Sex related differences in cognitive deficits: Disrupted Arc/Arg3.1 signaling in an HIV model

IF 2.5 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters Pub Date : 2025-01-10 DOI:10.1016/j.neulet.2024.138071

Yun-Kyung Hahn , Sara R. Nass , William D. Marks , Jason J. Paris , Kurt F. Hauser , Pamela E. Knapp

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Abstract

Combined and highly active anti-retroviral therapies (cART) have transitioned HIV into a more chronic disease. Roughly half of people living with HIV (PLWH) still experience neurocognitive disorders, albeit less severely than in the pre-cART era. Sex-related effects on memory/cognition remain understudied, although the percentage of PLWH that are female has increased. We utilized a transgenic mouse model of HIV that conditionally expresses HIV-1 Tat_1-86 in the CNS to examine cognitive behaviors and the expression of biomarkers related to learning and memory in both sexes. Tat+ males exhibited deficits in spatial learning/memory and object recognition, while Tat+ females showed enhanced fear memory. We investigated the involvement of activity-regulated cytoskeleton-associated protein (Arc), which is induced by novel experience related to learning/memory. We observed hippocampal Arc induction following foot shock in Tat+ females but not Tat+ males. Hippocampal levels of Arc, amyloid β (Aβ) monomers/oligomers and pCREB were altered in a sex-specific manner. CREB activity, which is highly associated with Arc induction, was reduced only in Tat+ males. Tat exposure also decreased Arc expression in cultured human neurons. Thus, HIV-1 Tat effects on CREB/Arc signaling may differ between sexes, contributing to differences in cognitive deficits observed here and in PLWH.

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认知缺陷的性别相关差异：HIV模型中Arc/Arg3.1信号中断

联合和高活性抗逆转录病毒疗法（cART）已将艾滋病毒转变为一种更慢性的疾病。大约一半的艾滋病毒感染者（PLWH）仍然患有神经认知障碍，尽管没有cart之前那么严重。尽管PLWH中女性的比例有所增加，但性别对记忆/认知的影响仍未得到充分研究。我们利用一种在中枢神经系统中有条件表达HIV-1 Tat1-86的转基因小鼠模型来检测两性的认知行为和与学习和记忆相关的生物标志物的表达。结果表明， + 男性在空间学习/记忆和物体识别方面表现出缺陷，而 + 女性在恐惧记忆方面表现出增强。我们研究了活动调节的细胞骨架相关蛋白（Arc）的参与，这是由与学习/记忆相关的新体验诱导的。我们在Tat + 女性中观察到足部电击后的海马弧诱导，而在Tat + 男性中没有。海马中Arc、β淀粉样蛋白（a β）单体/低聚物和pCREB的水平以性别特异性的方式改变。与Arc诱导高度相关的CREB活性仅在Tat + 男性中降低。这种暴露也降低了培养的人类神经元中Arc的表达。因此，HIV-1对CREB/Arc信号的影响可能因性别而异，导致本研究和PLWH观察到的认知缺陷差异。

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来源期刊

Neuroscience Letters 医学-神经科学

CiteScore

5.20

自引率

0.00%

发文量

408

审稿时长

50 days

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