1,721,037 research outputs found
Whole- Brain Functional Ultrasound Imaging Reveals Brain Modules for Visuomotor Integration
No full textLarge numbers of brain regions are active during behaviors. A high-resolution, brain-wide activity map could identify brain regions involved in specific behaviors. We have developed functional ultrasound imaging to record whole-brain activity in behaving mice at a resolution of ∼100 μm. We detected 87 active brain regions during visual stimulation that evoked the optokinetic reflex, a visuomotor behavior that stabilizes the gaze both horizontally and vertically. Using a genetic mouse model of congenital nystagmus incapable of generating the horizontal reflex, we identified a subset of regions whose activity was reflex dependent. By blocking eye motion in control animals, we further separated regions whose activity depended on the reflex's motor output. Remarkably, all reflex-dependent but eye motion-independent regions were located in the thalamus. Our work identifies functional modules of brain regions involved in sensorimotor integration and provides an experimental approach to monitor whole-brain activity of mice in normal and disease states.sponsorship: We thank A. Drinnenberg, G. Kosche, D. Hillier, P. King, and S. Oakeley for commenting on the manuscript. We thank P. Argast for assistance with the head and probe holder prototyping. We acknowledge the following grants: Human Frontier Science Program Postdoctoral Fellowship (LT000769/2015) to E.M.; Swiss National Science Foundation Ambizione Grant (PZOOP3_168213) and Canada Research Chair Grant to S.T.; Swiss National Science Foundation grants (3100330B_163457), the National Center of Competence in Research Molecular Systems Engineering grant, European Research Council (669157, RETMUS), and DARPA (HR0011-17-C-0038, Cortical Sight) grants to B.R. (Human Frontier Science Program Postdoctoral Fellowship|LT000769/2015, Swiss National Science Foundation Ambizione Grant|PZOOP3_168213, Canada Research Chair Grant, Swiss National Science Foundation|3100330B_163457, European Research Council|669157, DARPA|HR0011-17-C-0038, National Center of Competence in Research Molecular Systems Engineering grant, European Research Council (ERC)|669157)status: Publishe
Learning-dependent modulation of inhibitory transmission in hippocampal CA1 area of adult mice
Full text linkLearning not only shapes the brain to form new memories but also affects future learning. Previous studies show that Pavlovian contextual fear conditioning (cFC) and environmental enrichment (EE) can inhibit or facilitate further learning via shifting parvalbumin (PV) interneurons network towards a high PV or low PV state in hippocampal neural circuit, respectively (Donato et al., 2013). The aim of my thesis study is to reveal the physiological relevance of learning-induced changes in PV interneuron network, and to investigate how these changes affect information processing of excitatory microcircuits.
By combining transgenic mouse lines, electrophysiological and behavioural studies, we showed that cFC homogenized the firing behaviour of PV cells. More PV cells fired with no adaptation and higher firing rates; on the contrary, EE led to more diversified firing behaviour in PV cells: more cells fired with pronounced adaptation but within a wide range of firing frequency. Such learning-dependent intrinsic plasticity of PV cells further modified hippocampal CA1 inhibitory transmission. The results showed that the inhibitory transmission in CA1 area was enhanced upon cFC; similar to the modulation effect on intrinsic excitability, EE diversified its modulation on inhibitory transmission with different directions onto two sub-groups. Interestingly, when we examined the Lsi1 subpopulation of principal cells, cFC exerted equal modulation on PV cell-mediated inhibitory transmission in Lsi1 cells as in averaged group of pyramidal cells; while EE enhanced the total Inhibitory postsynaptic currents (IPSC) and slightly increased PV cell-mediated IPSCs, which is different from the averaged group of pyramidal cells in hippocampus.
Overall, these results suggest that the behavioural experience can differentially modulate inhibitory transmission in hippocampal CA1 with a subpopulation specific manner. This neurophysiological knowledge will facilitate our understanding on the information processing in experience-modified neural circuits and how such modulation influence further learning. Future studies will be required to examine the molecular mechanism supporting these changes in inhibitory circuits upon learning
Regional and subpopulation rules for plasticity in the adult mouse hippocampus
Full text linkThe aim of my thesis was to elucidate regional and subpopulation rules for structural plasticity in the adult mouse hippocampus, which can provide insights to information processing and memory formation within the hippocampal circuitry.
