Past events

How information is processed within the brain is a key question in systems neuroscience. We address the issue in spiking neuronal networks of freely moving mice. I will describe our recent findings and conclusions pertaining to three specific information processing steps: transmission, representation, and storage. First, using feedforward optogenetic injection of white noise input to a small group of adjacent neocortical excitatory cells, we find that spike transmission to a postsynaptic cell exhibits error correction, improved precision, and temporal coding. The results are consistent with a nonlinear coincidence detection model in the postsynaptic neuron. Second, by triggering input on animal kinematics, we create an artificial place field in an otherwise-silent pyramidal cell. In hippocampal region CA1 but not in the neocortex, artificial fields exhibit synthetic phase precession that persists for a full cycle. The local conversion of an induced rate code into an emerging phase code is compatible with a dual-oscillator interference model. Third, by triggering input on spontaneous spiking, we impose self-terminating spike patterns in a group of presynaptic excitatory neurons and a postsynaptic cell. The precise timing of all pre- and postsynaptic spikes has a more substantial impact on long-lasting effective connectivity than that of individual cell pairs, revealing an unexpected plasticity mechanism. We conclude that intrinsic properties of single neurons support millisecond-timescale operations, and that cortical networks are organized in functional modules which we refer to as “converging assemblies”.

In families with febrile seizures and temporal lobe epilepsy, mutations affecting different GABAergic mechanisms suggest that failure of chloride conductance to limit depolarization may be directly epileptogenic. This “GABAergic disinhibition” hypothesis has been discounted historically for two reasons. First, early attempts to produce hippocampal sclerosis and epilepsy simply by eliminating hippocampal GABA neurons consistently failed to do so. Second, the notion persists that because clinical epilepsy diagnosis is typically delayed for years or decades after brain injury, temporal lobe epileptogenesis should be presumed to involve a complex pathological transformation process that reaches completion during this “latent period.” Recent advances clarify both issues. Although spatially limited hippocampal GABA neuron ablation causes only submaximal granule cell hyperexcitability, more spatially extensive ablation maximizes granule cell hyperexcitability and triggers nonconvulsive granule cell status epilepticus, hippocampal sclerosis, and epilepsy. Recent studies also show that disinhibited granule cells begin to generate clinically subtle seizures immediately post-injury, and these seizures then gradually increase in duration to become clinically obvious. Therefore, rather than being a seizure-free “gestational” state of potentially interruptible epileptogenesis, the “latent period” is more likely an active epileptic state when barriers to seizure spread and clinical expression are gradually overcome by a kindling process. The likelihood that an epileptic brain state exists long before clinical diagnosis has significant implications for anti-epileptogenesis studies. The location, magnitude, and spatial extent of inherited, autoimmune, and injury-induced disinhibition may determine the latency to clinical diagnosis and establish the continuum between the benign, treatable, and refractory forms of temporal lobe epilepsy.

Brain-computer interfaces (BCI), have important applications both in medicine and as a research tool. Typically, BCIs rely on electrode arrays to capture electrical signals, which are then processed by algorithms to translate neural activity into actions of an external device. However, these electrophysiological techniques are often inadequate for tracking large populations of the same neurons over timescales longer than ~1 day. To address this, we developed calcium imaging-based BCI for freely behaving mice, facilitating continuous recording and analysis of specific neuronal populations over extended periods. This BCI allowed investigating the long-term neuronal coding dynamics in the hippocampus, revealing changes in neuronal population activity both within and across days. I am hopeful that this BCI will advance studies on spatial cognition and long-term memory.

Successful goal-directed navigation requires estimating one’s current position in the environment, representing the future goal location, and maintaining a map that preserves the topological relationship between positions. In addition, we often need to implement similar navigational strategies in a continuously changing environment, thereby necessitating certain invariance in the underlying spatial maps. Previous research has identified neurons in the hippocampus and parahippocampal cortices that fire specifically when an animal visits a particular location, implying the presence of a spatial map in the brain. However, this map largely encodes the current position of an animal and is context-dependent, whereby changing the room or shape of the arena results in a new map orthogonal to the previous one. These observations raise the question, are there other spatial maps that fulfill the cognitive requirements necessary for goal-directed navigation? Using a goal-directed navigation task with multiple reward locations, we observed that neurons in the orbitofrontal cortex (OFC) exhibit distinct firing patterns depending on the goal location, and this goal-specific OFC activity originates even before the onset of the journey. Further, the difference in the ensemble firing patterns representing two target locations is proportional to the physical distance between these locations, implying the preservation of spatial topology. Finally, carrying out the task across different spatial contexts revealed that the mapping of target locations in the OFC is largely preserved and that the maps formed in two different contexts occupy similar neural subspaces and could be aligned by a linear transformation. Taken together, the OFC forms a topology-preserved schema of spatial locations that is used to represent the future spatial goal, making it a potentially crucial brain region for planning context-invariant goal-directed navigational strategies.

