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Introduction
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January 2010 - present
April 2000 - December 2009
September 1994 - March 2000
Publications
Publications (197)
Non-rapid eye movement (NREM) sleep facilitates memory consolidation by transferring information from the hippocampus to the neocortex. Recent evidence suggests that this transfer occurs primarily when hippocampal sharp-wave ripples (SWRs) and thalamocortical spindles are synchronized. In this study, we asked what role cortical layer 1 NDNF-express...
The reward and novelty related neuromodulator dopamine plays an important role in hippocampal long-term memory, which is thought to involve protein synthesis-dependent synaptic plasticity. However, the direct effects of dopamine on protein synthesis, and the functional implications of newly synthesized proteins for synaptic plasticity, have not yet...
The reward and novelty related neuromodulator dopamine plays an important role in hippocampal long-term memory, which is thought to involve protein synthesis-dependent synaptic plasticity. However, the direct effects of dopamine on protein synthesis, and the functional implications of newly synthesized proteins for synaptic plasticity, have not yet...
The reward and novelty related neuromodulator dopamine plays an important role in hippocampal long-term memory, which is thought to involve protein synthesis-dependent synaptic plasticity. However, the direct effects of dopamine on protein synthesis, and the functional implications of newly synthesized proteins for synaptic plasticity, have not yet...
Extracellular recordings of neuronal activity constitute a powerful tool for investigating the intricate dynamics of neural networks and the activity of individual neurons. Microelectrode arrays (MEAs) allow for recordings with a high electrode count, ranging from 10s to 1000s, generating extensive datasets of neuronal information. Furthermore, MEA...
Microelectrode array (MEA) recordings are commonly used to compare firing and burst rates in neuronal cultures. MEA recordings can also reveal microscale functional connectivity, topology and network dynamics—patterns seen in brain networks across spatial scales. Network topology is frequently characterized in neuroimaging with graph theoretical me...
Background
Amyloid‐beta (Aβ) pathology is suggested to precede the onset of clinical Alzheimer’s disease symptoms by up to two decades. The humanised App NL‐G‐F knock‐in model of amyloidopathy has accelerated pathogenesis and can be used to study AD progression. Here we used it to quantify the temporal and spatial characteristics of Aβ plaque accum...
Background
Hyperexcitability of neurons in the hippocampus and entorhinal cortex has been demonstrated in Alzheimer’s disease.
Method
We performed multi‐electrode array (MEA) recordings of hippocampal slices from young wild‐type mice, and the App NL‐F and App NL‐G‐F knock‐in (App‐KI) mouse models of Alzheimer’s disease amyloidopathy. To investigat...
Real-time neural signal processing is essential for brain-machine interfaces and closed-loop neuronal perturbations. However, most existing applications sacrifice cell-specific identity and temporal spiking information for speed. We developed a hybrid hardware-software system that utilizes a Field Programmable Gate Array (FPGA) chip to acquire and...
A fundamental unresolved problem in neuroscience is how the brain associates in memory events that are separated in time. Here we propose that reactivation-induced synaptic plasticity can solve this problem. Previously, we reported that the reinforcement signal dopamine converts hippocampal spike timing-dependent depression into potentiation during...
Synaptic plasticity plays a central role in the study of neural mechanisms of learning and memory. Plasticity rules are not invariant over time but are under neuromodulatory control, enabling behavioral states to influence memory formation. Neuromodulation controls synaptic plasticity at network level by directing information flow, at circuit level...
A fundamental unresolved problem in neuroscience is how the brain associates in memory events that are separated in time. Here we propose that reactivation-induced synaptic plasticity can solve this problem. Previously, we reported that the reinforcement signal dopamine converts hippocampal spike timing-dependent depression into potentiation during...
Amyloid-beta (Aβ) and tau protein are both involved in the pathogenesis of Alzheimer’s disease. Aβ produces synaptic deficits in wild-type mice that are not seen in Mapt−/− mice, suggesting that tau protein is required for these effects of Aβ. However, whether some synapses are more selectively affected and what factors may determine synaptic vulne...
Economical efficiency has been a popular explanation for how networks organize themselves within the developing nervous system. However, the precise nature of the economic negotiations governing this self- organization remain unclear. We approach this problem by combining high-density microelectrode array (HD-MEA) recordings, which allow for detail...
