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Dopaminergic modulation of auditory cortex-dependent memory consolidation through mTOR.

Schicknick H, Schott BH, Budinger E, Smalla KH, Riedel A, Seidenbecher CI, Scheich H, Gundelfinger ED, Tischmeyer W - Cereb. Cortex (2008)

Bottom Line: This led to the hypothesis that the dopaminergic system might modulate memory formation via regulation of mTOR, which is implicated in translational control.Although acquisition performance during initial training was normal, the discrimination of FMs was enhanced during retraining performed hours or days after agonist injection compared with vehicle-injected controls.The D1/D5 receptor antagonist SCH-23390, the mTOR inhibitor rapamycin, and the protein synthesis blocker anisomycin suppressed this effect.

View Article: PubMed Central - PubMed

Affiliation: Leibniz Institute for Neurobiology, D-39118 Magdeburg, Germany.

ABSTRACT
Previous studies in the auditory cortex of Mongolian gerbils on discrimination learning of the direction of frequency-modulated tones (FMs) revealed that long-term memory formation involves activation of the dopaminergic system, activity of the protein kinase mammalian target of rapamycin (mTOR), and protein synthesis. This led to the hypothesis that the dopaminergic system might modulate memory formation via regulation of mTOR, which is implicated in translational control. Here, we report that the D1/D5 dopamine receptor agonist SKF-38393 substantially improved gerbils' FM discrimination learning when administered systemically or locally into the auditory cortex shortly before, shortly after, or 1 day before conditioning. Although acquisition performance during initial training was normal, the discrimination of FMs was enhanced during retraining performed hours or days after agonist injection compared with vehicle-injected controls. The D1/D5 receptor antagonist SCH-23390, the mTOR inhibitor rapamycin, and the protein synthesis blocker anisomycin suppressed this effect. By immunohistochemistry, D1 dopamine receptors were identified in the gerbil auditory cortex predominantly in the infragranular layers. Together, these findings suggest that in the gerbil auditory cortex dopaminergic inputs regulate mTOR-mediated, protein synthesis-dependent mechanisms, thus controlling for hours or days the consolidation of memory required for the discrimination of complex auditory stimuli.

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Related in: MedlinePlus

The SKF-38393–induced increment in FM discrimination learning requires mTOR activity and protein synthesis. Data were collected in Experiment 4. Gerbils were trained on the FM discrimination task every 24 h for 2 days. Injections were locally applied to the auditory cortex. (A) Experiment 4A: 0.2 mM SKF-38393 was applied either alone (n = 10) or in combination with 60 nM rapamycin (n = 12) twice, 24 and 22 h prior to initial training. (B) Experiment 4B: 0.2 mM SKF-38393 was applied twice, that is, 24 and 22 h prior to initial training; vehicle (n = 7) or 60 nM rapamycin (n = 14) was applied twice, that is, immediately and 2 h after completion of initial training. (C) Experiment 4C: Vehicle (n = 5), or 0.2 mM SKF-38393 (n = 3), or 0.2 mM SKF-38393 in combination with 75 mM anisomycin (n = 8) was applied twice, 24 and 22 h prior to initial training. (D) Experiment 4D: 0.2 mM SKF-38393 was applied twice, that is, 24 and 22 h prior to initial training; vehicle (n = 8) or 75 mM anisomycin (n = 9) was applied twice, that is, immediately and 2 h after completion of initial training. Discrimination rates D per training session are shown. Filled arrows indicate the approximate injection times for SKF-38393, open arrows indicate the approximate injection times for vehicle or inhibitors. All data points represent group means ± SEM; (*) significantly different from the value in SKF-38393-treated gerbils; (§) significantly different from the value in vehicle-treated gerbils.
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fig4: The SKF-38393–induced increment in FM discrimination learning requires mTOR activity and protein synthesis. Data were collected in Experiment 4. Gerbils were trained on the FM discrimination task every 24 h for 2 days. Injections were locally applied to the auditory cortex. (A) Experiment 4A: 0.2 mM SKF-38393 was applied either alone (n = 10) or in combination with 60 nM rapamycin (n = 12) twice, 24 and 22 h prior to initial training. (B) Experiment 4B: 0.2 mM SKF-38393 was applied twice, that is, 24 and 22 h prior to initial training; vehicle (n = 7) or 60 nM rapamycin (n = 14) was applied twice, that is, immediately and 2 h after completion of initial training. (C) Experiment 4C: Vehicle (n = 5), or 0.2 mM SKF-38393 (n = 3), or 0.2 mM SKF-38393 in combination with 75 mM anisomycin (n = 8) was applied twice, 24 and 22 h prior to initial training. (D) Experiment 4D: 0.2 mM SKF-38393 was applied twice, that is, 24 and 22 h prior to initial training; vehicle (n = 8) or 75 mM anisomycin (n = 9) was applied twice, that is, immediately and 2 h after completion of initial training. Discrimination rates D per training session are shown. Filled arrows indicate the approximate injection times for SKF-38393, open arrows indicate the approximate injection times for vehicle or inhibitors. All data points represent group means ± SEM; (*) significantly different from the value in SKF-38393-treated gerbils; (§) significantly different from the value in vehicle-treated gerbils.

