Answering hastily retards learning

<div><p>Appropriate decisions involve at least two aspects: the speed of the decision and the correctness of the decision. Although a quick and correct decision is generally believed to work favorably, these two aspects may be interdependent in terms of overall task performance. In this study, we scrutinized learning behaviors in an operant task in which rats were required to poke their noses into either of two holes by referring to a light cue. All 22 rats reached the learning criterion, an 80% correct rate, within 4 days of testing, but they were diverse in the number of sessions spent to reach the learning criterion. Individual analyses revealed that the mean latency for responding was negatively correlated with the number of sessions until learning, suggesting that the rats that responded more rapidly to the cues learned the task more slowly. For individual trials, the mean latency for responding in correct trials (<i>L</i>_C) was significantly longer than that in incorrect trials (<i>L</i>_I), suggesting that, on average, long deliberation times led to correct answers in the trials. The success ratio before learning was not correlated with the learning speed. Thus, deliberative decision-making, rather than overall correctness, is critical for learning.</p></div

Nose-poke behavior test.

<p>(a) Experimental procedure. The behavior test consisted of a training phase (Days 1–2) and a test phase (Days 3–6). (b) Illustration of the operant chamber with the two nose-poke holes (<i>left</i>). In the training phase, a rat was rewarded whenever the nose was poked into either nose-poke hole. In the test phase, however, the rat could gain a reward pellet only when it poked the nose into the hole that was not illuminated by a green light (<i>right)</i>.</p

Relationship between nose-poke latencies in the during-learning period and task performance.

<p>(a) The number of sessions spent to reach the criterion is plotted against the latency to respond. Each dot indicates data from a single rat. The blue line is the best-fit line determined by the least-squares method, and its 95% confidence intervals are shown by two broken lines. As a whole, rats with shorter latencies reached the criterion more slowly (<i>P =</i> 0.024, <i>R</i> = -0.48, Pearson's correlation test, <i>n</i> = 22 rats). (b) The latencies of individual trials are separately plotted for correct trials (<i>L</i>_C) and incorrect trials (<i>L</i>_I). <i>L</i>_I was significantly shorter than <i>L</i>_C (<i>P =</i> 0.016, bootstrap resampling test). Error bars represent SEMs for 22 rats. (c) Same as a, but against the latency ratio <i>L</i>_I/<i>L</i>_C. Rats with a smaller <i>L</i>_I/<i>L</i>_C ratio learned more slowly (<i>P =</i> 0.012, <i>R</i> = -0.52). (d) Same as a, but against the mean correct-trial ratio from the beginning of the test phase to the first session that reached the criterion (<i>P</i> = 0.197, <i>R</i> = -0.29).</p

Behavioral parameters before, during, and after learning.

<p>(a) <i>Left</i>: time changes in the correct rates for 22 individual rats (gray) were aligned to the first session that reached the criterion. The blue line indicates the mean value. <i>Right</i>: training represents data from the last 4 sessions on Day 2 in the training phase. Four sessions immediately before and 5-to-8 sessions after reaching the criterion were defined as the during-learning and post-learning periods, respectively. These periods are shown by the black bars in the left panel. The mean correct rate in the during-learning period was significantly lower than the mean correct rates in the training period and the post-learning period. Training <i>versus</i> during-learning: <i>P =</i> 9.56 × 10⁻¹⁰, <i>Q</i>_3,63 = 28.0; during-learning <i>versus</i> post-learning: <i>P =</i> 9.56 × 10⁻¹⁰, <i>Q</i>_3,63 = 24.0; <i>P =</i> 1.14 × 10⁻²⁹, <i>F</i>_2,63 = 230; Tukey's test after one-way ANOVA. (b) Same as a, but for the rates of omission trials. Training <i>versus</i> during-learning: <i>P =</i> 0.034, <i>Q</i>_3,63 = 3.62; during-learning <i>versus</i> post-learning: <i>P =</i> 6.91 × 10⁻⁴, <i>Q</i>_3,63 = 5.51; <i>P =</i> 9.12 × 10⁻⁴, <i>F</i>_2,63 = 7.84. (c) Same as a, but for the latencies to respond. Training <i>versus</i> during-learning: <i>P =</i> 0.984, <i>Q</i>_3,63 = 0.235; during-learning <i>versus</i> post-learning: <i>P =</i> 0.092, <i>Q</i>_3,63 = 3.01; <i>P =</i> 0.044, <i>F</i>_2,63 = 3.28.</p

Summarized data of behavioral performance during the training and test phases of the operant task.

<p>(a) Time changes in the mean correct rates in the training phase (<i>left</i>) and the test phase (<i>right</i>). (b) Same as a, but for the mean omission rates, <i>i</i>.<i>e</i>., a percentage of trials in which the rats did not respond within the time limit. (c) Same as a, but for the mean latencies to respond. Error bars represent SEMs for 22 rats.</p

Preference bias during the training and test phases.

