Natarajan Reka, Forrester Laura, Chiaia Nicolas L, Yamamoto Bryan K
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202, and.
Department of Neurosciences, University of Toledo College of Medicine, Toledo, Ohio 43614.
J Neurosci. 2017 Jun 28;37(26):6214-6223. doi: 10.1523/JNEUROSCI.3781-16.2017. Epub 2017 May 25.
The current study examined the neurochemical mechanisms and neuroanatomical changes underlying coexisting behavioral effects associated with chronic-stress-induced alterations in serotonin (5HT) neurons. Chronic unpredictable stress (CUS) to adult male rats produced depression-like changes with cognitive dysfunction and selective cell death in the interfascicular nucleus of the dorsal raphe (DRif), resulting in decreased 5HTergic innervation of medial prefrontal cortex (mPFC). Twenty-one days of CUS decreased basal plasma levels of corticosterone and produced a shorter latency to immobility and longer durations of immobility in the force-swim test that persisted for 1 month after CUS. Deficits in acquisition, recall, perseveration, and reversal learning were evident 1 month after CUS. MK801 treatment during CUS blocked the changes in the forced-swim test and deficits in memory recall. These behavioral changes were associated with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive soma and the eventual loss of 5HT neurons in the DRif and its projections to the mPFC as evidenced by fewer labeled cells in the DRif after retrograde tracer injections into the mPFC of stressed rats. Similar to the effects of MK801 on behavior, MK801 pretreatment during stress blocked the CUS-induced decreases in 5HT soma within the DRif and its projections to the mPFC. Finally, the depression-like behaviors were blocked by acute injection of the 5HT2A/C agonist (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride into the mPFC before forced-swim testing. These results identify a cause and mechanism of 5HTergic dysfunction of the mPFC and associated mood and cognitive behaviors. Chronic stress causes persistent mood and cognitive changes typically associated with dysregulated serotonin (5HT) transmission in the medial prefrontal cortex (mPFC), but the cause of this dysregulation is unknown. Prior studies have focused on 5HTergic terminals in this region, but this study shows that chronic stress causes NMDA-receptor-dependent and subregion-specific cell death of 5HT neurons in the dorsal raphe. The consequent decreased 5HT innervation of the mPFC was associated with mood and cognitive changes that persisted long after the termination of stress. These findings identify a mechanism of subregion-selective death of 5HT neurons in the dorsal raphe, a defined neuroanatomical pathway, and a behavioral phenotype that mirror stress-associated diseases such as major depressive disorder.
本研究探讨了与慢性应激诱导的血清素（5HT）神经元改变相关的共存行为效应背后的神经化学机制和神经解剖学变化。对成年雄性大鼠施加慢性不可预测应激（CUS），导致其出现类似抑郁的变化，伴有认知功能障碍以及背侧中缝核束间核（DRif）中的选择性细胞死亡，进而导致内侧前额叶皮质（mPFC）的5HT能神经支配减少。21天的CUS降低了皮质酮的基础血浆水平，并在强迫游泳试验中使不动潜伏期缩短、不动持续时间延长，且在CUS后1个月仍持续存在。CUS后1个月，在习得、回忆、持续和逆向学习方面存在明显缺陷。在CUS期间给予MK801治疗可阻断强迫游泳试验中的变化以及记忆回忆缺陷。这些行为变化与末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）阳性的胞体以及DRif中5HT神经元及其向mPFC投射的最终丧失相关，这在将逆行示踪剂注射到应激大鼠的mPFC后，DRif中标记细胞减少得以证明。与MK801对行为的影响相似，在应激期间进行MK801预处理可阻断CUS诱导的DRif中5HT胞体及其向mPFC投射的减少。最后，在强迫游泳试验前，向mPFC急性注射5HT2A/C激动剂（-）-2,5-二甲氧基-4-碘苯丙胺盐酸盐可阻断类似抑郁的行为。这些结果确定了mPFC的5HT能功能障碍以及相关情绪和认知行为的原因和机制。慢性应激会导致持续的情绪和认知变化，通常与内侧前额叶皮质（mPFC）中血清素（5HT）传递失调有关，但这种失调的原因尚不清楚。先前的研究集中在该区域的5HT能终末，但本研究表明，慢性应激会导致背侧中缝核中5HT神经元的NMDA受体依赖性和亚区域特异性细胞死亡。随后mPFC的5HT神经支配减少与应激终止后长期持续的情绪和认知变化有关。这些发现确定了背侧中缝核中5HT神经元亚区域选择性死亡的机制、一条明确的神经解剖学通路以及一种行为表型，这些与诸如重度抑郁症等应激相关疾病相似。