Mentions: In Experiment 4, rapamycin and the global protein synthesis inhibitor anisomycin were utilized to assess the role of mTOR activity and protein synthesis for the SKF-38393–induced FM discrimination increment. The long-lasting persistence of the SKF-38393–induced effect shown in Experiment 3 provided the opportunity to analyze its induction separately from its action on postacquisition memory processing. Therefore, injections were applied to the auditory cortex 24 and 22 h before the beginning of the first training session as in Experiment 3; where indicated (Experiments 4B and 4D), additional injections were applied immediately and 2 h after completion of the first training session. Gerbils were trained on the FM discrimination task every 24 h for 2 days. The mean discrimination rates D calculated per training session and treatment group are shown in Figure 4.


Dopaminergic modulation of auditory cortex-dependent memory consolidation through mTOR.

Schicknick H, Schott BH, Budinger E, Smalla KH, Riedel A, Seidenbecher CI, Scheich H, Gundelfinger ED, Tischmeyer W - Cereb. Cortex (2008)

The SKF-38393–induced increment in FM discrimination learning requires mTOR activity and protein synthesis. Data were collected in Experiment 4. Gerbils were trained on the FM discrimination task every 24 h for 2 days. Injections were locally applied to the auditory cortex. (A) Experiment 4A: 0.2 mM SKF-38393 was applied either alone (n = 10) or in combination with 60 nM rapamycin (n = 12) twice, 24 and 22 h prior to initial training. (B) Experiment 4B: 0.2 mM SKF-38393 was applied twice, that is, 24 and 22 h prior to initial training; vehicle (n = 7) or 60 nM rapamycin (n = 14) was applied twice, that is, immediately and 2 h after completion of initial training. (C) Experiment 4C: Vehicle (n = 5), or 0.2 mM SKF-38393 (n = 3), or 0.2 mM SKF-38393 in combination with 75 mM anisomycin (n = 8) was applied twice, 24 and 22 h prior to initial training. (D) Experiment 4D: 0.2 mM SKF-38393 was applied twice, that is, 24 and 22 h prior to initial training; vehicle (n = 8) or 75 mM anisomycin (n = 9) was applied twice, that is, immediately and 2 h after completion of initial training. Discrimination rates D per training session are shown. Filled arrows indicate the approximate injection times for SKF-38393, open arrows indicate the approximate injection times for vehicle or inhibitors. All data points represent group means ± SEM; (*) significantly different from the value in SKF-38393-treated gerbils; (§) significantly different from the value in vehicle-treated gerbils.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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fig4: The SKF-38393–induced increment in FM discrimination learning requires mTOR activity and protein synthesis. Data were collected in Experiment 4. Gerbils were trained on the FM discrimination task every 24 h for 2 days. Injections were locally applied to the auditory cortex. (A) Experiment 4A: 0.2 mM SKF-38393 was applied either alone (n = 10) or in combination with 60 nM rapamycin (n = 12) twice, 24 and 22 h prior to initial training. (B) Experiment 4B: 0.2 mM SKF-38393 was applied twice, that is, 24 and 22 h prior to initial training; vehicle (n = 7) or 60 nM rapamycin (n = 14) was applied twice, that is, immediately and 2 h after completion of initial training. (C) Experiment 4C: Vehicle (n = 5), or 0.2 mM SKF-38393 (n = 3), or 0.2 mM SKF-38393 in combination with 75 mM anisomycin (n = 8) was applied twice, 24 and 22 h prior to initial training. (D) Experiment 4D: 0.2 mM SKF-38393 was applied twice, that