Genetic disruption of dopamine β-hydroxylase dysregulates innate responses to predator odor in mice

IF 4.3 2区 医学 Q1 NEUROSCIENCES
Joyce Liu , Daniel J. Lustberg , Abigail Galvez, L. Cameron Liles, Katharine E. McCann, David Weinshenker
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引用次数: 0

Abstract

In rodents, exposure to predator odors such as cat urine acts as a severe stressor that engages innate defensive behaviors critical for survival in the wild. The neurotransmitters norepinephrine (NE) and dopamine (DA) modulate anxiety and predator odor responses, and we have shown previously that dopamine β-hydroxylase knockout (Dbh −/−), which reduces NE and increases DA in mouse noradrenergic neurons, disrupts innate behaviors in response to mild stressors such as novelty. We examined the consequences of Dbh knockout on responses to predator odor (bobcat urine) and compared them to Dbh-competent littermate controls. Over the first 10 min of predator odor exposure, controls exhibited robust defensive burying behavior, whereas Dbh −/− mice showed high levels of grooming. Defensive burying was potently suppressed in controls by drugs that reduce NE transmission, while excessive grooming in Dbh −/− mice was blocked by DA receptor antagonism. In response to a cotton square scented with a novel “neutral” odor (lavender), most control mice shredded the material, built a nest, and fell asleep within 90 min. Dbh −/− mice failed to shred the lavender-scented nestlet, but still fell asleep. In contrast, controls sustained high levels of arousal throughout the predator odor test and did not build nests, while Dbh −/− mice were asleep by the 90-min time point, often in shredded bobcat urine-soaked nesting material. Compared with controls exposed to predator odor, Dbh −/− mice demonstrated decreased c-fos induction in the anterior cingulate cortex, lateral septum, periaqueductal gray, and bed nucleus of the stria terminalis, but increased c-fos in the locus coeruleus and medial amygdala. These data indicate that relative ratios of central NE and DA signaling coordinate the type and valence of responses to predator odor.

基因干扰多巴胺β-羟化酶会导致小鼠对捕食者气味的先天反应失调
对于啮齿类动物来说,暴露于捕食者气味(如猫尿)是一种严重的应激反应,会引发对野外生存至关重要的先天防御行为。神经递质去甲肾上腺素(NE)和多巴胺(DA)调节焦虑和捕食者气味反应,我们之前已经证明,多巴胺β-羟化酶敲除(Dbh -/-)会减少小鼠去甲肾上腺素能神经元中的NE,增加DA,从而破坏对新奇事物等轻度应激源的先天性行为。我们研究了Dbh基因敲除(Dbh -/-)对捕食者气味(山猫尿液)反应的影响,并将其与Dbh功能正常的同窝对照组进行了比较。在暴露于捕食者气味的最初10分钟内,对照组小鼠表现出强烈的防御性掩埋行为,而Dbh -/-小鼠则表现出高水平的梳理行为。降低NE传递的药物可有效抑制对照组的防御性掩埋行为,而Dbh -/-小鼠的过度梳理行为可被DA受体拮抗剂阻断。对于带有新奇 "中性 "气味(薰衣草)的棉花方块,大多数对照组小鼠会在90分钟内将其撕碎、筑巢并入睡。Dbh -/-小鼠未能撕碎薰衣草香味的小窝,但仍然睡着了。相比之下,对照组在整个捕食者气味测试过程中都保持着高水平的唤醒,并且没有筑巢,而Dbh -/-小鼠在90分钟的时间点前就已经睡着了,通常是在山猫尿液浸泡过的碎巢材料中睡着的。与暴露于捕食者气味的对照组相比,Dbh -/-小鼠在前扣带回皮层、外侧隔膜、丘脑周围灰质和纹状体末端床核中的c-fos诱导减少,但在脑室和内侧杏仁核中的c-fos诱导增加。这些数据表明,中枢NE和DA信号的相对比例协调了对捕食者气味的反应类型和情绪。
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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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