下視丘SF1神經元對本能⾏為的狀態依賴性編碼

Abstract

下視丘腹中側核 (Ventromedial Nucleus of Hypothalamus, VMH) 係主掌本能行為、食慾、與代謝調控的關鍵樞紐，腹中側核內具備高度異質之神經組成，其中表現類固醇生成因子一型 (Steroidogenic Factor 1, SF1)之神經元亞群已知對動物遭遇掠食者的本能防禦行為有至關重要的調控能力。然腹中側核亦為社交行為神經迴路的中樞節點，而VMHSF1神經元在社交互動過程中的角色仍舊未明。 本研究採用活體鈣影像（In vivo Ca2+ Imaging）技術結合基因轉殖鼠以選擇性紀錄清醒、自由活動雄性小鼠的VMHSF1神經元活動。我們發現部分VMHSF1神經元對社交刺激有強烈反應，且對遭遇之同種所屬性別有專一且偏好雄性之編碼模式。為解析VMHSF1神經元產生性別選擇性反應所仰賴的感覺通道 (Sensory Modality)，我們嘗試感官剝奪並發現雄性小鼠散發的非揮發性費洛蒙為VMHSF1神經元建構雄性偏好之重要感官成分。先前研究發現終紋床核 (Bed nucleus of Stria Terminalis, BNST) 能接收並傳遞社交相關化學感覺資訊至下視丘，因此我們嘗試以光遺傳學 (Optogenetics) 技術操縱BNST投射至VMH之神經迴路。當BNST-VMH迴路遭到抑制，VMHSF1神經元不再表現族群層級的性別偏好，上述結果揭示了VMHSF1神經元編碼社交目標性別的感官與神經迴路機制。 為了探究在社交情境下VMHSF1神經元活動與社交行為之關聯性，我們讓小鼠執行交互社交測驗（Reciprocal Social Interaction test, RSI）並同時執行針對VMHSF1神經元之鈣影像紀錄。行為解析結果顯示VMHSF1神經元的活化與探索性社交互動時機高度重合，惟在攻擊、交配、逃跑等終結行為 (Consummatory Behaviors) 出現時被強烈抑制，此外若以化學遺傳學 (Chemogenetics) 手段降低VMHSF1神經元可激活性，小鼠在社交情境下執行探索行為的頻率與時長都顯著下降。據上述結果，我們推想VMHSF1神經元在社交互動過程中的激活編碼著重資訊搜集與分析的欲求階段 (Appetitive Phase)，驅使動物靠近並嗅探同種個體，一但接收的感官訊息完成處理並做出決策，VMHSF1神經元對應的探索行為模組就會被關閉，以確保後續終結行為的精確執行。 然而VMHSF1神經族群也編碼著應對掠食風險的防禦內在狀態，使動物尋找藏匿處、遠離捕食者或僵直。為理解VMHSF1神經族群如何既能驅動遠離目標的防禦行為又得以產生促進探索目標的社交行為，我們設計了掠食者防禦測驗 (Predator Defense Assay, PDA)。當我們將同一群VMHSF1神經元在PDA以及RSI情境下的活動相互對照，我們發現遭遇掠食者和遭遇社交情境不僅能對應至VMHSF1族群完全迥異的活動模式，動態系統分析結果也揭示掠食者和社交分別能讓VMHSF1族群進入具備獨特幾何特徵的神經狀態 (Neural State)。若細究單一神經尺度的情境或行為關聯性，我們也發現掠食者所召集的是與編碼社交刺激者近乎不相交的VMHSF1神經亞群，這代表VMHSF1神經元其實不是功能上均質、單純掌管掠食者恐懼反應的行為模組。 最後，為近一步深究功能多樣的VMHSF1神經元如何處理本能需求間的衝突，我們設計了進食社交衝突測驗（Feeding-Social Conflict Test, FSC）。我們使用纖維光度計（Fiber Photometry）與鈣離子影像分別觀察族群或單細胞層級VMHSF1神經活動如何表徵動物行為在社交互動與進食行為間的偏好。我們發現在動物飢餓使進食偏好上升的同時，VMHSF1神經元對食物與社交刺激的編碼都更具選擇性，大大降低非專一性神經元之佔比，此外在群體層級神經元間的連結與同步率亦顯著上升。這顯示在面對進食與社交的選擇時，VMHSF1神經元並非以典型的模組競爭編碼並影響行為偏好，而是以更廣域全面的神經網路重塑來調整刺激物表徵的精確性以及群體的輸出強度，以因應當下行為決策之需求，無論是優先保持彈性或盡量減少錯誤。上述研究發現有助我們重新審視過往將下視丘神經核單純看做特定行為或生理調控開關的認知，這些演化上原始的腦部結構之所以能在缺乏皮質等高等認知區域的狀態下確保物種存續，或許正是因為他們本就具備足以應付基本決策的運算功能。

Innate social behaviors rely on hypothalamic circuits that encode internal motivational states. The ventromedial nucleus of hypothalamus (VMH) is a predominant hub amidst the hypothalamic social network, with steroidogenic factor-1 (SF1)-expressing neurons as one of its major neural subgroups. While VMHSF1 neurons are established drivers of predator-induced defensive behaviors, their potential roles in social contexts remain unknown. To determine how VMHSF1 neurons encode social cues, we used cell-type–specific Ca²⁺ imaging in freely behaving sf1-cre male mice. Our results showed that a subgroup of VMHSF1 neurons were strongly activated by social stimuli, with a male-biased sex preference. In addition, conspecifics with different sexes recruited distinct VMHSF1 neural subsets, establishing a stable and decodable sex representation. Through sensory ablation and circuit perturbation, we identified pheromonal signal and inputs from the bed nucleus of stria terminalis (BNST) as critical sensory and circuit components for shaping the male-preferring conspecific sex representation of VMHSF1 neurons, respectively. During social interaction, VMHSF1 neurons were highly tuned to investigative behaviors, showing sex-specific population trajectories in low-dimensional neural subspace. These neurons are selectively engaged in the appetitive phase of male-male interaction but inhibited during consummatory or defensive episodes, indicating a state-dependent gating of social drive. Moreover, encountering predator cues and social cues evoke highly separable neural states in VMHSF1 population, so did behavioral actions correspond to social investigation or predatory defense, which were likely implemented through stimulus-specific recruitment of distinct neural subgroups. In addition, silencing VMHSF1 neurons reduced the duration of social investigation, further confirming their causal role under social context. Lastly, we tested how VMHSF1 neurons encode behavioral preference while facing conflicting survival needs. Optogenetic stimulation of entire VMHSF1 population overwhelmingly evoked defensive actions while suppressing social needs, implying predator defensive state as a dominating behavioral module over that driving social investigation. However, the conflict between socializing and feeding, as revealed by our FSC behavioral paradigm, was hunger-dependently represented in VMHSF1 population. 24-hour fasting rendered individual VMHSF1 neurons more selective to either social or food cues, strengthened the overall network coupling, and sharpened the contrast in population coding between food- and social-oriented explorations. Moreover, chemogenetic VMHSF1 activation induced a defense-like behavioral state, making animal prioritizing food consumption over social interaction even in sated metabolic state. Altogether, our work not only identified a VMHSF1 subpopulation that transforms conspecific cues into a motivational state promoting social investigation but challenge the longstanding notion that each hypothalamic circuit node acts as simple modular switch for singular motivational state. Hence, this study extends the functional repertoire of VMHSF1 neurons beyond predator defense and illustrates how hypothalamic circuits carry out complex computations for survival behaviors.