Previous studies have shown that dorsal, intermediate and ventral hippocampus have distinct coding and behavioural roles, consistent with the distinct afferent and efferent connectivities along the longitudinal (dorsoventral) axis of the hippocampus. In addition, evidence for distinct hippocampal regions has been provided in the form of discrete molecular domains of gene expression across the hippocampus. However, none of these studies has investigated the anatomy and connectivity at the level of individual identified neurons. Also, it still remains unknown whether structural plasticity upon experience and learning may differ along the dorsoventral axis of the hippocampus and across distinct mossy fibre subpopulations.
To address these questions, I mapped granule cell mossy fibre anatomy and connectivity throughout the hippocampus in three “sparse” Thy1 transgenic reporter mice (Lsi1, Lsi2 and Lsi3) that express membrane-targeted GFP in a subset of principal neurons. By combining behavioural and lesion experiments, as well as high-resolution confocal microscopy and gene expression analysis, I provide evidence that distinct regions of the hippocampus (dorsal, intermediate and ventral) and distinct subpopulations of granule cells exhibit different anatomy and connectivity under baseline conditions and upon learning. Using the growth of filopodial synapses that mediate feed-forward inhibition to the network in CA3 as a specific readout for learning, I show that the dorsal hippocampus encodes spatial information and is specifically recruited for spatial learning, while the ventral hippocampus encodes goal-oriented information and is specifically recruited for goal-oriented learning. Moreover, the results reveal objective distinctions at the circuit level between hippocampal-dependent memory and hippocampal-dependent learning. In addition, I provide evidence that distinct granule cell subpopulations respond in unique ways to experience and learning, suggesting that principal neuron subpopulations may have distinct functional roles in hippocampal-dependent learning and memory
Formation & maintenance of photoreceptor outer segments
Full text linkHigh-resolution vision is mediated by cone photoreceptors. The molecular programs responsible for the formation and maintenance of their light sensor, the outer segment, are not well understood.
In my main project, I correlated daily changes in ultrastructure and gene expression in postmitotic mouse cone photoreceptors in the retina, between birth and eye opening, using serial block-face electron microscopy and RNA sequencing. Outer segments appeared rapidly at postnatal day six and their appearance coincided with a switch in gene expression. The switch affected more than 14\% of all genes expressed in cones. Genes that switched off were rich in transcription factors and neurogenic genes. Those that switched on contained genes relevant for cone function. Extensive chromatin rearrangements in enhancer regions occurred before the switch but not after. This work shows that the growth of a key compartment of a postmitotic sensory cell involves a rapid and extensive switch in gene expression and chromatin accessibility.
In a side project, my coworkers and me found that miRNAs 182 and 183 are necessary for cone outer segment maintenance in vivo and functional outer segment formation in stem cell derived retinal organoids
Excess dopamine D2R activation accounts for PV+ basket cell and learning alterations in mouse model of schizophrenia
Full text linkSchizophrenia is consistently associated with alterations in parvalbumin-positive basket cell functions, and with reduced gamma power of network activity, but causal relationships between PV dysfunctions and clinical manifestations of schizophrenia have remained unclear. Here I investigated LgDel+/- mice, a genetic model closely reproducing chromosomal deletions in 22q11 patients. I found that early-born PV interneurons are specifically affected in the LgDel+/- mice, suggesting a specific deficit in synaptic excitation of PV neurons. The PV alterations were associated with specific deficits in long-term memory consolidation and in top-down executive control. Delivery of the D2-receptor antagonist haloperidol to mutant mice rescued PV network alterations and long-term memory. My findings are consistent with the notion that PV network deregulation has an important role in cognitive deficits of schizophrenia model mice
Restoring vision: therapy and mechanisms of disease
Full text linkEnabling near-infrared light sensitivity in a blind human retina may supplement or restore visual function in patients with regional retinal degeneration. We induced near-infrared light sensitivity using gold nanorods bound to temperature-sensitive engineered transient receptor potential (TRP) channels. We expressed mammalian or snake TRP channels in light-insensitive retinal cones in a mouse model of retinal degeneration. Near-infrared stimulation increased activity in cones, ganglion cell layer neurons and cortical neurons, and enabled mice to perform a learned, light-driven behavior. We tuned responses to different wavelengths by using nanorods with different lengths, and to different radiant powers by using engineered channels with different temperature thresholds. We targeted TRP channels to human retinas, which allowed the activation of different cell types by near-infrared light, post-mortem
Combining Atomic Force Microscopy and Novel Methods in Viral Tracing to Study Neural Connectivity
No full textCortical control of forelimb movement
Full text linkCortical control of movement is mediated by wide-spread projections impacting many nervous system regions in a top-down manner. Although much knowledge about cortical circuitry has been accumulated from local cortical microcircuits, cortico-cortical and cortico-subcortical networks, how cortex communicates to regions closer to motor execution, including the brainstem, is less well understood.
