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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

Local injections of SKF-38393 into the gerbil auditory cortex 1 day before conditioning improve the FM discrimination reaction monitored during retraining 2 days after injections. Data were collected in Experiment 3. Gerbils were trained on the FM discrimination task every 24 h for 3 days. Vehicle (n = 9) or 0.2 mM SKF-38393 (n = 8) was applied twice, that is, 24 and 22 h prior to the beginning of the first training session. Left: Discrimination rates D per training session. Middle: Numbers of hurdle crossings in response to FMs, that is, the sums of correct conditioned responses and false alarms, expressed as percent of total trial number. Right: Escape latencies, that is, the times required to change the compartment after the onset of foot-shock. Arrows indicate the approximate injection times. All data points represent group means ± SEM; (*) significantly different from the value of vehicle-treated controls.
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fig3: Local injections of SKF-38393 into the gerbil auditory cortex 1 day before conditioning improve the FM discrimination reaction monitored during retraining 2 days after injections. Data were collected in Experiment 3. Gerbils were trained on the FM discrimination task every 24 h for 3 days. Vehicle (n = 9) or 0.2 mM SKF-38393 (n = 8) was applied twice, that is, 24 and 22 h prior to the beginning of the first training session. Left: Discrimination rates D per training session. Middle: Numbers of hurdle crossings in response to FMs, that is, the sums of correct conditioned responses and false alarms, expressed as percent of total trial number. Right: Escape latencies, that is, the times required to change the compartment after the onset of foot-shock. Arrows indicate the approximate injection times. All data points represent group means ± SEM; (*) significantly different from the value of vehicle-treated controls.

Mentions: In Experiment 3 we examined whether SKF-38393 may influence FM discrimination learning on subsequent days when applied to naïve gerbils 1 day before conditioning. Gerbils were trained on the FM discrimination task every 24 h for 3 days. The mean discrimination rates D calculated per session are shown in Figure 3 for gerbils locally infused into the auditory cortex with SKF-38393 or vehicle twice, that is, 24 and 22 h before the beginning of the first training session. ANOVA comparing D over sessions 1–3 across treatment groups showed no significant group effect (F1,15 = 0.64, P = 0.437), a significant session effect (F2,30 = 22.03, P < 0.001), and a significant group × session interaction (F2,30 = 5.10, P = 0.012). Within-group analyses of D revealed significant session effects in both the vehicle-treated control group (F2,16 = 10.59, P = 0.002) and the group of SKF-38393–treated gerbils (F2,14 = 16.58, P < 0.001), indicating that, over sessions 1–3, both groups improved their performance. To further analyze the significant interaction, an ANOVA was performed to compare D over sessions 1–2 and over sessions 2–3 separately. ANOVA over sessions 1–2 across treatment groups revealed no significant group effect (F1,15 = 2.37, P = 0.144), a significant session effect (F1,15 = 31.20, P < 0.001), and a significant group × session interaction (F1,15 = 11.43, P = 0.004). Within-group analyses of D over sessions 1–2 revealed a significant session effect in SKF-38393–treated gerbils (F1,7 = 37.99, P < 0.001), but not in vehicle-treated controls (F1,8 = 2.58, P = 0.147). ANOVA over sessions 2–3 across treatment groups revealed no significant effects of group (F1,15 = 1.79, P = 0.201) or session (F1,15 = 2.62, P = 0.126), but again a significant group × session interaction was observed (F1,15 = 6.36, P = 0.024). In this case, within-group ANOVA of D revealed a significant session effect in vehicle-treated controls (F1,8 = 12.16, P = 0.009) but not in SKF-38393–treated gerbils (F1,7 = 0.30, P = 0.602). Thus, the discrimination rates of vehicle-treated controls increased significantly between sessions 2 and 3 but not between sessions 1 and 2. In contrast, the discrimination rates of SKF-38393–treated gerbils increased already between sessions 1 and 2 and remained stable in session 3.


