Sex differences in contextual fear conditioning and extinction after acute and chronic nicotine treatment.

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Biology of Sex Differences Pub Date : 2024-10-31 DOI:10.1186/s13293-024-00656-6
Jack V Keady, Marissa C Hessing, Judy C Songrady, Kristen McLaurin, Jill R Turner
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Abstract

Background: Chronic cigarette smokers report withdrawal symptomology, including affective dysfunction and cognitive deficits. While there are studies demonstrating sex specific withdrawal symptomology in nicotine-dependent individuals, literature examining the underlying biological mediators of this is scant and not in complete agreement. Therefore, in this study, we evaluated the sex specific effects of nicotine and withdrawal on contextual fear memory, a hippocampally dependent aspect of cognition that is disrupted in nicotine withdrawal.

Methods: Male and female B6/129F1 mice (8-13 weeks old) were used in all experiments. For the acute nicotine experiment, mice received intraperitoneal saline or nicotine (0.5 mg/kg) prior to contextual fear conditioning and test. For the chronic nicotine experiment, mice received nicotine (18 mg/kg/day) or saline for 11 days, then underwent contextual fear conditioning and test. Following the test, mice underwent minipump removal to elicit withdrawal or sham surgery, followed by the fear extinction assay. Bulk cortical tissue was used to determine nicotinic acetylcholine receptor levels via single point [3H]Epibatidine binding assay. Gene expression levels in the dorsal and ventral hippocampus were quantified via RT-PCR.

Results: We found that female mice had a stronger expression of contextual fear memory than their male counterparts. Further, following acute nicotine treatment, male, but not female, subjects demonstrated augmented contextual fear memory expression. In contrast, no significant effects of chronic nicotine treatment on fear conditioning were observed in either sex. When examining extinction of fear learning, we observed that female mice withdrawn from nicotine displayed impaired extinction learning, but no effect was observed in males. Nicotine withdrawal caused similar suppression of fosb, cfos, and bdnf, our proxy for neuronal activation and plasticity changes, in the dorsal and ventral hippocampus of both sexes. Additionally, we found that ventral hippocampus erbb4 expression, a gene implicated in smoking cessation outcomes, was elevated in both sexes following nicotine withdrawal.

Conclusions: Despite the similar impacts of nicotine withdrawal on gene expression levels, fosb, cfos, bdnf and erbb4 levels in the ventral hippocampus were predictive of delays in female extinction learning alone. This suggests sex specific dysfunction in hippocampal circuitry may contribute to female specific nicotine withdrawal induced deficits in extinction learning.

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急性和慢性尼古丁治疗后情境恐惧条件反射和消退的性别差异。
背景:长期吸烟者会出现戒断症状,包括情感功能障碍和认知障碍。虽然有研究表明尼古丁依赖者会出现特定性别的戒断症状,但研究其潜在生物学介导因素的文献却很少,而且并不完全一致。因此,在本研究中,我们评估了尼古丁和戒断对情境恐惧记忆的性别特异性影响:所有实验均使用雄性和雌性B6/129F1小鼠(8-13周大)。在急性尼古丁实验中,小鼠在情境恐惧条件反射和测试前腹腔注射生理盐水或尼古丁(0.5 毫克/千克)。在慢性尼古丁实验中,小鼠接受尼古丁(18 毫克/千克/天)或生理盐水治疗 11 天,然后进行情境恐惧条件反射和测试。测试后,小鼠接受微型泵移除以引起戒断或假手术,然后进行恐惧消退实验。通过单点[3H]表巴丁定结合试验,使用大块皮层组织测定烟碱乙酰胆碱受体水平。通过 RT-PCR 对海马背侧和腹侧的基因表达水平进行量化:结果:我们发现雌性小鼠比雄性小鼠有更强的情境恐惧记忆表达。此外,在急性尼古丁治疗后,雄性受试者(而非雌性受试者)的情境恐惧记忆表达增强。与此相反,慢性尼古丁治疗对恐惧条件反射没有明显的影响。在研究恐惧学习的消退时,我们观察到,雌性小鼠在戒断尼古丁后,消退学习能力受损,而雄性小鼠则没有受到影响。尼古丁戒断会导致雌雄小鼠海马背侧和腹侧的 fosb、cfos 和 bdnf(神经元活化和可塑性变化的代表)受到类似的抑制。此外,我们还发现,在尼古丁戒断后,两种性别的腹侧海马erbb4表达均升高,而erbb4是一种与戒烟结果有关的基因:结论:尽管尼古丁戒断对基因表达水平的影响相似,但腹侧海马中的fosb、cfos、bdnf和erbb4水平可预测雌性单独绝迹学习的延迟。这表明,海马回路中的性别特异性功能障碍可能是女性尼古丁戒断引起的消退学习障碍的原因之一。
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来源期刊
Biology of Sex Differences
Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY
CiteScore
12.10
自引率
1.30%
发文量
69
审稿时长
14 weeks
期刊介绍: Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.
期刊最新文献
Sex differences in the human brain related to visual motion perception. A call for inclusive research, policies, and leadership to close the global women's health gap. Sex differences in contextual fear conditioning and extinction after acute and chronic nicotine treatment. Sex dimorphism and tissue specificity of gene expression changes in aging mice. The Four Core Genotypes mouse model: evaluating the impact of a recently discovered translocation.
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