Hajós M, Richards C D, Székely A D, Sharp T
Department of Clinical Pharmacology, Radcliffe Infirmary, University of Oxford, UK.
Neuroscience. 1998 Nov;87(1):95-108. doi: 10.1016/s0306-4522(98)00157-2.
In this study we utilized electrophysiological and pathway tracing methods to investigate the projections from the medial prefrontal cortex to the midbrain raphe nuclei of the rat. Initial pathway tracing experiments using retrograde (horseradish peroxidase conjugates with wheatgerm agglutinin or choleratoxin B subunit) and anterograde (Phaseolus vulgaris-leucoagglutinin) markers demonstrated a direct, bilateral projection to the dorsal raphe nucleus and median raphe nucleus from the medial prefrontal cortex, and the origin of this projection was localized predominantly in the ventral medial prefrontal cortex (infralimbic/dorsal penduncular cortices). Using chloral hydrate-anaesthetized rats, extracellular recordings were made mostly from 5-hydroxytryptamine neurons in the dorsal raphe nucleus, but non-5-hydroxytryptamine dorsal raphe neurons were also studied, as was a small number of 5-hydroxytryptamine neurons in the median raphe nucleus. In an initial study, electrical stimulation of the ventral medial prefrontal cortex caused a post-stimulus inhibition in the majority (49/56) of dorsal raphe 5-hydroxytryptamine neurons tested (mean duration of inhibition, 200+/-17 ms); in some cases (8/56) the inhibition was preceded by short-latency (26 +/-3 ms) orthodromic activation, and a small number of cells was antidromically activated (6/56). Both single spiking and burst-firing 5-hydroxytryptamine neurons in the dorsal raphe nucleus responded in the same way, and median raphe 5-hydroxytryptamine neurons were also inhibited (5/5). In contrast, few (2/12) of the non-5-hydroxytryptamine dorsal raphe neurons tested were inhibited by ventral medial prefrontal cortex stimulation. The effects of stimulation of the dorsal and ventral medial prefrontal cortex were compared on the same raphe 5-hydroxytryptamine neurons (n=17): ventral medial prefrontal cortex stimulation inhibited 16/17 of these neurons while only 8/17 were inhibited by dorsal medial prefrontal cortex stimulation. Finally, the inhibitory effect of ventral medial prefrontal cortex stimulation on 5-hydroxytryptamine cell-firing was not altered by 5-hydroxytryptamine depletion with p-chlorophenylalanine or by systemic administration of the selective 5-hydroxytryptamine1A receptor antagonist WAY 100635. The latter findings indicate that the inhibition is not due to release of raphe 5-hydroxytryptamine which could theoretically arise from anti- or orthodromically activated 5-hydroxytryptamine neurons. Our results show that stimulation of the ventral medial prefrontal cortex causes a marked post-stimulus inhibition in the vast majority of midbrain raphe 5-hydroxytryptamine neurons tested. It seems likely that the projection from ventral medial prefrontal cortex to the midbrain raphe nuclei mediates the responses of 5-hydroxytryptamine neurons to cortical stimulation. These data are relevant to recent discoveries of functional and structural abnormalities in the medial prefrontal cortex of patients with major depressive illness.
在本研究中，我们利用电生理和通路追踪方法来研究大鼠内侧前额叶皮质向中脑缝际核的投射。最初的通路追踪实验使用逆行（辣根过氧化物酶与麦胚凝集素或霍乱毒素B亚基结合物）和顺行（菜豆白细胞凝集素）标记物，证实内侧前额叶皮质向背侧缝际核和中缝核有直接的双侧投射，且该投射的起源主要定位于腹内侧前额叶皮质（边缘下/背侧脚周皮质）。使用水合氯醛麻醉的大鼠，细胞外记录主要来自背侧缝际核中的5-羟色胺能神经元，但也研究了非5-羟色胺能的背侧缝际核神经元以及中缝核中的少数5-羟色胺能神经元。在一项初步研究中，电刺激腹内侧前额叶皮质在大多数（49/56）被测试的背侧缝际核5-羟色胺能神经元中引起刺激后抑制（抑制的平均持续时间为200±17毫秒）；在某些情况下（8/56），抑制之前有短潜伏期（26±3毫秒）的顺向激活，少数细胞被逆向激活（6/56）。背侧缝际核中的单峰发放和爆发式发放5-羟色胺能神经元反应方式相同，中缝核5-羟色胺能神经元也受到抑制（5/5）。相比之下，被测试的非5-羟色胺能背侧缝际核神经元中很少（2/12）被腹内侧前额叶皮质刺激所抑制。比较了背内侧和腹内侧前额叶皮质刺激对同一缝际5-羟色胺能神经元（n = 17）的影响：腹内侧前额叶皮质刺激抑制了其中16/17的神经元，而背内侧前额叶皮质刺激仅抑制了8/17的神经元。最后，用对氯苯丙氨酸耗竭5-羟色胺或全身给予选择性5-羟色胺1A受体拮抗剂WAY 100635，并未改变腹内侧前额叶皮质刺激对5-羟色胺能细胞发放的抑制作用。后一发现表明，这种抑制不是由于理论上可能由逆向或顺向激活的5-羟色胺能神经元释放缝际5-羟色胺所致。我们的结果表明，刺激腹内侧前额叶皮质在绝大多数被测试的中脑缝际5-羟色胺能神经元中引起明显的刺激后抑制。腹内侧前额叶皮质向中脑缝际核的投射似乎介导了5-羟色胺能神经元对皮质刺激的反应。这些数据与近期在重度抑郁症患者内侧前额叶皮质中发现的功能和结构异常有关。