Hippocampal place cells fire at specific locations in the environment. They form a cognitive map that encodes spatial relations in the environment, including reward locations.¹ As part of this encoding, dorsal CA1 (dCA1) place cells accumulate at reward.2, 3, 4, 5 The encoding of learned reward location could vary between the dorsal and intermediat...
Amyotrophic lateral sclerosis overlapping with frontotemporal dementia (ALS/FTD) is a fatal and currently untreatable disease characterized by rapid cognitive decline and paralysis. Elucidating initial cellular pathologies is central to therapeutic target development, but obtaining samples from presymptomatic patients is not feasible. Here, we repo...
Hippocampal neurons encode a cognitive map for spatial navigation. When they fire at specific locations in the environment, they are known as place cells. In the dorsal hippocampus place cells accumulate at current navigational goals, such as learned reward locations. In the intermediate-to-ventral hippocampus (here collectively referred to as vent...
Slow-wave sleep is characterized by near-synchronous alternation of active Up states and quiescent Down states in the neocortex. Although the cortex itself can maintain these oscillations, the full expression of Up-Down states requires intact thalamocortical circuits. Sensory thalamic input can drive the cortex into an Up state. Here we show that m...
To survive, animals have to quickly modify their behaviour when the reward changes. The internal representations responsible for this are updated through synaptic weight changes, mediated by certain neuromodulators conveying feedback from the environment. In previous experiments, we discovered a form of hippocampal Spike-Timing-Dependent-Plasticity...
Neural correlates of external variables provide potential internal codes that guide an animal’s behavior. Notably, first-order features of neural activity, such as single-neuron firing rates, have been implicated in encoding information. However, the extent to which higher-order features, such as multineuron coactivity, play primary roles in encodi...
The hippocampus plays a central role in long-term memory formation, and different hippocampal network states are thought to have different functions in this process. These network states are controlled by neuromodulatory inputs, including the cholinergic input from the medial septum. Here, we used optogenetic stimulation of septal cholinergic neuro...
Optogenetics has revolutionised research in cell biology over the past 15 years, yet devices that can effectively stimulate cells using light are often costly and specifically designed for a single experimental set-up with little flexibility. Our novel ‘OptoGenie’ stimulation device can be conveniently transferred between cell culture incubators fo...
Cholinergic tone is high during wake and rapid eye movement sleep and lower during slow wave sleep (SWS). Nevertheless, the low tone of acetylcholine during SWS modulates sharp wave ripple incidence in the hippocampus and slow wave activity in the neocortex. Linking the hippocampus and neocortex, the medial entorhinal cortex (mEC) regulates the cou...
The hippocampus plays a central role in long-term memory formation, and different hippocampal network states are thought to play distinct roles in this process. These network states are controlled by neuromodulatory inputs, in particular the cholinergic input from the medial septum. Here, we used optogenetic stimulation of septal cholinergic neuron...
Coincidental spike discharge amongst distributed groups of neurons is thought to provide an efficient mechanism for encoding percepts, actions and cognitive processes. Short timescale coactivity can indeed bind neurons with similar tuning, giving rise to robust representations congruent with those of the participating neurons. Alternatively, coacti...
Spike-timing-dependent synaptic plasticity (STDP) is a leading cellular model for behavioral learning and memory with rich computational properties. However, the relationship between the millisecond-precision spike timing required for STDP and the much slower timescales of behavioral learning is not well understood. Neuromodulation offers an attrac...
Neural organoids have the potential to improve our understanding of human brain development and neurological disorders. However, it remains to be seen whether these tissues can model circuit formation with functional neuronal output. Here we have adapted air–liquid interface culture to cerebral organoids, leading to improved neuronal survival and a...
In addition to reducing seizures, anti-epileptic treatments should preserve physiological network activity. Here, we used a thalamocortical slice preparation displaying physiological slow oscillations to investigate the effects of anticonvulsant drugs on physiological activity and epileptiform activity in two pharmacological epilepsy models. Thus,...
In the classical view, postsynaptic NMDA receptors (NMDARs) trigger Hebbian plasticity via Ca2+ influx. However, unconventional presynaptic NMDARs (preNMDARs) which regulate both long-term and short-term plasticity at several synapse types have also been found. A lack of sufficiently specific experimental manipulations and a poor understanding of h...