In this dissertation, we investigate the organization of cortico-medulla projections and their roles in controlling forelimb movement. We focus on anatomical and functional relationships between cortex and lateral rostral medulla (LatRM), a region in caudal brainstem which is shown to be key in the control of forelimb movement. Our findings reveal the precise anatomical and functional organization between different cortical regions and matched postsynaptic neurons in the caudal brainstem, tuned to different phases of one carefully orchestrated behavior, which advance the our knowledge on circuit mechanisms involved in the control of body movements, and unravel the logic of how the top-level control region in the mammalian nervous system – the cortex – intersects with a high degree of specificity with command centers in the brainstem and beyond
Characterization of the genetic landscape of hereditary retinopathies in Pakistan
Full text linkHereditary retinopathies (HRPs) are a group of rare Mendelian disorders often leading to progressive vision loss and potential blindness. Despite their monogenic nature, HRPs exhibit extensive genetic heterogeneity, with pathogenic variants identified in nearly 300 genes. In this study, we investigated the genetic landscape of HRPs in Pakistan, a population with high consanguinity and unique demographic features. A cohort of 213 families (722 affected individuals) underwent genetic analysis, primarily through whole-exome sequencing, achieving a molecular diagnosis in 80.3% of cases. Pathogenic or likely pathogenic variants were identified in 60 HRP-associated genes, with ABCA4, CRB1, MYO7A, PDE6B, and RP1 being the most prevalent. The findings underscore a distinct mutational spectrum, shaped by endogamy and recurrent founder mutations, differing from other populations
Mechanisms of pattern processing in olfactory bulb-like circuits
Full text linkThe scope of brain research spans several orders of magnitude ranging from
small groups of amino acid residues in ion channels to fMRI signals reflecting
activity averaged over thousands of neurones. From a theoreticians point of
view very interesting questions arise at an intermediate level of cellular but
not sub-cellular resolution. How do neuronal units interact to process
information? Is it possible to find general laws or a repertoire of
computational motifs that would allow mastering the enormous challenge posed
by the brain’s sheer complexity?
Here I took advantage of the zebrafish olfactory bulb which combines a number
of features that make it an ideal target for theoretical analysis. Firstly,
the primary input to the olfactory bulb is known and can be administered by
the experimenter, allowing for both, control over and an obvious
interpretation of evoked activity. Secondly, due to the small size of the
olfactory bulb (20.000—30.000 neurones) a substantial fraction of all neurones
participating in an odour response can be recorded from in a single
experiment. Finally, the synaptic architecture of the olfactory bulb is
comparatively well-understood and simple.
In this study I used computational models to identify the structural features
of the olfactory bulb that are essential to its function. In order to
mechanistically understand this relation I complemented computer simulations
with mathematical analysis.
It is known from large-scale imaging experiments that peripheral odour
representations consisting of overlapping spatial patterns of afferent
activity are transformed into less overlapping representations carried by
mitral and tufted cells, the output elements of the olfactory bulb. It is
hypothesised that in refining odour representations for the benefit of
downstream circuits this pattern decorrelation serves an important function
(see chapter 1). Interestingly, a minimalistic circuit model (chapter 1) was
sufficient to reproduce most aspects of experimentally observed mitral cell
responses suggesting that decorrelation in the olfactory bulb is a network
phenomenon rather than a consequence of sophisticated computational properties
of individual neurones. In addition, the model was mathematically tractable
which allowed me to describe to a high level of detail and stringency the
mechanism by which this circuit achieves universal pattern decorrelation. In
the course I could explain why sparse connectivity and a high mitral cell
spontaneous activity lead to effective pattern decorrelation.
In simulations I also observed that symmetric connectivity further improves
decorrelation performance. In chapter 2 I present partial results towards a
theoretical analysis of this effect.
I also performed computer simulations with more detailed models consisting of
integrate-and-fire units. These were mostly exploratory in nature and are
therefore not described in this thesis. I did, however, include technical
documentation for the simulator I programmed (appendices 4 and 5) in the hope
that it will be useful.
The final chapter makes a simple observation regarding odour categorisation
- …
