Abstract
Multiple brain regions including the amygdala and prefrontal cortex are crucial for modulating fear conditioning and extinction. The primary motor cortex is known to participate in the planning, control, and execution of voluntary movements. Whether and how the primary motor cortex is involved in modulating freezing responses related to fear conditioning and extinction remains unclear. Here we show that inactivation of the mouse primary motor cortex impairs both the acquisition and extinction of freezing responses induced by auditory-cued fear conditioning. Fear conditioning significantly increases the elimination of dendritic spines on apical dendrites of layer 5 pyramidal neurons in the motor cortex. These eliminated spines are further apart from each other than expected from random distribution along dendrites. On the other hand, fear extinction causes the formation of new spines that are located near the site of spines eliminated previously after fear conditioning. We further show that fear conditioning decreases and fear extinction increases somatic activities of layer 5 pyramidal neurons in the motor cortex respectively. Taken together, these findings indicate fear conditioning and extinction induce opposing changes in synaptic connections and somatic activities of layer 5 pyramidal neurons in the primary motor cortex, a cortical region important for the acquisition and extinction of auditory-cued conditioned freezing responses.
Highlights
Pavlovian fear conditioning has been widely used as an experimental paradigm for investigating mechanisms underlying fear memory formation and extinction[1]
When muscimol was infused into the primary motor cortex 1 hour before CS (1 kHz auditory tone)-US pairings on day 0, mice showed a significant decrease in freezing responses when compared to vehicle-infused mice during the recall test on day 2 (Fig. 1E, Muscimol: 1 μl, Two-Way ANOVA: drug: F1,75 = 41.06, P < 0.0001; trial: F4,75 = 0.2117, P = 0.9312; interaction: F4,75 = 0.1154, P = 0.9767) (Supplementary Fig. S1C, Muscimol: 0.2 μl, Two-Way ANOVA: drug: F1,65 = 6.931, P = 0.0106; trial: F4,65 = 1.245, P = 0.3009; interaction: F4,65 = 0.5115, P = 0.7274)
On the other hand, when muscimol was infused into the primary motor cortex immediately after fear conditioning on day 0, the freezing responses during the recall test on day 2 were comparable to that in vehicle-infused mice (Supplementary Fig. S2, Two-Way ANOVA: drug: F1,65 = 0.006, P = 0.9383; trial: F4,65 = 0.9201, P = 0.4577; interaction: F4,65 = 0.7673, P = 0.5504)
Summary
Pavlovian fear conditioning has been widely used as an experimental paradigm for investigating mechanisms underlying fear memory formation and extinction[1]. Bottom: bilateral infusion of muscimol into the motor cortex before CS extinction significantly reduced freezing during the recall test on day 4 (n = 7 and 8 mice for muscimol and vehicle groups respectively). We show that inactivation of the primary motor cortex impairs auditory-cued fear conditioning and extinction. Similar to the frontal association cortex, fear conditioning induces the elimination of dendritic spines of layer 5 pyramidal neurons while fear extinction causes the formation of new spines near the site of previously eliminated spines in the primary motor cortex. We show that fear conditioning reduces while fear extinction increases somatic activity in layer 5 pyramidal neurons in the motor cortex Together, these findings suggest that changes in synaptic connections and neuronal activities in the motor cortex are important for regulating freezing responses after auditory-cued fear conditioning and extinction
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