In the classical view, postsynaptic NMDA receptors (NMDARs) trigger Hebbian plasticity via Ca2+influx. However, unconventional presynaptic NMDARs (preNMDARs) which regulate both long-term and short-term plasticity at several synapse types have also been found. A lack of sufficiently specific experimental manipulations and a poor understanding of ho...
The central cholinergic system and the amygdala are important for motivation and mnemonic processes. Different cholinergic populations innervate the amygdala, but it is unclear how these projections impact amygdala processes. Using optogenetic circuit-mapping strategies in choline acetyltransferase (ChAT)-cre mice, we demonstrate that amygdala-proj...
The central cholinergic system and the amygdala are important for motivation and mnemonic processes. Different cholinergic populations innervate the amygdala but it is unclear how these projections impact amygdala processes. Using optogenetic circuit-mapping strategies in ChAT-cre mice we demonstrate that amygdala-projecting basal forebrain and bra...
Three-dimensional neural organoids are emerging tools with the potential for improving our understanding of human brain development and neurological disorders. Recent advances in this field have demonstrated their capacity to model neurogenesis, neuronal migration and positioning, and even response to sensory input. However, it remains to be seen w...
Neuromodulation plays a fundamental role in the acquisition of new behaviours. Our experimental findings show that, whereas acetylcholine biases hippocampal synaptic plasticity towards depression, the subsequent application of dopamine can retroactively convert depression into potentiation. We previously demonstrated that incorporating this sequent...
Hypofunction of N-methyl-d-aspartate receptors (NMDARs) in inhibitory GABAergic interneurons is implicated in the pathophysiology of schizophrenia (SZ), a heritable disorder with many susceptibility genes. However, it is still unclear how SZ risk genes interfere with NMDAR-mediated synaptic transmission in diverse inhibitory interneuron populations...
Activity-dependent synaptic plasticity is critical for cortical circuit refinement. The synaptic homeostasis hypothesis suggests that synaptic connections are strengthened during wake and downscaled during sleep; however, it is not obvious how the same plasticity rules could explain both outcomes. Using whole-cell recordings and optogenetic stimula...
Hypofunction of N-methyl-D-aspartate receptors (NMDARs) in inhibitory GABAergic interneurons is implicated in the pathophysiology of schizophrenia (SZ), a heritable disorder with many susceptibility genes. However, it is still unclear how SZ risk genes interfere with NMDAR-mediated synaptic transmission in diverse inhibitory interneuron populations...
The entorhinal-hippocampal system is an important circuit in the brain, essential for certain cognitive tasks such as memory and navigation. Different gamma oscillations occur in this circuit, with the medial entorhinal cortex (mEC), CA3, and CA1 all generating gamma oscillations with different properties. These three gamma oscillations converge wi...
The entorhinal-hippocampal system is an important circuit in the brain, essential for certain cognitive tasks such as memory and navigation. Different gamma oscillations occur in this circuit, with the medial entorhinal cortex (mEC), CA3, and CA1 all generating gamma oscillations with different properties. These three gamma oscillations converge wi...
Slow-wave sleep is thought to be important for retuning cortical synapses, but the cellular mechanisms remain unresolved. During slow-wave activity, cortical neurons display synchronized transitions between depolarized Up states and hyperpolarized Down states. Here, using recordings from LIII pyramidal neurons from acute slices of mouse medial ento...
Spike timing-dependent plasticity (STDP) is under neuromodulatory control, which is correlated with distinct behavioral states. Previously, we reported that dopamine, a reward signal, broadens the time window for synaptic potentiation and modulates the outcome of hippocampal STDP even when applied after the plasticity induction protocol (Brzosko et...
Source data for Figure 1—figure supplement 1.DOI:
http://dx.doi.org/10.7554/eLife.27756.004
Source data for Figure 2—figure supplement 1.DOI:
http://dx.doi.org/10.7554/eLife.27756.010
Source data for Figure 1.DOI:
http://dx.doi.org/10.7554/eLife.27756.003
Source data for Figure 1—figure supplement 2.DOI:
http://dx.doi.org/10.7554/eLife.27756.005
Source data for Figure 2.DOI:
http://dx.doi.org/10.7554/eLife.27756.009
Microtubule associated protein tau (MAPT) is involved in the pathogenesis of Alzheimer's disease and many forms of frontotemporal dementia (FTD). We recently reported that Aβ-mediated inhibition of hippocampal long-term potentiation (LTP) in mice requires tau. Here, we asked whether expression of human MAPT can restore Aβ-mediated inhibition on a m...
