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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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PTZ increased exploratory behavior in entrained animals during memory tests.Arm entries and exploration times for animals from figure 5. (A) The number of arm entries made during SA at both doses of PTZ were higher in the afternoon at ZT15 compared to the early morning at ZT3. This effect appeared to be due to a decrease in arm entries at ZT3, but this apparent reduction was not statistically significant (see text for analysis). (B) A similar effect of PTZ was found for time spent exploring objects during the sample phase of NOR. (C) PTZ had no effect on exploration time 24 h later during the test phase. * P<0.05, ** P<0.01, *** P<0.001 for ZT3 vs. ZT15 comparisons;n.s.  =  nonsignificant difference.
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pone-0072433-g006: PTZ increased exploratory behavior in entrained animals during memory tests.Arm entries and exploration times for animals from figure 5. (A) The number of arm entries made during SA at both doses of PTZ were higher in the afternoon at ZT15 compared to the early morning at ZT3. This effect appeared to be due to a decrease in arm entries at ZT3, but this apparent reduction was not statistically significant (see text for analysis). (B) A similar effect of PTZ was found for time spent exploring objects during the sample phase of NOR. (C) PTZ had no effect on exploration time 24 h later during the test phase. * P<0.05, ** P<0.01, *** P<0.001 for ZT3 vs. ZT15 comparisons;n.s.  =  nonsignificant difference.

Mentions: There were significant effects of PTZ on exploratory behavior in both tests (Fig. 6). In regards to the number of arm entries made during SA, a two-way ANOVA (group×time of day; repeated measures for time of day) revealed a significant effect for time of day (F(3, 72 = 10.91, P<0.001), but not for treatment group (P>0.05; Fig. 6A). There was, however, a significant interaction between these two variables (F(3,72) = 4.91, P<0.01), so pairwise t-tests (Tukey’s post-hoc correction applied) were performed for time of day. Hamsters treated with PTZ made significantly more arm entries at ZT15 compared to ZT3 at both doses (0.3 mg/kg, P<0.05; 1.0 mg/kg, P<0.001; Fig. 6A).


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)

PTZ increased exploratory behavior in entrained animals during memory tests.Arm entries and exploration times for animals from figure 5. (A) The number of arm entries made during SA at both doses of PTZ were higher in the afternoon at ZT15 compared to the early morning at ZT3. This effect appeared to be due to a decrease in arm entries at ZT3, but this apparent reduction was not statistically significant (see text for analysis). (B) A similar effect of PTZ was found for time spent exploring objects during the sample phase of NOR. (C) PTZ had no effect on exploration time 24 h later during the test phase. * P<0.05, ** P<0.01, *** P<0.001 for ZT3 vs. ZT15 comparisons;n.s.  =  nonsignificant difference.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3756994&req=5

pone-0072433-g006: PTZ increased exploratory behavior in entrained animals during memory tests.Arm entries and exploration times for animals from figure 5. (A) The number of arm entries made during SA at both doses of PTZ were higher in the afternoon at ZT15 compared to the early morning at ZT3. This effect appeared to be due to a decrease in arm entries at ZT3, but this apparent reduction was not statistically significant (see text for analysis). (B) A similar effect of PTZ was found for time spent exploring objects during the sample phase of NOR. (C) PTZ had no effect on exploration time 24 h later during the test phase. * P<0.05, ** P<0.01, *** P<0.001 for ZT3 vs. ZT15 comparisons;n.s.  =  nonsignificant difference.
Mentions: There were significant effects of PTZ on exploratory behavior in both tests (Fig. 6). In regards to the number of arm entries made during SA, a two-way ANOVA (group×time of day; repeated measures for time of day) revealed a significant effect for time of day (F(3, 72 = 10.91, P<0.001), but not for treatment group (P>0.05; Fig. 6A). There was, however, a significant interaction between these two variables (F(3,72) = 4.91, P<0.01), so pairwise t-tests (Tukey’s post-hoc correction applied) were performed for time of day. Hamsters treated with PTZ made significantly more arm entries at ZT15 compared to ZT3 at both doses (0.3 mg/kg, P<0.05; 1.0 mg/kg, P<0.001; Fig. 6A).

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