Activation of nucleus accumbens d1 neurons enhances fear extinction in mice with post-traumatic stress disorder

Background The core pathological feature of post-traumatic stress disorder (PTSD) is impaired fear memory extinction, and current research on medium and long-term fear memory extinction remains extremely limited.

Objective To investigate the role of nucleus accumbens D1 neurons in the extinction of long-term fear memory in a mouse model of post-traumatic stress disorder.

Methods A mouse model of conditioned fear memory was established by delivering unpredictable foot shocks to provide paired "context-shock" stimuli. Mice were divided into control group (n=8) and model group (n=8). The control group received no foot shocks, while the model group was subjected to foot shocks. Freezing time was measured two weeks later to evaluate the level of long-term fear memory. Two distinct extinction training protocols were established, with 8 mice in each group: a modified light-associated extinction training group and a continuous 40 minute extinction training group. The effects of the two protocols on the extinction of long-term fear memory were compared, and the one with better extinction efficacy was selected for subsequent experiments. Chemogenetic techniques were used to activate nucleus accumbens D1 neurons. Mice were divided into control group (n=7) and D1 activation group (n= 9). The D1 activation group received intraperitoneal injection of clozapine-N-oxide (CNO). Changes in freezing time were observed to verify the effect on long-term fear memory extinction. Immunofluorescence staining was performed to examine c-Fos expression in nucleus accumbens D1 neurons following chemogenetic activation.

Results Compared with the control group, the model group exhibited significantly increased average freezing rates on days 15, 17, and 28 after fear conditioning (P < 0.05). Compared with the freezing rate on day 15, the modified light-associated extinction training reduced the freezing rate of model mice on day 28 (P < 0.05). In contrast, continuous 40-minute extinction training significantly decreased the freezing rate on days 17 and 28 (P < 0.05). Chemogenetic activation of nucleus accumbens D1 neurons significantly reduced the freezing rate of mice in the D1 activation group on day 28 (P < 0.01). Compared with control group, CNO administration increased c-Fos expression in D1 neurons within the nucleus accumbens (P < 0.05).

Conclusion Both the 40-min continuous extinction session and chemogenetic activation of nucleus accumbens D1 neurons promoted fear memory extinction in PTSD model mice.