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Zolpidem Reduces Hippocampal Neuronal Activity in Freely Behaving Mice: A Large Scale Calcium Imaging Study with Miniaturized Fluorescence Microscope
- Source :
- PLoS ONE, Vol 9, Iss 11, p e112068 (2014), PLoS ONE
- Publication Year :
- 2014
- Publisher :
- Public Library of Science (PLoS), 2014.
-
Abstract
- Therapeutic drugs for cognitive and psychiatric disorders are often characterized by their molecular mechanism of action. Here we demonstrate a new approach to elucidate drug action on large-scale neuronal activity by tracking somatic calcium dynamics in hundreds of CA1 hippocampal neurons of pharmacologically manipulated behaving mice. We used an adeno-associated viral vector to express the calcium sensor GCaMP3 in CA1 pyramidal cells under control of the CaMKII promoter and a miniaturized microscope to observe cellular dynamics. We visualized these dynamics with and without a systemic administration of Zolpidem, a GABAA agonist that is the most commonly prescribed drug for the treatment of insomnia in the United States. Despite growing concerns about the potential adverse effects of Zolpidem on memory and cognition, it remained unclear whether Zolpidem alters neuronal activity in the hippocampus, a brain area critical for cognition and memory. Zolpidem, when delivered at a dose known to induce and prolong sleep, strongly suppressed CA1 calcium signaling. The rate of calcium transients after Zolpidem administration was significantly lower compared to vehicle treatment. To factor out the contribution of changes in locomotor or physiological conditions following Zolpidem treatment, we compared the cellular activity across comparable epochs matched by locomotor and physiological assessments. This analysis revealed significantly depressive effects of Zolpidem regardless of the animal's state. Individual hippocampal CA1 pyramidal cells differed in their responses to Zolpidem with the majority (∼ 65%) significantly decreasing the rate of calcium transients, and a small subset (3%) showing an unexpected and significant increase. By linking molecular mechanisms with the dynamics of neural circuitry and behavioral states, this approach has the potential to contribute substantially to the development of new therapeutics for the treatment of CNS disorders.
- Subjects :
- Agonist
Zolpidem
Neural Networks
Pyridines
medicine.drug_class
Cognitive Neuroscience
Neurophysiology
lcsh:Medicine
Hippocampus
chemistry.chemical_element
Neuroimaging
Pharmacology
Hippocampal formation
Calcium
Behavioral Neuroscience
Mice
Learning and Memory
Calcium imaging
medicine
Animals
Premovement neuronal activity
GABA-A Receptor Agonists
lcsh:Science
CA1 Region, Hippocampal
Multidisciplinary
Behavior, Animal
Chemistry
GABAA receptor
Pyramidal Cells
musculoskeletal, neural, and ocular physiology
Neurotransmission
Optical Imaging
lcsh:R
Biology and Life Sciences
Calcium Imaging
Molecular Imaging
Brain Electrophysiology
Microscopy, Fluorescence
Cellular Neuroscience
lcsh:Q
Locomotion
psychological phenomena and processes
Research Article
Neuroscience
medicine.drug
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....1897c53315b5dd9d3f3b1c39934f3d69