<p>(a) Time changes in the preference bias of individual 22 rats (gray lines) in the training phase (<i>left</i>) and the test phase (<i>right</i>). The yellow line indicates the means ± SEMs of 22 rats. (b) Same as (a), but they were aligned to the first session that reached the criterion. (c) Comparisons of the mean ± SEM preference biases during the training period, the during-learning period, and the post-learning period. The mean preference bias in the during-learning period was significantly lower than that in the training period and was significantly higher than that in the post-learning period. Training <i>versus</i> during-learning: <i>P =</i> 4.16 × 10⁻⁵, <i>Q</i>_3,63 = 6.66; during-learning <i>versus</i> post-learning: <i>P =</i> 5.59 × 10⁻⁶, <i>Q</i>_3,63 = 7.43; <i>P =</i> 1.12 × 10⁻¹³, <i>F</i>_2,63 = 49.7; Tukey's test after one-way ANOVA.</p

Image_3_Distinct mechanisms of allopregnanolone and diazepam underlie neuronal oscillations and differential antidepressant effect.tif

The rapid relief of depressive symptoms is a major medical requirement for effective treatments for major depressive disorder (MDD). A decrease in neuroactive steroids contributes to the pathophysiological mechanisms associated with the neurological symptoms of MDD. Zuranolone (SAGE-217), a neuroactive steroid that acts as a positive allosteric modulator of synaptic and extrasynaptic δ-subunit-containing GABAA receptors, has shown rapid-onset, clinically effective antidepressant action in patients with MDD or postpartum depression (PPD). Benzodiazepines, on the other hand, act as positive allosteric modulators of synaptic GABAA receptors but are not approved for the treatment of patients with MDD. It remains unclear how differences in molecular mechanisms contribute to the alleviation of depressive symptoms and the regulation of associated neuronal activity. Focusing on the antidepressant-like effects and neuronal activity of the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC), we conducted a head-to-head comparison study of the neuroactive steroid allopregnanolone and the benzodiazepine diazepam using a mouse social defeat stress (SDS) model. Allopregnanolone but not diazepam exhibited antidepressant-like effects in a social interaction test in SDS mice. This antidepressant-like effect of allopregnanolone was abolished in extrasynaptic GABAA receptor δ-subunit knockout mice (δko mice) subjected to the same SDS protocol. Regarding the neurophysiological mechanism associated with these antidepressant-like effects, allopregnanolone but not diazepam increased theta oscillation in the BLA of SDS mice. This increase did not occur in δko mice. Consistent with this, allopregnanolone potentiated tonic inhibition in BLA interneurons via δ-subunit-containing extrasynaptic GABAA receptors. Theta oscillation in the mPFC of SDS mice was also increased by allopregnanolone but not by diazepam. Finally, allopregnanolone but not diazepam increased frontal theta activity in electroencephalography recordings in naïve and SDS mice. Neuronal network alterations associated with MDD showed decreased frontal theta and beta activity in depressed SDS mice. These results demonstrated that, unlike benzodiazepines, neuroactive steroids increased theta oscillation in the BLA and mPFC through the activation of δ-subunit-containing GABAA receptors, and this change was associated with antidepressant-like effects in the SDS model. Our findings support the notion that the distinctive mechanism of neuroactive steroids may contribute to the rapid antidepressant effects in MDD.</p

Image_4_Distinct mechanisms of allopregnanolone and diazepam underlie neuronal oscillations and differential antidepressant effect.tif

The rapid relief of depressive symptoms is a major medical requirement for effective treatments for major depressive disorder (MDD). A decrease in neuroactive steroids contributes to the pathophysiological mechanisms associated with the neurological symptoms of MDD. Zuranolone (SAGE-217), a neuroactive steroid that acts as a positive allosteric modulator of synaptic and extrasynaptic δ-subunit-containing GABAA receptors, has shown rapid-onset, clinically effective antidepressant action in patients with MDD or postpartum depression (PPD). Benzodiazepines, on the other hand, act as positive allosteric modulators of synaptic GABAA receptors but are not approved for the treatment of patients with MDD. It remains unclear how differences in molecular mechanisms contribute to the alleviation of depressive symptoms and the regulation of associated neuronal activity. Focusing on the antidepressant-like effects and neuronal activity of the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC), we conducted a head-to-head comparison study of the neuroactive steroid allopregnanolone and the benzodiazepine diazepam using a mouse social defeat stress (SDS) model. Allopregnanolone but not diazepam exhibited antidepressant-like effects in a social interaction test in SDS mice. This antidepressant-like effect of allopregnanolone was abolished in extrasynaptic GABAA receptor δ-subunit knockout mice (δko mice) subjected to the same SDS protocol. Regarding the neurophysiological mechanism associated with these antidepressant-like effects, allopregnanolone but not diazepam increased theta oscillation in the BLA of SDS mice. This increase did not occur in δko mice. Consistent with this, allopregnanolone potentiated tonic inhibition in BLA interneurons via δ-subunit-containing extrasynaptic GABAA receptors. Theta oscillation in the mPFC of SDS mice was also increased by allopregnanolone but not by diazepam. Finally, allopregnanolone but not diazepam increased frontal theta activity in electroencephalography recordings in naïve and SDS mice. Neuronal network alterations associated with MDD showed decreased frontal theta and beta activity in depressed SDS mice. These results demonstrated that, unlike benzodiazepines, neuroactive steroids increased theta oscillation in the BLA and mPFC through the activation of δ-subunit-containing GABAA receptors, and this change was associated with antidepressant-like effects in the SDS model. Our findings support the notion that the distinctive mechanism of neuroactive steroids may contribute to the rapid antidepressant effects in MDD.</p

