elongated plankton in simple flows (2018). IMA Journal of Applied Mathematics W Clifton, RN Bearon, & MA Bees. [2] Elongation enhances migration through hydrodynamic shear (in Prep), RN Bearon & WM Durham.
Plasticity in hypothalamic circuits for oxytocin release
Mammalian babies are “sensory traps” for parents. Various sensory cues from the newborn are tremendously efficient in triggering parental responses in caregivers. We recently showed that core aspects of maternal behavior such as pup retrieval in response to infant vocalizations rely on active learning of auditory cues from pups facilitated by the neurohormone oxytocin (OT). Release of OT from the hypothalamus might thus help induce recognition of different infant cues but it is unknown what sensory stimuli can activate OT neurons. I performed unprecedented in vivo whole-cell and cell-attached recordings from optically-identified OT neurons in awake dams. I found that OT neurons, but not other hypothalamic cells, increased their firing rate after playback of pup distress vocalizations. Using anatomical tracing approaches and channelrhodopsin-assisted circuit mapping, I identified the projections and brain areas (including inferior colliculus, auditory cortex, and posterior intralaminar thalamus) relaying auditory information about social sounds to OT neurons. In hypothalamic brain slices, when optogenetically stimulating thalamic afferences to mimic high-frequency thalamic discharge, observed in vivo during pup calls playback, I found that thalamic activity led to long-term depression of synaptic inhibition in OT neurons. This was mediated by postsynaptic NMDARs-induced internalization of GABAARs. Therefore, persistent activation of OT neurons following pup calls in vivo is likely mediated by disinhibition. This gain modulation of OT neurons by infant cries, may be important for sustaining motivation. Using a genetically-encoded OT sensor, I demonstrated that pup calls were efficient in triggering OT release in downstream motivational areas. When thalamus projections to hypothalamus were inhibited with chemogenetics, dams exhibited longer latencies to retrieve crying pups, suggesting that the thalamus-hypothalamus noncanonical auditory pathway may be a specific circuit for the detection of social sounds, important for disinhibiting OT neurons, gating OT release in downstream brain areas, and speeding up maternal behavior.
Using evolutionary algorithms to explore single-cell heterogeneity and microcircuit operation in the hippocampus
The hippocampus-entorhinal system is critical for learning and memory. Recent cutting-edge single-cell technologies from RNAseq to electrophysiology are disclosing a so far unrecognized heterogeneity within the major cell types (1). Surprisingly, massive high-throughput recordings of these very same cells identify low dimensional microcircuit dynamics (2,3). Reconciling both views is critical to understand how the brain operates. " "The CA1 region is considered high in the hierarchy of the entorhinal-hippocampal system. Traditionally viewed as a single layered structure, recent evidence has disclosed an exquisite laminar organization across deep and superficial pyramidal sublayers at the transcriptional, morphological and functional levels (1,4,5). Such a low-dimensional segregation may be driven by a combination of intrinsic, biophysical and microcircuit factors but mechanisms are unknown." "Here, we exploit evolutionary algorithms to address the effect of single-cell heterogeneity on CA1 pyramidal cell activity (6). First, we developed a biophysically realistic model of CA1 pyramidal cells using the Hodgkin-Huxley multi-compartment formalism in the Neuron+Python platform and the morphological database Neuromorpho.org. We adopted genetic algorithms (GA) to identify passive, active and synaptic conductances resulting in realistic electrophysiological behavior. We then used the generated models to explore the functional effect of intrinsic, synaptic and morphological heterogeneity during oscillatory activities. By combining results from all simulations in a logistic regression model we evaluated the effect of up/down-regulation of different factors. We found that muyltidimensional excitatory and inhibitory inputs interact with morphological and intrinsic factors to determine a low dimensional subset of output features (e.g. phase-locking preference) that matches non-fitted experimental data.
