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Spatial memory and long-term object recognition are impaired by circadian arrhythmia and restored by the GABAAAntagonist pentylenetetrazole.

Ruby NF, Fernandez F, Garrett A, Klima J, Zhang P, Sapolsky R, Heller HC - PLoS ONE (2013)

Bottom Line: PTZ restored long-term object recognition and spatial working memory for at least 30 days after drug treatment without restoring circadian rhythms.PTZ did not augment memory in control (entrained) animals, but did increase their activity during the memory tests.Our findings support the hypothesis that circadian arrhythmia impairs declarative memory by increasing the relative influence of GABAergic inhibition in the hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Biology Department, Stanford University, Stanford, California, USA. ruby@stanford.edu

ABSTRACT
Performance on many memory tests varies across the day and is severely impaired by disruptions in circadian timing. We developed a noninvasive method to permanently eliminate circadian rhythms in Siberian hamsters (Phodopus sungorus) [corrected] so that we could investigate the contribution of the circadian system to learning and memory in animals that are neurologically and genetically intact. Male and female adult hamsters were rendered arrhythmic by a disruptive phase shift protocol that eliminates cycling of clock genes within the suprachiasmatic nucleus (SCN), but preserves sleep architecture. These arrhythmic animals have deficits in spatial working memory and in long-term object recognition memory. In a T-maze, rhythmic control hamsters exhibited spontaneous alternation behavior late in the day and at night, but made random arm choices early in the day. By contrast, arrhythmic animals made only random arm choices at all time points. Control animals readily discriminated novel objects from familiar ones, whereas arrhythmic hamsters could not. Since the SCN is primarily a GABAergic nucleus, we hypothesized that an arrhythmic SCN could interfere with memory by increasing inhibition in hippocampal circuits. To evaluate this possibility, we administered the GABAA antagonist pentylenetetrazole (PTZ; 0.3 or 1.0 mg/kg/day) to arrhythmic hamsters for 10 days, which is a regimen previously shown to produce long-term improvements in hippocampal physiology and behavior in Ts65Dn (Down syndrome) mice. PTZ restored long-term object recognition and spatial working memory for at least 30 days after drug treatment without restoring circadian rhythms. PTZ did not augment memory in control (entrained) animals, but did increase their activity during the memory tests. Our findings support the hypothesis that circadian arrhythmia impairs declarative memory by increasing the relative influence of GABAergic inhibition in the hippocampus.

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Related in: MedlinePlus

Representative actograms of entrained and arrhythmic hamsters showing the effects of drug injections on locomotor activity.Brief bursts of locomotor activity were exhibited by ENT (left panels), but not by ARR (middle panels) animals, around the time of drug injections. Locomotor activity patterns were altered by the injection regimen in only two ARR animals (right panels). Those two animals decreased the amount of daily activity until after the end of the injections. Arrows indicated the first and last day of injections that were given at ZT14 each day. Light and dark bars represent the daily illumination cycle.
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pone-0072433-g007: Representative actograms of entrained and arrhythmic hamsters showing the effects of drug injections on locomotor activity.Brief bursts of locomotor activity were exhibited by ENT (left panels), but not by ARR (middle panels) animals, around the time of drug injections. Locomotor activity patterns were altered by the injection regimen in only two ARR animals (right panels). Those two animals decreased the amount of daily activity until after the end of the injections. Arrows indicated the first and last day of injections that were given at ZT14 each day. Light and dark bars represent the daily illumination cycle.

Mentions: PTZ had no effect on the amount of locomotor activity of ENT or ARR animals (Fig. 7). Mean daily activity in the animal’s home cages was compared during three 10-day periods before, during, and after injections of PTZ or VEH. Activity levels did not change significantly during these times (one-way ANOVA with repeated measures for PTZ and VEH groups; P>0.05). Activity levels were not compared between groups. Both PTZ and VEH injections produced a brief burst of locomotor activity after each daily injection in ENT animals (Fig. 7, left panels). Because this effect is typical of drug injection studies, we expected to observe the same effect in the ARR hamsters, but there was no evidence of it (Fig. 7, middle panels). Two ARR animals did, however, alter their activity patterns in response to PTZ and VEH injections. Both of these animals reduced their daily activity at the start of the injections, and resumed pre-injection activity levels after the injections were terminated (Fig. 7, right panels).