(A) Protein stain of ACSF with Aβ42 (at a concentration of 44 μM to allow detection) following 2 h from preparation showing oligomeric composition.
Microtubule associated protein tau (MAPT) is involved in the pathogenesis of Alzheimer’s disease and many forms of frontotemporal dementia (FTD). We recently reported that Aβ-mediated inhibition of hippocampal long-term potentiation (LTP) in mice requires tau. Here, we asked whether expression of human $MAPT$ can restore Aβ-mediated inhibition on a...
Defining the organizational principles of neuronal network s at the cellular scale, or $\textit{micro-connectomics}$, is a key challenge of modern neuroscience. Accelerated by methodological advances, recent experimental studies have generated rich data on anatomical, physiological and genetic factors determining the organization of neuronal networ...
The medial entorhinal cortex (mEC) is a key structure which controls the communication between the hippocampus and the neocortex. During slow-wave sleep, it stands out from other cortical regions by exhibiting persistent activity that outlasts neocortical Up states, decoupling the entorhinal cortex-hippocampal interaction from the neocortex. Here,...
Lateralization of brain function has primarily been studied at the macroscopic level. Studies have detected gross anatomical differences in neuron types, numbers, distribution, and connectivity and related these to functional divisions between the two hemispheres. Comparatively little is known about lateralization of synaptic function. A notable ex...
The medial entorhinal cortex (mEC) is a key structure which controls the communication between the hippocampus and the neocortex. During slow-wave sleep, it stands out from other cortical regions by exhibiting persistent activity that outlasts neocortical Up states, decoupling the entorhinal cortex-hippocampal interaction from the neocortex. Here,...
Optogenetic studies in mice have revealed new relationships between well-defined neurons and brain functions. However, there are currently no means to achieve the same cell-type specificity in monkeys, which possess an expanded behavioral repertoire and closer anatomical homology to humans. Here, we present a resource for cell-type-specific channel...
Most cortical neurons fire regularly when excited by a constant stimulus. In contrast, irregular-spiking (IS) interneurons are remarkable for the intrinsic variability of their spike timing, which can synchronize amongst IS cells via specific gap junctions. Here, we have studied the biophysical mechanisms of this irregular spiking in mice, and how...
Spike timing-dependent plasticity (STDP) is a Hebbian learning rule important for synaptic refinement during development and
for learning and memory in the adult. Given the importance of the hippocampus in memory, surprisingly little is known about
the mechanisms and functions of hippocampal STDP. In the present work, we investigated the requiremen...
Tools that allow acute and selective silencing of synaptic transmission in vivo would be invaluable for understanding the synaptic basis of specific behaviors. Here, we show that presynaptic expression of the proton pump archaerhodopsin enables robust, selective, and reversible optogenetic synaptic silencing with rapid onset and offset. Two-photon...
Accurate identification of bursting activity is an essential element in the characterization of neuronal network activity. Despite this, no one technique for identifying bursts in spike trains has been widely adopted. Instead, many methods have been developed for the analysis of bursting activity, often on an ad hoc basis. Here, we provide an unbia...
Unlabelled:
Gamma oscillations (30-120 Hz) are thought to be important for various cognitive functions, including perception and working memory, and disruption of these oscillations has been implicated in brain disorders, such as schizophrenia and Alzheimer's disease. The cornu ammonis area 1 (CA1) of the hippocampus receives gamma frequency input...
Human brains possess sophisticated information processing capabilities, which rely on the coordinated interplay of billions of neurons. Despite recent advances in characterizing the collective neuronal dynamics, however, it remains a major challenge to understand the principles of how functional neuronal networks develop and maintain these processi...
Presynaptic NMDA receptors (preNMDARs) play pivotal roles in excitatory neurotransmission and synaptic plasticity. They facilitate presynaptic neurotransmitter release and modulate mechanisms controlling synaptic maturation and plasticity during formative periods of brain development. There is an increasing understanding of the roles of preNMDARs i...
Source data for Figure 3.DOI:
http://dx.doi.org/10.7554/eLife.09685.008