Department of Neurobiology and Neuropsychology, Institute of Applied Psychology, Jagiellonian University, 4 Lojasiewicza Street, 30-348 Krakow, Poland; Department of Molecular Neuropharmacology, Institute of Pharmacology Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
Department of Neurobiology and Neuropsychology, Institute of Applied Psychology, Jagiellonian University, 4 Lojasiewicza Street, 30-348 Krakow, Poland.
Eur Neuropsychopharmacol. 2017 Aug;27(8):782-794. doi: 10.1016/j.euroneuro.2017.05.008. Epub 2017 Jun 9.
Activity of the ventral tegmental area (VTA) and its terminals has been implicated in the Pavlovian associative learning of both stressful and rewarding stimuli. However, the role of the VTA noradrenergic signaling in fear responses remains unclear. We aimed to examine how alpha-adrenergic receptor (α-AR) signaling in the VTA affects conditioned fear. The role of α-AR was assessed using the micro-infusions into the VTA of the selective antagonists (0.1-1µg/0.5µl prazosin and 1µg/0.5µl terazosin) in acquisition and expression of fear memory. In addition, we performed control experiments with α-AR blockade in the mammillary bodies (MB) - a brain region with α-AR expression adjacent to the VTA. Intra-VTA but not intra-MB α-AR blockade prevented formation and retrieval of fear memories. Importantly, local administration of α-AR antagonists did not influence footshock sensitivity, locomotion or anxiety-like behaviors. Similarly, α-AR blockade in the VTA had no effects on negative affect measured as number of 22kHz ultrasonic vocalizations during fear conditioning training. We propose that noradrenergic signaling in the VTA via α-AR regulates formation and retrieval of fear memories but not other behavioral responses to stressful environmental stimuli. It enhances the encoding of environmental stimuli by the VTA to form and retrieve conditioned fear memories and to predict future behavioral outcomes. Our results provide novel insight into the role of the VTA α-AR signaling in the regulation of stress responsiveness and fear memory.
腹侧被盖区（VTA）的活动及其末梢与应激和奖励刺激的条件性关联学习有关。然而，VTA 去甲肾上腺素能信号在恐惧反应中的作用仍不清楚。我们旨在研究 VTA 中的α-肾上腺素能受体（α-AR）信号如何影响条件性恐惧。使用 VTA 中的选择性拮抗剂（0.1-1μg/0.5μl 哌唑嗪和 1μg/0.5μl 特拉唑嗪）的微输注来评估 α-AR 的作用，以评估在恐惧记忆的获得和表达中的作用。此外，我们在与 VTA 相邻的具有 α-AR 表达的脑区乳状体（MB）中进行了 α-AR 阻断的对照实验。VTA 内而非 MB 内的 α-AR 阻断可防止恐惧记忆的形成和检索。重要的是，局部给予 α-AR 拮抗剂不会影响足部电击的敏感性、运动或焦虑样行为。同样，VTA 中的 α-AR 阻断对恐惧条件训练期间作为 22kHz 超声发声次数测量的负性情绪没有影响。我们提出，VTA 中的去甲肾上腺素能信号通过 α-AR 调节恐惧记忆的形成和检索，但不调节对应激环境刺激的其他行为反应。它增强了 VTA 对环境刺激的编码，以形成和检索条件性恐惧记忆，并预测未来的行为结果。我们的结果为 VTA α-AR 信号在调节应激反应性和恐惧记忆中的作用提供了新的见解。