Misplaced and misconnected: circuit-level defects in malformations of cortical development
During histogenesis of the cerebral cortex, a proper laminar placement of defined numbers of specific cellular types is necessary to ensure proper functional connectivity patterns. There is a wide range of cortical malformations causing epilepsy and intellectual disability in humans, characterized with various degrees of neuronal misplacement, aberrant circuit organization or abnormal folding patterns. Although progress in human neurogenetics and brain imaging techniques have considerably advanced the identification of their causative genes, the pathophysiological mechanisms associated with defective cerebral cortex development remain poorly understood. In my presentation, I will outline some of our recent works in rodent models illustrating how misplaced neurons forming grey matter heterotopia, a cortical malformation subtype, interfere with the proper development of cortical circuits, and induce both local and distant circuitry changes associated with the subsequent emergence of epilepsy.
The evolutionary origins of cortical cell types
In the last 500 million years, the dorsal telencephalon changed like no other region of the vertebrate brain. Differences range from the six-layered neocortex of mammals, to the small three-layered cortex of reptiles, and the complete absence of lamination in birds. These anatomical differences have prompted endless discussions on the origins and evolution of the cerebral cortex. We have approached this problem from a cell type and transcriptomics perspective. This reveals a more granular picture, where different cell types and classes have followed independent trajectories of evolutionary change. In this presentation, I will discuss how the molecular analysis of cell types in the brains of turtles, lizards and amphibians is updating our views on the evolution of the cerebral cortex, and the new questions emerging from these results.
Stable cortical coding for a dexterous reach-to-grasp task across motor cortical laminae
Bernstein Conference 2024
Neuronal-laminar mechanisms of interictal epileptiform discharges
COSYNE 2025
Anisotropy in visual crowding is reflected in inter-laminar interactions of macaque V1
COSYNE 2023
State-dependent modulation of dependencies in a laminar cortical circuit
COSYNE 2023
An alternative to treat depression-like behaviors: The effects of S-mecamylamine in the dorsal raphe nucleus
FENS Forum 2024
Cell- and layer-type specific intracortical effects of pulsed and continuous wave infrared neural stimulation revealed by high-density laminar recordings in the rat neocortex
FENS Forum 2024
Complex sublamination of cortical marginal zone in human and monkey at midgestation
FENS Forum 2024
Cortex-wide high-density ECoG and translaminar local field potential recordings reveal rich broad-band spatio-temporal dynamics
FENS Forum 2024
Effects of methylcobalamin on bone formation via peripheral nerves and macrophages
FENS Forum 2024
Exploring the potential of readthrough drugs on MMACHC nonsense mutation R132* responsible for cobalamin C defect
FENS Forum 2024
Fiber density analysis of the catecholaminergic projections in the Japanese quail
FENS Forum 2024
Filamin A modulates dendritic branching via integrin-Akt axis and actin cytoskeleton
FENS Forum 2024
Intermale aggression is inhibited by posterior intralaminar thalamic neurons in rats
FENS Forum 2024
Laminar distribution pattern and size of crossed corticostriatal neurons in macaques
FENS Forum 2024
Laminar synaptic characteristics of the human entorhinal cortex
FENS Forum 2024
Linking hippocampal population firing dynamics to ripples laminar profiles
FENS Forum 2024
Maternally activated connections of the ventral lateral septum reveal input from the posterior intralaminar thalamus
FENS Forum 2024
Methylcobalamin promotes angiogenesis after peripheral nerve injury
FENS Forum 2024
Methylcobalamin promotes Ras-mediated Akt phosphorylation to induce anti-inflammatory phenotype in macrophages following peripheral nerve injury: A rat model study
FENS Forum 2024
Modulation of event segmentation dynamics through catecholamines: Exploring the role of learning and stimulus novelty
FENS Forum 2024
N-methylpropargylamino-quinazoline derivatives as potential multi-target directed ligands in the therapy of Alzheimer's disease
FENS Forum 2024
Noradrenergic modulation of stress-induced catecholamine release optimizes motivated decision-making behavior
FENS Forum 2024
A three-dimensional laminar electrode array for semi-chronic neural recordings in human cortex
FENS Forum 2024
Transcriptomic and sublaminar dynamics of the developing human frontal cortex: A novel approach
FENS Forum 2024
The variability of spectro-laminar beta rhythm patterns in macaque motor cortex reflects task and behavioral parameters
FENS Forum 2024