How information is processed within the brain is a key question in systems neuroscience. We address the issue in spiking neuronal networks of freely moving mice. I will describe our recent findings and conclusions pertaining to three specific information processing steps: transmission, representation, and storage. First, using feedforward optogenetic injection of white noise input to a small group of adjacent neocortical excitatory cells, we find that spike transmission to a postsynaptic cell exhibits error correction, improved precision, and temporal coding. The results are consistent with a nonlinear coincidence detection model in the postsynaptic neuron. Second, by triggering input on animal kinematics, we create an artificial place field in an otherwise-silent pyramidal cell. In hippocampal region CA1 but not in the neocortex, artificial fields exhibit synthetic phase precession that persists for a full cycle. The local conversion of an induced rate code into an emerging phase code is compatible with a dual-oscillator interference model. Third, by triggering input on spontaneous spiking, we impose self-terminating spike patterns in a group of presynaptic excitatory neurons and a postsynaptic cell. The precise timing of all pre- and postsynaptic spikes has a more substantial impact on long-lasting effective connectivity than that of individual cell pairs, revealing an unexpected plasticity mechanism. We conclude that intrinsic properties of single neurons support millisecond-timescale operations, and that cortical networks are organized in functional modules which we refer to as “converging assemblies”.

In families with febrile seizures and temporal lobe epilepsy, mutations affecting different GABAergic mechanisms suggest that failure of chloride conductance to limit depolarization may be directly epileptogenic. This “GABAergic disinhibition” hypothesis has been discounted historically for two reasons. First, early attempts to produce hippocampal sclerosis and epilepsy simply by eliminating hippocampal GABA neurons consistently failed to do so. Second, the notion persists that because clinical epilepsy diagnosis is typically delayed for years or decades after brain injury, temporal lobe epileptogenesis should be presumed to involve a complex pathological transformation process that reaches completion during this “latent period.” Recent advances clarify both issues. Although spatially limited hippocampal GABA neuron ablation causes only submaximal granule cell hyperexcitability, more spatially extensive ablation maximizes granule cell hyperexcitability and triggers nonconvulsive granule cell status epilepticus, hippocampal sclerosis, and epilepsy. Recent studies also show that disinhibited granule cells begin to generate clinically subtle seizures immediately post-injury, and these seizures then gradually increase in duration to become clinically obvious. Therefore, rather than being a seizure-free “gestational” state of potentially interruptible epileptogenesis, the “latent period” is more likely an active epileptic state when barriers to seizure spread and clinical expression are gradually overcome by a kindling process. The likelihood that an epileptic brain state exists long before clinical diagnosis has significant implications for anti-epileptogenesis studies. The location, magnitude, and spatial extent of inherited, autoimmune, and injury-induced disinhibition may determine the latency to clinical diagnosis and establish the continuum between the benign, treatable, and refractory forms of temporal lobe epilepsy.

Brain-computer interfaces (BCI), have important applications both in medicine and as a research tool. Typically, BCIs rely on electrode arrays to capture electrical signals, which are then processed by algorithms to translate neural activity into actions of an external device. However, these electrophysiological techniques are often inadequate for tracking large populations of the same neurons over timescales longer than ~1 day. To address this, we developed calcium imaging-based BCI for freely behaving mice, facilitating continuous recording and analysis of specific neuronal populations over extended periods. This BCI allowed investigating the long-term neuronal coding dynamics in the hippocampus, revealing changes in neuronal population activity both within and across days. I am hopeful that this BCI will advance studies on spatial cognition and long-term memory.

Successful goal-directed navigation requires estimating one’s current position in the environment, representing the future goal location, and maintaining a map that preserves the topological relationship between positions. In addition, we often need to implement similar navigational strategies in a continuously changing environment, thereby necessitating certain invariance in the underlying spatial maps. Previous research has identified neurons in the hippocampus and parahippocampal cortices that fire specifically when an animal visits a particular location, implying the presence of a spatial map in the brain. However, this map largely encodes the current position of an animal and is context-dependent, whereby changing the room or shape of the arena results in a new map orthogonal to the previous one. These observations raise the question, are there other spatial maps that fulfill the cognitive requirements necessary for goal-directed navigation? Using a goal-directed navigation task with multiple reward locations, we observed that neurons in the orbitofrontal cortex (OFC) exhibit distinct firing patterns depending on the goal location, and this goal-specific OFC activity originates even before the onset of the journey. Further, the difference in the ensemble firing patterns representing two target locations is proportional to the physical distance between these locations, implying the preservation of spatial topology. Finally, carrying out the task across different spatial contexts revealed that the mapping of target locations in the OFC is largely preserved and that the maps formed in two different contexts occupy similar neural subspaces and could be aligned by a linear transformation. Taken together, the OFC forms a topology-preserved schema of spatial locations that is used to represent the future spatial goal, making it a potentially crucial brain region for planning context-invariant goal-directed navigational strategies.