Sex-specific threat responding and neuronal engagement in carbon dioxide associated fear and extinction: Noradrenergic involvement in female mice

IF 4.3 2区 医学 Q1 NEUROSCIENCES Neurobiology of Stress Pub Date : 2024-02-20 DOI:10.1016/j.ynstr.2024.100617
Rebecca Ahlbrand , Allison Wilson , Patrick Woller , Yuv Sachdeva , Jayden Lai , Nikki Davis , James Wiggins , Renu Sah
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Abstract

Difficulty in appropriately responding to threats is a key feature of psychiatric disorders, especially fear-related conditions such as panic disorder (PD) and posttraumatic stress disorder (PTSD). Most prior work on threat and fear regulation involves exposure to external threatful cues. However, fear can also be triggered by aversive, within-the-body, sensations. This interoceptive signaling of fear is highly relevant to PD and PTSD but is not well understood, especially in the context of sex. Using female and male mice, the current study investigated fear-associated spontaneous and conditioned behaviors to carbon dioxide (CO2) inhalation, a potent interoceptive threat that induces fear and panic. We also investigated whether behavioral sensitivity to CO2 is associated with delayed PTSD-relevant behaviors. CO2 evoked heterogenous freezing behaviors in both male and female animals. However, active, rearing behavior was significantly reduced in CO2-exposed male but not female mice. Interestingly, behavioral sensitivity to CO2 was associated with compromised fear extinction, independent of sex. However, in comparison to CO2-exposed males, females elicited less freezing and higher rearing during extinction suggesting an engagement of active versus passive defensive coping. Persistent neuronal activation marker ΔFosB immuno-mapping revealed attenuated engagement of infralimbic-prefrontal areas in both sexes but higher activation of brain stem locus coeruleus (LC) area in females. Inter-regional co-activation mapping revealed sex-independent disruptions in the infralimbic-amygdala associations but altered LC associations only in CO2-exposed female mice. Lastly, dopamine β hydroxylase positive (DβH + ve) noradrenergic neuronal cell counts in the LC correlated with freezing and rearing behaviors during CO2 inhalation and extinction only in female but not male mice. Collectively, these data provide evidence for higher active defensive responding to interoceptive threat CO2-associated fear in females that may stem from increased recruitment of the brainstem noradrenergic system. Our findings reveal distinct contributory mechanisms that may promote sex differences in fear and panic associated pathologies.

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与二氧化碳相关的恐惧和消退中的性别特异性威胁反应和神经元参与:雌性小鼠去甲肾上腺素能的参与
难以对威胁做出适当反应是精神疾病的一个主要特征,尤其是与恐惧相关的疾病,如惊恐障碍(PD)和创伤后应激障碍(PTSD)。之前关于威胁和恐惧调节的研究大多涉及暴露于外部威胁线索的情况。然而,身体内部的厌恶感觉也会引发恐惧。这种恐惧的感知间信号与帕金森病和创伤后应激障碍高度相关,但人们对其了解不多,尤其是在性别背景下。本研究使用雌性和雄性小鼠,调查了吸入二氧化碳(CO2)时与恐惧相关的自发行为和条件行为。我们还研究了对二氧化碳的行为敏感性是否与创伤后应激障碍相关的延迟行为有关。二氧化碳会诱发雄性和雌性动物出现不同的冻结行为。然而,暴露于二氧化碳的雄性小鼠的主动饲养行为明显减少,而雌性小鼠则没有。有趣的是,对二氧化碳的行为敏感性与恐惧消退能力受损有关,与性别无关。然而,与暴露于二氧化碳的雄性小鼠相比,雌性小鼠在熄灭过程中引起的冻结更少,饲养程度更高,这表明雌性小鼠参与了主动与被动的防御应对。持续性神经元激活标记物ΔFosB免疫图谱显示,雌雄动物的下边缘-前额叶区的参与程度都有所降低,但雌性动物的脑干定位区(LC)的激活程度更高。区域间共同激活图谱显示,下边缘-杏仁核关联的中断与性别无关,但只有暴露于二氧化碳的雌性小鼠的LC关联发生了改变。最后,LC 中多巴胺 β 羟化酶阳性(DβH + ve)去甲肾上腺素能神经元细胞数量与吸入二氧化碳时的冻结和饲养行为相关,只有雌性小鼠与之相关,雄性小鼠则不然。总之,这些数据提供了证据,证明雌性小鼠对二氧化碳相关恐惧的感知威胁做出了更高的主动防御反应,这可能源于脑干去甲肾上腺素能系统招募的增加。我们的研究结果揭示了可能导致恐惧和恐慌相关病症的性别差异的不同机制。
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来源期刊
Neurobiology of Stress
Neurobiology of Stress Biochemistry, Genetics and Molecular Biology-Biochemistry
CiteScore
9.40
自引率
4.00%
发文量
74
审稿时长
48 days
期刊介绍: Neurobiology of Stress is a multidisciplinary journal for the publication of original research and review articles on basic, translational and clinical research into stress and related disorders. It will focus on the impact of stress on the brain from cellular to behavioral functions and stress-related neuropsychiatric disorders (such as depression, trauma and anxiety). The translation of basic research findings into real-world applications will be a key aim of the journal. Basic, translational and clinical research on the following topics as they relate to stress will be covered: Molecular substrates and cell signaling, Genetics and epigenetics, Stress circuitry, Structural and physiological plasticity, Developmental Aspects, Laboratory models of stress, Neuroinflammation and pathology, Memory and Cognition, Motivational Processes, Fear and Anxiety, Stress-related neuropsychiatric disorders (including depression, PTSD, substance abuse), Neuropsychopharmacology.
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