Raju Sharvada, Notaras Michael, Grech Adrienne M, Schroeder Anna, van den Buuse Maarten, Hill Rachel A
Behavioural Neuroscience Laboratory, Department of Psychiatry, Monash University, Melbourne, Victoria, Australia.
Behavioural Neuroscience Laboratory, Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia; Centre for Neurogenetics, Feil Family Brain & Mind Research Institute, Weill Cornell Medical College, Cornell University, NY, New York, USA.
Horm Behav. 2022 Aug;144:105231. doi: 10.1016/j.yhbeh.2022.105231. Epub 2022 Jun 29.
The BDNF Val66Met single nucleotide polymorphism has been implicated in stress sensitivity and Post-Traumatic Stress Disorder (PTSD) risk. We previously reported that chronic young-adult stress hormone treatment enhanced fear memory in adult BDNF mice with the Met/Met genotype. This study aimed to extend this work to fear extinction learning, spontaneous recovery of fear, and neurobiological correlates in the amygdala.
Male and female Val/Val and Met/Met mice received corticosterone in their drinking water during late adolescence to model chronic stress. Following a 2-week recovery period, the mice underwent fear conditioning and extinction training. Immunofluorescent labelling was used to assess density of three interneuron subtypes; somatostatin, parvalbumin and calretinin, within distinct amygdala nuclei.
No significant effects of genotype, treatment or sex were found for fear learning. However, adolescent CORT treatment selectively abolished fear extinction of female Met/Met mice. No effect of genotype, sex, or treatment was observed for spontaneous recovery of fear. Significant main effects of genotype and CORT emerged for somatostatin and calretinin cell density, again in females only, further supporting sex-specific effects of the Met/Met genotype and chronic CORT exposure.
BDNF Val66Met genotype interacts with chronic adolescent stress hormone exposure to abolish fear extinction in female Met/Met mice in adulthood. This effect was associated with female-specific interneuron dysfunction induced by either genotype or stress hormone exposure, depending on the interneuron subtype. These data provide biological insight into the role of BDNF in sex differences in sensitivity to stress and vulnerability to stress-related disorders in adulthood.
脑源性神经营养因子（BDNF）Val66Met单核苷酸多态性与应激敏感性和创伤后应激障碍（PTSD）风险有关。我们之前报道过，成年期慢性应激激素治疗会增强具有Met/Met基因型的成年BDNF小鼠的恐惧记忆。本研究旨在将这项工作扩展到恐惧消退学习、恐惧的自发恢复以及杏仁核中的神经生物学相关性。
雄性和雌性Val/Val和Met/Met小鼠在青春期后期通过饮用含皮质酮的水来模拟慢性应激。经过2周的恢复期后，小鼠接受恐惧条件反射和消退训练。免疫荧光标记用于评估不同杏仁核核团中三种中间神经元亚型（生长抑素、小白蛋白和钙视网膜蛋白）的密度。
在恐惧学习方面未发现基因型、治疗或性别的显著影响。然而，青春期皮质酮治疗选择性地消除了雌性Met/Met小鼠的恐惧消退。在恐惧的自发恢复方面未观察到基因型、性别或治疗的影响。生长抑素和钙视网膜蛋白细胞密度出现了基因型和皮质酮的显著主效应，同样仅在雌性中出现，进一步支持了Met/Met基因型和慢性皮质酮暴露的性别特异性效应。
BDNF Val66Met基因型与青春期慢性应激激素暴露相互作用，导致成年雌性Met/Met小鼠的恐惧消退被消除。这种效应与由基因型或应激激素暴露诱导的雌性特异性中间神经元功能障碍有关，具体取决于中间神经元亚型。这些数据为BDNF在成年期应激敏感性性别差异和应激相关障碍易感性中的作用提供了生物学见解。
