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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

Dose response for PTZ in arrhythmic hamsters.(A) PTZ restored SA behavior when administered at 1.0 mg/kg (** P<0.01), but had no effect at 0.3 mg/kg (P>0.05). (B) PTZ dose had no effect on arm entries during SA (P>0.05). (C) PTZ was effective in restoring NOR only at the higher dose. Neither CON nor VEH animals performed better than chance (P>0.05). (D) PTZ had no effect on exploration times in NOR (P>0.05).
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pone-0072433-g003: Dose response for PTZ in arrhythmic hamsters.(A) PTZ restored SA behavior when administered at 1.0 mg/kg (** P<0.01), but had no effect at 0.3 mg/kg (P>0.05). (B) PTZ dose had no effect on arm entries during SA (P>0.05). (C) PTZ was effective in restoring NOR only at the higher dose. Neither CON nor VEH animals performed better than chance (P>0.05). (D) PTZ had no effect on exploration times in NOR (P>0.05).

Mentions: PTZ restored performance on the SA and NOR tests to normal levels in ARR hamsters treated with 1.0 mg/kg PTZ (n = 10), but had no effect when the dose was reduced to 0.3 mg/kg (n = 10; P>0.05; Fig. 2A, C). As in experiment 1, PTZ had no effect on the number of arm entries in the T-maze (one-way ANOVA) nor on the amount of exploration time in the NOR test in any of the four groups (two-way ANOVA with repeated measures for phase; P>0.05; Fig. 3B, D). There were also no differences in the time spent with both objects during either phase of the NOR test (P>0.05; Fig. 3D). ARR hamsters that were not injected (CON; n = 10) or given the vehicle solution (VEH; n = 10) failed at both tests (Fig. 3A, C).


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)

Dose response for PTZ in arrhythmic hamsters.(A) PTZ restored SA behavior when administered at 1.0 mg/kg (** P<0.01), but had no effect at 0.3 mg/kg (P>0.05). (B) PTZ dose had no effect on arm entries during SA (P>0.05). (C) PTZ was effective in restoring NOR only at the higher dose. Neither CON nor VEH animals performed better than chance (P>0.05). (D) PTZ had no effect on exploration times in NOR (P>0.05).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0072433-g003: Dose response for PTZ in arrhythmic hamsters.(A) PTZ restored SA behavior when administered at 1.0 mg/kg (** P<0.01), but had no effect at 0.3 mg/kg (P>0.05). (B) PTZ dose had no effect on arm entries during SA (P>0.05). (C) PTZ was effective in restoring NOR only at the higher dose. Neither CON nor VEH animals performed better than chance (P>0.05). (D) PTZ had no effect on exploration times in NOR (P>0.05).
Mentions: PTZ restored performance on the SA and NOR tests to normal levels in ARR hamsters treated with 1.0 mg/kg PTZ (n = 10), but had no effect when the dose was reduced to 0.3 mg/kg (n = 10; P>0.05; Fig. 2A, C). As in experiment 1, PTZ had no effect on the number of arm entries in the T-maze (one-way ANOVA) nor on the amount of exploration time in the NOR test in any of the four groups (two-way ANOVA with repeated measures for phase; P>0.05; Fig. 3B, D). There were also no differences in the time spent with both objects during either phase of the NOR test (P>0.05; Fig. 3D). ARR hamsters that were not injected (CON; n = 10) or given the vehicle solution (VEH; n = 10) failed at both tests (Fig. 3A, C).

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