Image_2_Distinct mechanisms of allopregnanolone and diazepam underlie neuronal oscillations and differential antidepressant effect.tif

The rapid relief of depressive symptoms is a major medical requirement for effective treatments for major depressive disorder (MDD). A decrease in neuroactive steroids contributes to the pathophysiological mechanisms associated with the neurological symptoms of MDD. Zuranolone (SAGE-217), a neuroactive steroid that acts as a positive allosteric modulator of synaptic and extrasynaptic δ-subunit-containing GABAA receptors, has shown rapid-onset, clinically effective antidepressant action in patients with MDD or postpartum depression (PPD). Benzodiazepines, on the other hand, act as positive allosteric modulators of synaptic GABAA receptors but are not approved for the treatment of patients with MDD. It remains unclear how differences in molecular mechanisms contribute to the alleviation of depressive symptoms and the regulation of associated neuronal activity. Focusing on the antidepressant-like effects and neuronal activity of the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC), we conducted a head-to-head comparison study of the neuroactive steroid allopregnanolone and the benzodiazepine diazepam using a mouse social defeat stress (SDS) model. Allopregnanolone but not diazepam exhibited antidepressant-like effects in a social interaction test in SDS mice. This antidepressant-like effect of allopregnanolone was abolished in extrasynaptic GABAA receptor δ-subunit knockout mice (δko mice) subjected to the same SDS protocol. Regarding the neurophysiological mechanism associated with these antidepressant-like effects, allopregnanolone but not diazepam increased theta oscillation in the BLA of SDS mice. This increase did not occur in δko mice. Consistent with this, allopregnanolone potentiated tonic inhibition in BLA interneurons via δ-subunit-containing extrasynaptic GABAA receptors. Theta oscillation in the mPFC of SDS mice was also increased by allopregnanolone but not by diazepam. Finally, allopregnanolone but not diazepam increased frontal theta activity in electroencephalography recordings in naïve and SDS mice. Neuronal network alterations associated with MDD showed decreased frontal theta and beta activity in depressed SDS mice. These results demonstrated that, unlike benzodiazepines, neuroactive steroids increased theta oscillation in the BLA and mPFC through the activation of δ-subunit-containing GABAA receptors, and this change was associated with antidepressant-like effects in the SDS model. Our findings support the notion that the distinctive mechanism of neuroactive steroids may contribute to the rapid antidepressant effects in MDD.</p

Image_1_Distinct mechanisms of allopregnanolone and diazepam underlie neuronal oscillations and differential antidepressant effect.tif

The rapid relief of depressive symptoms is a major medical requirement for effective treatments for major depressive disorder (MDD). A decrease in neuroactive steroids contributes to the pathophysiological mechanisms associated with the neurological symptoms of MDD. Zuranolone (SAGE-217), a neuroactive steroid that acts as a positive allosteric modulator of synaptic and extrasynaptic δ-subunit-containing GABAA receptors, has shown rapid-onset, clinically effective antidepressant action in patients with MDD or postpartum depression (PPD). Benzodiazepines, on the other hand, act as positive allosteric modulators of synaptic GABAA receptors but are not approved for the treatment of patients with MDD. It remains unclear how differences in molecular mechanisms contribute to the alleviation of depressive symptoms and the regulation of associated neuronal activity. Focusing on the antidepressant-like effects and neuronal activity of the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC), we conducted a head-to-head comparison study of the neuroactive steroid allopregnanolone and the benzodiazepine diazepam using a mouse social defeat stress (SDS) model. Allopregnanolone but not diazepam exhibited antidepressant-like effects in a social interaction test in SDS mice. This antidepressant-like effect of allopregnanolone was abolished in extrasynaptic GABAA receptor δ-subunit knockout mice (δko mice) subjected to the same SDS protocol. Regarding the neurophysiological mechanism associated with these antidepressant-like effects, allopregnanolone but not diazepam increased theta oscillation in the BLA of SDS mice. This increase did not occur in δko mice. Consistent with this, allopregnanolone potentiated tonic inhibition in BLA interneurons via δ-subunit-containing extrasynaptic GABAA receptors. Theta oscillation in the mPFC of SDS mice was also increased by allopregnanolone but not by diazepam. Finally, allopregnanolone but not diazepam increased frontal theta activity in electroencephalography recordings in naïve and SDS mice. Neuronal network alterations associated with MDD showed decreased frontal theta and beta activity in depressed SDS mice. These results demonstrated that, unlike benzodiazepines, neuroactive steroids increased theta oscillation in the BLA and mPFC through the activation of δ-subunit-containing GABAA receptors, and this change was associated with antidepressant-like effects in the SDS model. Our findings support the notion that the distinctive mechanism of neuroactive steroids may contribute to the rapid antidepressant effects in MDD.</p