Limits...
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.

Show MeSH

Related in: MedlinePlus

Entrained hamsters exhibit a daily rhythm in spontaneous alternation, but not in exploratory behavior.(A) ENT animals performed well on the SA test late in the day and at night, but not early in the day. By contrast, ARR hamsters could not perform this test successfully at any time of day. Gray bar indicates the time of the 8-h dark phase. * P<0.05 compared to random arm choices (i.e., 50%). (B) Exploratory behavior (i.e., number of arm entries) did not change across the day and did not differ among ENT and ARR hamsters at any single time point (P>0.05).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3756994&req=5

pone-0072433-g004: Entrained hamsters exhibit a daily rhythm in spontaneous alternation, but not in exploratory behavior.(A) ENT animals performed well on the SA test late in the day and at night, but not early in the day. By contrast, ARR hamsters could not perform this test successfully at any time of day. Gray bar indicates the time of the 8-h dark phase. * P<0.05 compared to random arm choices (i.e., 50%). (B) Exploratory behavior (i.e., number of arm entries) did not change across the day and did not differ among ENT and ARR hamsters at any single time point (P>0.05).

Mentions: There was a robust daily rhythm in performance on the SA test among ENT animals (n = 9–10 per group at each time point; Fig. 4A). ENT hamsters exhibited significant alternation rates late in the afternoon and at night (one-sample t-test comparing performance to random chance (i.e., 50%; P<0.05), but not early in the light period (one-sample t-test, P>0.05). By contrast, ARR hamsters could not perform the SA test at any time of day or night, as their alternation scores did not exceed chance levels (n = 9–10 per group; one-sample t-test, P>0.05; Fig. 4A).


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)

Entrained hamsters exhibit a daily rhythm in spontaneous alternation, but not in exploratory behavior.(A) ENT animals performed well on the SA test late in the day and at night, but not early in the day. By contrast, ARR hamsters could not perform this test successfully at any time of day. Gray bar indicates the time of the 8-h dark phase. * P<0.05 compared to random arm choices (i.e., 50%). (B) Exploratory behavior (i.e., number of arm entries) did not change across the day and did not differ among ENT and ARR hamsters at any single time point (P>0.05).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0072433-g004: Entrained hamsters exhibit a daily rhythm in spontaneous alternation, but not in exploratory behavior.(A) ENT animals performed well on the SA test late in the day and at night, but not early in the day. By contrast, ARR hamsters could not perform this test successfully at any time of day. Gray bar indicates the time of the 8-h dark phase. * P<0.05 compared to random arm choices (i.e., 50%). (B) Exploratory behavior (i.e., number of arm entries) did not change across the day and did not differ among ENT and ARR hamsters at any single time point (P>0.05).
Mentions: There was a robust daily rhythm in performance on the SA test among ENT animals (n = 9–10 per group at each time point; Fig. 4A). ENT hamsters exhibited significant alternation rates late in the afternoon and at night (one-sample t-test comparing performance to random chance (i.e., 50%; P<0.05), but not early in the light period (one-sample t-test, P>0.05). By contrast, ARR hamsters could not perform the SA test at any time of day or night, as their alternation scores did not exceed chance levels (n = 9–10 per group; one-sample t-test, P>0.05; Fig. 4A).

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