抗抑郁药,虽然有效治疗抑郁症和焦虑症,也会导致感觉(特别是听觉)加工缺陷,这反过来可能会加剧精神症状。抗抑郁药如何引起听觉特征缺陷仍然是未知的。这里,我们发现,与年龄匹配的对照大鼠相比,氟西汀治疗的成年雌性大鼠在执行音调-频率辨别任务时的准确度明显较低.他们的皮层神经元对声音频率的选择性反应也较少。行为和皮质加工的退化伴随着皮质神经周网的减少,特别是那些包裹在表达小白蛋白的抑制性中间神经元周围的细胞。此外,氟西汀在其已经成熟的听觉皮层中诱导了临界期样可塑性;因此,在丰富的声学环境下对这些药物治疗的大鼠进行了短暂的饲养,氟西汀降解了重整化的听觉处理。由于丰富的声音暴露,神经周网的皮质表达改变也被逆转。这些发现表明,抗抑郁药对听觉处理的不利影响,可能是因为皮质内抑制的减少,可以通过简单地将药物治疗与被动治疗配对来大大缓解,丰富的声音暴露。它们对于理解抗抑郁药对听力的影响的神经生物学基础以及设计针对精神疾病的新型药物治疗策略具有重要意义。临床经验表明,抗抑郁药对感觉(尤其是听觉)处理产生不利影响,这会加剧患者的精神症状。这里,我们表明抗抑郁药氟西汀可以减少成年大鼠的皮质抑制作用,导致声音的行为和皮层频谱处理退化。重要的是,氟西汀在成熟的皮质中诱导关键的可塑性周期样状态;因此,在丰富的声学环境下进行短暂的饲养足以逆转氟西汀给药引起的听觉处理变化。这些结果为抗抑郁药对听力的影响提供了推定的神经生物学基础,并表明抗抑郁药治疗结合丰富的感官体验可以优化临床结果。
Antidepressants, while effective in treating depression and anxiety disorders, also induce deficits in sensory (particularly auditory) processing, which in turn may exacerbate psychiatric symptoms. How antidepressants cause auditory signature deficits remains largely unknown. Here, we found that fluoxetine-treated adult female rats were significantly less accurate when performing a tone-frequency discrimination task compared with age-matched control rats. Their cortical neurons also responded less selectively to sound frequencies. The degraded behavioral and cortical processing was accompanied by decreased cortical perineuronal nets, particularly those wrapped around parvalbumin-expressing inhibitory interneurons. Furthermore, fluoxetine induced critical period-like plasticity in their already mature auditory cortices; therefore, a brief rearing of these drug-treated rats under an enriched acoustic environment renormalized auditory processing degraded by fluoxetine. The altered cortical expression of perineuronal nets was also reversed as a result of enriched sound exposure. These findings suggest that the adverse effects of antidepressants on auditory processing, possibly because of a reduction in intracortical inhibition, can be substantially alleviated by simply pairing drug treatment with passive, enriched sound exposure. They have important implications for understanding the neurobiological basis of antidepressant effects on hearing and for designing novel pharmacological treatment strategies for psychiatric disorders.SIGNIFICANCE STATEMENT Clinical experience suggests that antidepressants adversely affect sensory (particularly auditory) processing, which can exacerbate patients\' psychiatric symptoms. Here, we show that the antidepressant fluoxetine reduces cortical inhibition in adult rats, leading to degraded behavioral and cortical spectral processing of sound. Importantly, fluoxetine induces a critical period-like state of plasticity in the mature cortex; therefore, a brief rearing under an enriched acoustic environment is sufficient to reverse the changes in auditory processing caused by the administration of fluoxetine. These results provide a putative neurobiological basis for the effects of antidepressants on hearing and indicate that antidepressant treatment combined with enriched sensory experiences could optimize clinical outcomes.