Spatial memory and long-term object recognition are impaired by circadian arrhythmia and restored by the GABAAAntagonist pentylenetetrazole.

Ruby NF, Fernandez F, Garrett A, Klima J, Zhang P, Sapolsky R, Heller HC - PLoS ONE (2013)

Representative actograms of entrained and arrhythmic hamsters showing the effects of drug injections on locomotor activity.Brief bursts of locomotor activity were exhibited by ENT (left panels), but not by ARR (middle panels) animals, around the time of drug injections. Locomotor activity patterns were altered by the injection regimen in only two ARR animals (right panels). Those two animals decreased the amount of daily activity until after the end of the injections. Arrows indicated the first and last day of injections that were given at ZT14 each day. Light and dark bars represent the daily illumination cycle.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3756994&req=5

pone-0072433-g007: Representative actograms of entrained and arrhythmic hamsters showing the effects of drug injections on locomotor activity.Brief bursts of locomotor activity were exhibited by ENT (left panels), but not by ARR (middle panels) animals, around the time of drug injections. Locomotor activity patterns were altered by the injection regimen in only two ARR animals (right panels). Those two animals decreased the amount of daily activity until after the end of the injections. Arrows indicated the first and last day of injections that were given at ZT14 each day. Light and dark bars represent the daily illumination cycle.
Mentions: PTZ had no effect on the amount of locomotor activity of ENT or ARR animals (Fig. 7). Mean daily activity in the animal’s home cages was compared during three 10-day periods before, during, and after injections of PTZ or VEH. Activity levels did not change significantly during these times (one-way ANOVA with repeated measures for PTZ and VEH groups; P>0.05). Activity levels were not compared between groups. Both PTZ and VEH injections produced a brief burst of locomotor activity after each daily injection in ENT animals (Fig. 7, left panels). Because this effect is typical of drug injection studies, we expected to observe the same effect in the ARR hamsters, but there was no evidence of it (Fig. 7, middle panels). Two ARR animals did, however, alter their activity patterns in response to PTZ and VEH injections. Both of these animals reduced their daily activity at the start of the injections, and resumed pre-injection activity levels after the injections were terminated (Fig. 7, right panels).

Bottom Line: PTZ restored long-term object recognition and spatial working memory for at least 30 days after drug treatment without restoring circadian rhythms.PTZ did not augment memory in control (entrained) animals, but did increase their activity during the memory tests.Our findings support the hypothesis that circadian arrhythmia impairs declarative memory by increasing the relative influence of GABAergic inhibition in the hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Biology Department, Stanford University, Stanford, California, USA. ruby@stanford.edu

ABSTRACT
Performance on many memory tests varies across the day and is severely impaired by disruptions in circadian timing. We developed a noninvasive method to permanently eliminate circadian rhythms in Siberian hamsters (Phodopus sungorus) [corrected] so that we could investigate the contribution of the circadian system to learning and memory in animals that are neurologically and genetically intact. Male and female adult hamsters were rendered arrhythmic by a disruptive phase shift protocol that eliminates cycling of clock genes within the suprachiasmatic nucleus (SCN), but preserves sleep architecture. These arrhythmic animals have deficits in spatial working memory and in long-term object recognition memory. In a T-maze, rhythmic control hamsters exhibited spontaneous alternation behavior late in the day and at night, but made random arm choices early in the day. By contrast, arrhythmic animals made only random arm choices at all time points. Control animals readily discriminated novel objects from familiar ones, whereas arrhythmic hamsters could not. Since the SCN is primarily a GABAergic nucleus, we hypothesized that an arrhythmic SCN could interfere with memory by increasing inhibition in hippocampal circuits. To evaluate this possibility, we administered the GABAA antagonist pentylenetetrazole (PTZ; 0.3 or 1.0 mg/kg/day) to arrhythmic hamsters for 10 days, which is a regimen previously shown to produce long-term improvements in hippocampal physiology and behavior in Ts65Dn (Down syndrome) mice. PTZ restored long-term object recognition and spatial working memory for at least 30 days after drug treatment without restoring circadian rhythms. PTZ did not augment memory in control (entrained) animals, but did increase their activity during the memory tests. Our findings support the hypothesis that circadian arrhythmia impairs declarative memory by increasing the relative influence of GABAergic inhibition in the hippocampus.

Show MeSH
Related in: MedlinePlus