內生性感光視網膜神經節細胞與下視丘之功能性連接：視交叉上核與視上核之研究

Abstract

光線是調節哺乳動物生理與行為的主要環境信號。這些光訊號由表達黑視素的內生感光視網膜神經節細胞(ipRGCs)所捕捉，並傳遞至各個非視覺圖像形成中心。本研究旨在探討該通路內新型的功能連接性與突觸機制，並著重於下視丘的視交叉上核(SCN)與視上核(SON)。 視交叉上核是晝夜節律的控制中心，其中有核心區的血管活性腸肽(VIP)神經元與外殼區的精氨酸血管加壓素(AVP)神經元，共同將晝夜節律與光暗週期同步化。雖然傳統觀點認為AVP神經元遵循著ipRGCs-VIP-AVP迴路位於下游處理光訊號，但近期形態學證據顯示單個ipRGC形態學神經纖維能直接投射至SCN 的AVP神經元。因此本研究旨在利用離體活腦切片膜片鉗記錄與鈣成像技術來檢測此ipRGCs-AVP神經元迴路是否有功能性連接。發現聚集在腹側區域的一個特定AVP神經細胞群，接收來自的ipRGCs直接單突觸輸入，並且多數同時也接收多突觸的GABA間接輸入。這些發現證實SCN的AVP神經元直接整合到了光輸入通路中，形成了一個用於晝夜節律調節的複雜平行網路。 除了SCN之外，光照還會抑制SON的催產素(OT)神經元活性，進而損害社交識別記憶，同時活化SON核周區(pSON)的GABA神經元。然而，社交功能受損的程度會隨著光照強度而異，且編碼這些不同亮度信號的底層突觸機制此前仍不清楚。因此我們利用膜片鉗記錄，透過改變視神經束的電刺激頻率來模擬不同的光照強度，發現視網膜傳遞至OT神經元的訊號，受到該局部迴路中由 ipRGCs驅動的前饋抑制所控制。高頻率的刺激會強烈活化這些pSON的GABA神經元，從而在高強度光照下將OT神經元的淨輸出轉向抑制。這提供了一種迴路水平的機制，解釋了SON的OT神經元如何編碼依賴於亮度的光輸入，進而調節社交行為。 綜上所述，本研究揭示了相同的環境光訊號如何被下視丘內的不同迴路進行獨特的處理。我們證實在SCN中稀少的AVP神經元會接收光的直接輸入和間接接收GABA輸入，同時光訊號會同時活化SON的OT神經元與pSON的GABA神經元來調控整體SON的OT神經元的神經活性。這些不同光訊號傳遞路徑解釋了下視丘如何協調晝夜節律與體內平衡。

Light is the primary environmental cue modulating mammalian physiology and behavior. Photic signals captured by intrinsically photosensitive retinal ganglion cells (ipRGCs) are transmitted to various non-image-forming centers, including the suprachiasmatic nucleus (SCN) and the supraoptic nucleus (SON) in the hypothalamus. However、the precise connectivity and synaptic mechanisms within these pathways remain fully elucidated. The SCN acts as the master circadian pacemaker, where core vasoactive intestinal peptide (VIP) and shell arginine vasopressin (AVP) neurons synchronize circadian rhythms. Contrary to the traditional hierarchical ipRGCs-VIP-AVP processing model, recent morphological evidence suggests direct ipRGC innervation onto SCNAVP neurons. Using in vitro slice patch-clamp recordings and calcium imaging, we identified a distinct subpopulation of SCNAVP neurons clustered in the ventral region that receives direct monosynaptic inputs from ipRGCs, alongside concurrent polysynaptic GABAergic inputs. These findings demonstrate that SCNAVP neurons are directly integrated into the photic input pathway, forming a parallel network for circadian regulation. Beyond the SCN, light exposure activates GABAergic neurons in the perinuclear zone of the SON (pSON), thereby suppressing SON oxytocin (SONOT) neuron activity and impairing social recognition memory in a luminance-dependent manner. By varying optic tract stimulation frequencies to simulate different light intensities, we revealed that retinal signals to SONOT neurons are gated by local feed-forward inhibition. High-frequency stimulation strongly recruits pSONGABA neurons, shifting the net output of SONOT neurons toward inhibition. This provides a circuit-level mechanism for how SONOT neurons encode luminance signals to modulate social behavior. Collectively, this study reveals divergent hypothalamic routing mechanisms for light processing: SCNAVP receive a sparse direct input and a polysynaptic GABAergic network, and SONOT neurons recruit a strong, luminance-dependent pSON GABAergic network to gate neuroendocrine activity. These distinct pathways illustrate how the hypothalamus coordinates circadian rhythms and homeostatic systems.