is, 24 and 22 h prior to initial training; vehicle (n = 8) or 75 mM anisomycin (n = 9) was applied twice, that is, immediately and 2 h after completion of initial training. Discrimination rates D per training session are shown. Filled arrows indicate the approximate injection times for SKF-38393, open arrows indicate the approximate injection times for vehicle or inhibitors. All data points represent group means ± SEM; (*) significantly different from the value in SKF-38393-treated gerbils; (§) significantly different from the value in vehicle-treated gerbils.
Mentions: In Experiment 4, rapamycin and the global protein synthesis inhibitor anisomycin were utilized to assess the role of mTOR activity and protein synthesis for the SKF-38393–induced FM discrimination increment. The long-lasting persistence of the SKF-38393–induced effect shown in Experiment 3 provided the opportunity to analyze its induction separately from its action on postacquisition memory processing. Therefore, injections were applied to the auditory cortex 24 and 22 h before the beginning of the first training session as in Experiment 3; where indicated (Experiments 4B and 4D), additional injections were applied immediately and 2 h after completion of the first training session. Gerbils were trained on the FM discrimination task every 24 h for 2 days. The mean discrimination rates D calculated per training session and treatment group are shown in Figure 4.

Bottom Line: This led to the hypothesis that the dopaminergic system might modulate memory formation via regulation of mTOR, which is implicated in translational control.Although acquisition performance during initial training was normal, the discrimination of FMs was enhanced during retraining performed hours or days after agonist injection compared with vehicle-injected controls.The D1/D5 receptor antagonist SCH-23390, the mTOR inhibitor rapamycin, and the protein synthesis blocker anisomycin suppressed this effect.

View Article: PubMed Central - PubMed

Affiliation: Leibniz Institute for Neurobiology, D-39118 Magdeburg, Germany.

ABSTRACT
Previous studies in the auditory cortex of Mongolian gerbils on discrimination learning of the direction of frequency-modulated tones (FMs) revealed that long-term memory formation involves activation of the dopaminergic system, activity of the protein kinase mammalian target of rapamycin (mTOR), and protein synthesis. This led to the hypothesis that the dopaminergic system might modulate memory formation via regulation of mTOR, which is implicated in translational control. Here, we report that the D1/D5 dopamine receptor agonist SKF-38393 substantially improved gerbils' FM discrimination learning when administered systemically or locally into the auditory cortex shortly before, shortly after, or 1 day before conditioning. Although acquisition performance during initial training was normal, the discrimination of FMs was enhanced during retraining performed hours or days after agonist injection compared with vehicle-injected controls. The D1/D5 receptor antagonist SCH-23390, the mTOR inhibitor rapamycin, and the protein synthesis blocker anisomycin suppressed this effect. By immunohistochemistry, D1 dopamine receptors were identified in the gerbil auditory cortex predominantly in the infragranular layers. Together, these findings suggest that in the gerbil auditory cortex dopaminergic inputs regulate mTOR-mediated, protein synthesis-dependent mechanisms, thus controlling for hours or days the consolidation of memory required for the discrimination of complex auditory stimuli.

Show MeSH
Related in: MedlinePlus