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)

Local injections of SKF-38393 into the gerbil auditory cortex 1 day before conditioning improve the FM discrimination reaction monitored during retraining 2 days after injections. Data were collected in Experiment 3. Gerbils were trained on the FM discrimination task every 24 h for 3 days. Vehicle (n = 9) or 0.2 mM SKF-38393 (n = 8) was applied twice, that is, 24 and 22 h prior to the beginning of the first training session. Left: Discrimination rates D per training session. Middle: Numbers of hurdle crossings in response to FMs, that is, the sums of correct conditioned responses and false alarms, expressed as percent of total trial number. Right: Escape latencies, that is, the times required to change the compartment after the onset of foot-shock. Arrows indicate the approximate injection times. All data points represent group means ± SEM; (*) significantly different from the value of vehicle-treated controls.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2567422&req=5

fig3: Local injections of SKF-38393 into the gerbil auditory cortex 1 day before conditioning improve the FM discrimination reaction monitored during retraining 2 days after injections. Data were collected in Experiment 3. Gerbils were trained on the FM discrimination task every 24 h for 3 days. Vehicle (n = 9) or 0.2 mM SKF-38393 (n = 8) was applied twice, that is, 24 and 22 h prior to the beginning of the first training session. Left: Discrimination rates D per training session. Middle: Numbers of hurdle crossings in response to FMs, that is, the sums of correct conditioned responses and false alarms, expressed as percent of total trial number. Right: Escape latencies, that is, the times required to change the compartment after the onset of foot-shock. Arrows indicate the approximate injection times. All data points represent group means ± SEM; (*) significantly different from the value of vehicle-treated controls.
Mentions: In Experiment 3 we examined whether SKF-38393 may influence FM discrimination learning on subsequent days when applied to naïve gerbils 1 day before conditioning. Gerbils were trained on the FM discrimination task every 24 h for 3 days. The mean discrimination rates D calculated per session are shown in Figure 3 for gerbils locally infused into the auditory cortex with SKF-38393 or vehicle twice, that is, 24 and 22 h before the beginning of the first training session. ANOVA comparing D over sessions 1–3 across treatment groups showed no significant group effect (F1,15 = 0.64, P = 0.437), a significant session effect (F2,30 = 22.03, P < 0.001), and a significant group × session interaction (F2,30 = 5.10, P = 0.012). Within-group analyses of D revealed significant session effects in both the vehicle-treated control group (F2,16 = 10.59, P = 0.002) and the group of SKF-38393–treated gerbils (F2,14 = 16.58, P < 0.001), indicating that, over sessions 1–3, both groups improved their performance. To further analyze the significant interaction, an ANOVA was performed to compare D over sessions 1–2 and over sessions 2–3 separately. ANOVA over sessions 1–2 across treatment groups revealed no significant group effect (F1,15 = 2.37, P = 0.144), a significant session effect (F1,15 = 31.20, P < 0.001), and a significant group × session interaction (F1,15 = 11.43, P = 0.004). Within-group analyses of D over sessions 1–2 revealed a significant session effect in SKF-38393–treated gerbils (F1,7 = 37.99, P < 0.001), but not in vehicle-treated controls (F1,8 = 2.58, P = 0.147). ANOVA over sessions 2–3 across treatment groups revealed no significant effects of group (F1,15 = 1.79, P = 0.201) or session (F1,15 = 2.62, P = 0.126), but again a significant group × session interaction was observed (F1,15 = 6.36, P = 0.024). In this case, within-group ANOVA of D revealed a significant session effect in vehicle-treated controls (F1,8 = 12.16, P = 0.009) but not in SKF-38393–treated gerbils (F1,7 = 0.30, P = 0.602). Thus, the discrimination rates of vehicle-treated controls increased significantly between sessions 2 and 3 but not between sessions 1 and 2. In contrast, the discrimination rates of SKF-38393–treated gerbils increased already between sessions 1 and 2 and remained stable in session 3.

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