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Zolpidem reduces hippocampal neuronal activity in freely behaving mice: a large scale calcium imaging study with miniaturized fluorescence microscope.

Berdyyeva T, Otte S, Aluisio L, Ziv Y, Burns LD, Dugovic C, Yun S, Ghosh KK, Schnitzer MJ, Lovenberg T, Bonaventure P - PLoS ONE (2014)

Bottom Line: The rate of calcium transients after Zolpidem administration was significantly lower compared to vehicle treatment.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.

View Article: PubMed Central - PubMed

Affiliation: Janssen Research & Development, LLC, San Diego, California, United States of America.

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.

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Individual hippocampal CA1 pyramidal cells differed in their responses to Zolpidem.A: Representative raster plot of calcium transients in individual cells (n = 195) that are color-coded depending on their response to Zolpidem (Mann-Whitney-Wilcoxon test, p<0.05 criterion of significance): significant decrease (blue); significant increase (red), non-significant change (black). B: Locations of individual cells identified in the same representative imaging session, layered atop a mean fluorescent image. C: Rate of calcium transients post-Zolpidem (“Zolpidem Event Rate”) vs post-vehicle (“Vehicle Event Rate”); each dot is an individual cell (n = 1275). The majority of individual neurons (65%) significantly lowered neuronal activity following Zolpidem administration; 32% of neurons did not show a significant change; and a small neuronal subset (∼3%) showed a significant increase.
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pone-0112068-g004: Individual hippocampal CA1 pyramidal cells differed in their responses to Zolpidem.A: Representative raster plot of calcium transients in individual cells (n = 195) that are color-coded depending on their response to Zolpidem (Mann-Whitney-Wilcoxon test, p<0.05 criterion of significance): significant decrease (blue); significant increase (red), non-significant change (black). B: Locations of individual cells identified in the same representative imaging session, layered atop a mean fluorescent image. C: Rate of calcium transients post-Zolpidem (“Zolpidem Event Rate”) vs post-vehicle (“Vehicle Event Rate”); each dot is an individual cell (n = 1275). The majority of individual neurons (65%) significantly lowered neuronal activity following Zolpidem administration; 32% of neurons did not show a significant change; and a small neuronal subset (∼3%) showed a significant increase.

Mentions: We assessed the changes in rate of calcium transients between vehicle and Zolpidem imaging periods for each individual cell (Methods, “Statistical analysis of neuronal data”). Cells that showed a significant Zolpidem effect (MWW test, p<0.05) were subdivided into two groups depending on the direction of change (increased or decreased event rate). The approach is illustrated on the raster plot on Fig. 4A: in this representative session, the majority of individual cells (shown in blue) decreased their activity following Zolpidem administration relative to the vehicle, while some of the cells either increased their activity (shown in red) or had no significant change (shown in black, p>0.05, MWW test). Fig. 4B illustrates spatial positions for the cells within each class.


Zolpidem reduces hippocampal neuronal activity in freely behaving mice: a large scale calcium imaging study with miniaturized fluorescence microscope.

Berdyyeva T, Otte S, Aluisio L, Ziv Y, Burns LD, Dugovic C, Yun S, Ghosh KK, Schnitzer MJ, Lovenberg T, Bonaventure P - PLoS ONE (2014)

Individual hippocampal CA1 pyramidal cells differed in their responses to Zolpidem.A: Representative raster plot of calcium transients in individual cells (n = 195) that are color-coded depending on their response to Zolpidem (Mann-Whitney-Wilcoxon test, p<0.05 criterion of significance): significant decrease (blue); significant increase (red), non-significant change (black). B: Locations of individual cells identified in the same representative imaging session, layered atop a mean fluorescent image. C: Rate of calcium transients post-Zolpidem (“Zolpidem Event Rate”) vs post-vehicle (“Vehicle Event Rate”); each dot is an individual cell (n = 1275). The majority of individual neurons (65%) significantly lowered neuronal activity following Zolpidem administration; 32% of neurons did not show a significant change; and a small neuronal subset (∼3%) showed a significant increase.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4221229&req=5

pone-0112068-g004: Individual hippocampal CA1 pyramidal cells differed in their responses to Zolpidem.A: Representative raster plot of calcium transients in individual cells (n = 195) that are color-coded depending on their response to Zolpidem (Mann-Whitney-Wilcoxon test, p<0.05 criterion of significance): significant decrease (blue); significant increase (red), non-significant change (black). B: Locations of individual cells identified in the same representative imaging session, layered atop a mean fluorescent image. C: Rate of calcium transients post-Zolpidem (“Zolpidem Event Rate”) vs post-vehicle (“Vehicle Event Rate”); each dot is an individual cell (n = 1275). The majority of individual neurons (65%) significantly lowered neuronal activity following Zolpidem administration; 32% of neurons did not show a significant change; and a small neuronal subset (∼3%) showed a significant increase.
Mentions: We assessed the changes in rate of calcium transients between vehicle and Zolpidem imaging periods for each individual cell (Methods, “Statistical analysis of neuronal data”). Cells that showed a significant Zolpidem effect (MWW test, p<0.05) were subdivided into two groups depending on the direction of change (increased or decreased event rate). The approach is illustrated on the raster plot on Fig. 4A: in this representative session, the majority of individual cells (shown in blue) decreased their activity following Zolpidem administration relative to the vehicle, while some of the cells either increased their activity (shown in red) or had no significant change (shown in black, p>0.05, MWW test). Fig. 4B illustrates spatial positions for the cells within each class.

Bottom Line: The rate of calcium transients after Zolpidem administration was significantly lower compared to vehicle treatment.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.

View Article: PubMed Central - PubMed

Affiliation: Janssen Research & Development, LLC, San Diego, California, United States of America.

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.

Show MeSH
Related in: MedlinePlus