Abstract
Dopaminergic neurotransmission via dopamine D1 receptors (D1Rs) is considered to play an important role not only in reward-based learning but also in aversive learning. The contextual and auditory cued fear conditioning tests involve the processing of classical fear conditioning and evaluates aversive learning memory. It is possible to evaluate aversive learning memory in two different types of neural transmission circuits. In addition, when evaluating the role of dopaminergic neurotransmission via D1R, to avoid the effects in D1R-mediated neural circuitry alterations during development, it is important to examine using mice who D1R expression in the mature stage is suppressed. Herein, we investigated the role of dopaminergic neurotransmission via D1Rs in aversive memory formation in contextual and auditory cued fear conditioning tests using D1R knockdown (KD) mice, in which the expression of D1Rs could be conditionally and reversibly controlled with doxycycline (Dox) treatment. For aversive memory, we examined memory formation using recent memory 1 day after conditioning, and remote memory 4 weeks after conditioning. Furthermore, immunostaining of the brain tissues of D1RKD mice was performed after aversive footshock stimulation to investigate the distribution of activated c-Fos, an immediate-early gene, in the hippocampus (CA1, CA3, dentate gyrus), striatum, amygdala, and prefrontal cortex during aversive memory formation. After aversive footshock stimulation, immunoblotting was performed using hippocampal, striatal, and amygdalar samples from D1RKD mice to investigate the increase in the amount of c-Fos and phosphorylated SNAP-25 at Ser187 residue. When D1R expression was suppressed using Dox, behavioral experiments revealed impaired contextual fear learning in remote aversion memory following footshock stimulation. Furthermore, expression analysis showed a slight increase in the post-stimulation amount of c-Fos in the hippocampus and striatum, and a significant increase in the amount of phosphorylated SNAP-25 in the hippocampus, striatum, and prefrontal cortex before and after stimulation. These findings indicate that deficiency in D1R-mediated dopaminergic neurotransmission is an important factor in impairing contextual fear memory formation for remote memory.
Highlights
Dopamine neurotransmission through D1 receptors (D1Rs) and D1-like receptors is thought to play an important role in aversive memory (El-Ghundi et al, 2001; Ortiz et al, 2010; Sarinana et al, 2014; Soares-Cunha et al, 2016b; Schultz, 2019)
We investigated the effects of D1R suppression on long-term memory of contextual and auditory cued fear conditioning as aversive learning in mature mice, as well as the role of D1Rs in the hippocampus, dorsomedial striatum (DMS), prelimbic region of medial prefrontal cortex, and basal amygdala (BA)
We examined the effects of the suppression of D1R expression on fear memory formation in contextual and auditory cued fear conditioning in mature mice and compared the results of this study with results regarding aversive memory formation in the passive avoidance test reported previously (Saito et al, 2020)
Summary
Dopamine neurotransmission through D1Rs and D1-like receptors is thought to play an important role in aversive memory (El-Ghundi et al, 2001; Ortiz et al, 2010; Sarinana et al, 2014; Soares-Cunha et al, 2016b; Schultz, 2019). Dopamine neurotransmission through D2 dopamine receptors (D2Rs) and D2-like receptors is thought to play an important role in aversive memory (Bromberg-Martin et al, 2010; Danjo et al, 2014; Yamaguchi et al, 2015; Soares-Cunha et al, 2016b; Kawahata et al, 2021). D1R knockout (KO) mice or genetically modified mice, including conditional D1R knockdown mice using drug administration or the Cre-loxP system, have been utilized to elucidate the role of dopamine transmission through D1R in fear conditioning (El-Ghundi et al, 2001; Ortiz et al, 2010; Ikegami et al, 2014). The results of these analyses have been inconsistent, and the role of D1R-mediated dopamine neurotransmission in the hippocampus, amygdala, prefrontal cortex, and striatum remains to be fully elucidated
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