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Pedersen Laboratory - Epilepsy and Systems Neuroscience

In our Epilepsy and Systems Neuroscience Laboratory, we study the systems neuroscience of wakefulness and epilepsy in humans and animal models. There are two main streams of research. The first centers on the neurobiological basis of consciousness and the underlying wake-sustaining mechanisms upon which it depends (1-6); another group of projects examines brain networks in epileptic seizures, including the modulatory effects of sleep-wake circuits and networks through which seizures propagate.

We study large-scale brain circuits underlying wakefulness and sleep. Using a variety of genetically encoded technologies in mice, we have recently described a new component of the brain circuit that maintains wakefulness, the supramammillary hypothalamus (3). This region exerts control over both the hippocampal network (important for certain kinds of memory formation) as well as the wake network and cerebral cortex. A unique and interesting feature of this neuronal group is the presence of a subpopulation of neurons that we described to release both inhibitory GABA and excitatory glutamate on to a key population of hippocampal neurons - dentate granule cells (3). These neurons are sparsely firing neurons that control which activity enters the classical hippocampal tri-synaptic circuit. The supramammillary region, comprising three major neuronal populations (3), is thus able to control wakefulness and influence information flow into the hippocampus. Studies continue to understand the role of these circuits on attention, wakefulness and the role of this region in setting hippocampal excitability in epilepsy. A specific ongoing experiment involves disruption of GABA release by supramammillary neurons and examining spontaneous seizures and seizure threshold, using Cre-lox techniques. We are also examining the anatomical connectivity and spontaneous activity of identified supramammillary neuronal subpopulations using unit recording and, later, fiber photometry.

Human work is presently centered on two major types of project, both involving our patients admitted for intracranial monitoring for epilepsy surgery. One group of projects examines a technique for neurophysiological identification of human cortical networks using single-pulse electrical stimulation, providing key clinical information as well the best means of determining human cortical networks (given the limits of diffusion tensor MRI). The other group of projects is centered on the study of consciousness. A key research goal of this program is to understand the top-down control of sleep-wake circuits and brain rhythms by the cerebral cortex in humans, using electrical stimulation of depth (SEEG) electrodes.

We are also developing techniques of the distributed recording of field potentials and unit activity in mice using a combination of tetrodes and high-resolution 3D resin printing of a micro-drive housing that can target specific widely distributed brain regions. This will allow us to obtain SEEG-like recordings in the mouse to examine ictal propagation and the role of subcortical structures in seizure semiology including in impairment of consciousness, respiratory abnormalities in seizures and post-ictal obtundation.

Presently our lab consists of a laboratory assistant, neurology resident, an Emory undergrad, one Georgia Tech undergrad and several collaborators.

1. Saper, C. B., Fuller, P. M., Pedersen, N. P., Lu, J. & Scammell, T. E. Sleep state switching. Neuron 68, 1023–1042 (2010).
2. Anaclet, C., Pedersen, N. P. et al. Basal forebrain control of wakefulness and cortical rhythms. Nature Communications 6, 8744 (2015).
3. Pedersen, N. P. et al. Supramammillary glutamate neurons are a key node of the arousal system. In press (2017).
4. Anaclet, C., Pedersen, N. P., Fuller, P. M. & Lu, J. Brainstem circuitry regulating phasic activation of trigeminal motoneurons during REM sleep. PLoS ONE 5, e8788 (2010).
5. Gompf, H. S. et al. Locus ceruleus and anterior cingulate cortex sustain wakefulness in a novel environment. Journal of Neuroscience 30, 14543–14551 (2010).
6. Fuller, P., Sherman, D., Pedersen, N. P., Saper, C. B. & Lu, J. Reassessment of the structural basis of the ascending arousal system. J. Comp. Neurol. 519, 933–956 (2011).