Robke Rhiannon, Sansi Francesca, Arbab Tara, Tunez Adria, Moore Miranda, Bartsch Dusan, Schönig Kai, Willuhn Ingo
The Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam 1105BA, The Netherlands.
Department of Psychiatry, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam 1105AZ, The Netherlands.
J Neurosci. 2025 May 21;45(21):e1424242025. doi: 10.1523/JNEUROSCI.1424-24.2025.
Serotonin critically modulates the activity of many brain networks, including circuits that control motivation and responses to rewarding and aversive stimuli. Furthermore, the serotonin system is targeted by first-line pharmacological treatments for several psychiatric disorders, including obsessive-compulsive disorder. However, understanding the behavioral function of serotonin is hampered by methodological limitations: the (brainstem) location of serotonergic neuron cell-bodies is difficult to access, their innervation of the brain is diffuse, and they release serotonin in relatively low concentrations. Here, we advance this effort by developing novel Tph2-Cre rats, which we utilized to study serotonin in the context of motor, compulsive, and reinforced behaviors using optogenetics in both male and female rats. Specificity and sensitivity of Cre recombinase expression and Cre-dependent processes were validated immunohistochemically, and optogenetic induction of in vivo serotonin release was validated with fast-scan cyclic voltammetry. Optogenetic stimulation of serotonin neurons in the dorsal raphe nucleus did not initiate locomotion or alter aversion-induced locomotion, nor did it elicit (real-time) place preference, and it had no measurable effect on compulsive behavior in the schedule-induced polydipsia task. In contrast, this optogenetic stimulation moderately sustained ongoing spontaneous locomotion and robustly reinforced operant lever pressing for self-stimulation of serotonin neurons, which was exacerbated by food restriction. Together, this work both introduces a novel rat Cre line to study serotonin and advances our understanding of serotonin's behavioral functions. Complementing previous findings, we find that brainwide serotonin release has an overall relatively mild effect on behavior, which manifested only in the absence of natural reinforcers and was modulated by physiological state.
血清素对许多脑网络的活动起着关键的调节作用，包括控制动机以及对奖励性和厌恶性刺激做出反应的神经回路。此外，血清素系统是几种精神疾病一线药物治疗的靶点，包括强迫症。然而，方法学上的局限性阻碍了我们对血清素行为功能的理解：血清素能神经元细胞体（位于脑干）的位置难以触及，它们对大脑的神经支配较为分散，且释放血清素的浓度相对较低。在此，我们通过培育新型的Tph2-Cre大鼠推进了这一研究工作，我们利用这些大鼠在雄性和雌性大鼠中通过光遗传学方法研究运动、强迫行为和强化行为背景下的血清素。通过免疫组织化学方法验证了Cre重组酶表达和Cre依赖性过程的特异性和敏感性，并通过快速扫描循环伏安法验证了体内血清素释放的光遗传学诱导。对中缝背核中的血清素能神经元进行光遗传学刺激不会引发运动或改变厌恶诱导的运动，也不会引发（实时）位置偏好，并且对日程诱导的饮水中断任务中的强迫行为没有可测量的影响。相比之下，这种光遗传学刺激适度维持了正在进行的自发运动，并有力地强化了为自我刺激血清素能神经元而进行的操作性杠杆按压行为，食物限制会加剧这种行为。总之，这项工作既引入了一种用于研究血清素的新型大鼠Cre品系，又增进了我们对血清素行为功能的理解。与之前的研究结果相互补充，我们发现全脑血清素释放对行为的总体影响相对较小，这种影响仅在缺乏自然强化物的情况下才会出现，并受到生理状态的调节。
