Ghai Utkarsha, Chachra Parul, Mendon Suchith, Janakiraman Balaganesh, Fanibunda Sashaina E, Sarkar Ambalika, Gohil Dievya, Jayaprasad Amogh Bhaskaran, Kukkemane Kowshik, Singh Vivek, Kolthur-Seetharam Ullas, Vaidya Vidita A
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India; Kasturba Health Society-Medical Research Centre, Mumbai, India.
Biol Psychiatry. 2025 May 9. doi: 10.1016/j.biopsych.2025.04.026.
Serotonin shapes emotional neurocircuit development, and serotonergic neurotransmission is implicated in both the pathophysiology and treatment of neuropsychiatric disorders. The selective serotonin reuptake inhibitor fluoxetine is a common first-line treatment for childhood and adolescent mood disorders due to a favorable risk-benefit profile. Using a rodent model, we addressed specific long-term behavioral, molecular, bioenergetic, and cytoarchitectural consequences of postnatal fluoxetine (PNFlx) and juvenile fluoxetine (JFlx) treatment.
Rat pups received PNFlx (postnatal day 2 [P2]-P21) or JFlx (P28-P48) treatment with the impact on anxiety- and despair-like behavior examined in adulthood, along with assessing global gene expression, mitochondrial function, and dendritic cytoarchitecture in the medial prefrontal cortex (mPFC).
PNFlx and JFlx evoked long-lasting, opposing changes in anxiety- and despair-like behavior in male, but not female, rats. The PNFlx- and JFlx-evoked increase and decrease in anxiety- and despair-like behavior, respectively, were accompanied by distinctive, minimally overlapping, transcriptional changes in the mPFC in adulthood. Furthermore, we noted starkly differing outcomes of PNFlx and JFlx on mitochondrial function and dendritic cytoarchitecture in the mPFC. The PNFlx-evoked despair-like behavior was reversed by adult-onset treatment with nicotinamide, a NAD (oxidized nicotinamide adenosine dinucleotide) precursor that enhances mitochondrial bioenergetics.
Collectively, our findings highlight distinct developmental epochs wherein fluoxetine exposure can program long-term, sex-specific, opposing outcomes on mood-related behavior, accompanied by persistent changes in gene expression, mitochondrial function, and neuronal cytoarchitecture in the mPFC in adulthood. These findings provide motivation for future studies to examine a potential role for altered bioenergetics in shaping the differential impact of early fluoxetine treatment on emotionality.
血清素塑造情绪神经回路的发育，血清素能神经传递与神经精神疾病的病理生理学和治疗均有关联。选择性血清素再摄取抑制剂氟西汀因具有良好的风险效益比，是儿童和青少年情绪障碍常见的一线治疗药物。我们利用啮齿动物模型，研究了出生后氟西汀（PNFlx）和青少年期氟西汀（JFlx）治疗的特定长期行为、分子、生物能量和细胞结构后果。
给幼鼠进行PNFlx（出生后第2天[P2]-P21）或JFlx（P28-P48）治疗，检测成年后对焦虑样和绝望样行为的影响，同时评估内侧前额叶皮质（mPFC）的全局基因表达、线粒体功能和树突细胞结构。
PNFlx和JFlx在雄性大鼠而非雌性大鼠中引起了焦虑样和绝望样行为的长期、相反变化。PNFlx和JFlx分别引起的焦虑样和绝望样行为增加和减少，在成年期mPFC中伴随着独特的、几乎没有重叠的转录变化。此外，我们注意到PNFlx和JFlx对mPFC中线粒体功能和树突细胞结构的影响截然不同。成年期用烟酰胺（一种增强线粒体生物能量的NAD（氧化型烟酰胺腺嘌呤二核苷酸）前体）治疗可逆转PNFlx引起的绝望样行为。
总体而言，我们的研究结果突出了不同的发育时期，其中氟西汀暴露可对情绪相关行为产生长期、性别特异性的相反结果，并伴有成年期mPFC中基因表达、线粒体功能和神经元细胞结构的持续变化。这些发现为未来研究提供了动力，以探讨生物能量改变在塑造早期氟西汀治疗对情绪的不同影响方面的潜在作用。
