Shuto Hironobu, Mandai Michiko, Yamada Takayuki, Sho Junki, Hayakawa Chihiro, Koike Chieko, Takahashi Masayo, Matsuyama Take
Vision Care Inc., Kobe, Hyogo, Japan.
Graduate School of Pharmacy, Ritsumeikan University, Kusatsu, Siga, Japan.
J Neurosci Res. 2025 Jul;103(7):e70068. doi: 10.1002/jnr.70068.
Retinal degenerative diseases cause irreversible vision loss due to photoreceptor degeneration. Retinal organoid transplantation offers a promising strategy for restoring vision, but assessing functional recovery remains challenging. Standard visual function tests provide binary or coarse measures that do not fully capture how visual input influences natural behavior. Here, we applied a Hidden Markov Model (HMM)-based behavioral analysis to the visual cliff test to track locomotor state transitions in wild-type (WT) and rd1-2 J (RD) mice, evaluating depth perception and its recovery following photoreceptor transplantation. WT mice exhibited a strong cliff avoidance response, while RD mice showed no response, confirming the model's sensitivity to depth perception. Over repeated trials, WT mice rapidly habituated, shifting from three behavioral states (Resting, Exploring, and Navigating) to just two (Resting and Navigating). Transplanted RD mice began responding to the cliff at 2 weeks posttransplantation, coinciding with early synapse formation between grafted photoreceptors and host bipolar cells. The avoidance response became robust by 16 weeks but disappeared by 18 weeks, accompanied by state collapse, a hallmark of habituation never observed in untreated RD mice. These findings demonstrate that behavioral state-based analysis provides a sensitive and dynamic measure of functional vision recovery, capturing not only the emergence of depth perception but also its integration into adaptive behavior. This approach may help refine clinical evaluations of vision restoration therapies, bridging the gap between sensory recovery and real-world functional outcomes.
视网膜退行性疾病由于光感受器变性而导致不可逆的视力丧失。视网膜类器官移植为恢复视力提供了一种有前景的策略，但评估功能恢复仍然具有挑战性。标准视觉功能测试提供的是二元或粗略的测量方法，无法完全捕捉视觉输入如何影响自然行为。在这里，我们将基于隐马尔可夫模型（HMM）的行为分析应用于视觉悬崖测试，以追踪野生型（WT）和rd1-2 J（RD）小鼠的运动状态转换，评估深度感知及其在光感受器移植后的恢复情况。WT小鼠表现出强烈的悬崖回避反应，而RD小鼠则无反应，证实了该模型对深度感知的敏感性。在重复试验中，WT小鼠迅速习惯化，从三种行为状态（静止、探索和导航）转变为仅两种（静止和导航）。移植后的RD小鼠在移植后2周开始对悬崖做出反应，这与移植的光感受器和宿主双极细胞之间早期突触形成相吻合。回避反应在16周时变得强烈，但在18周时消失，同时伴随着状态崩溃，这是未经治疗的RD小鼠从未观察到的习惯化标志。这些发现表明，基于行为状态的分析为功能性视力恢复提供了一种敏感且动态的测量方法，不仅捕捉到了深度感知的出现，还捕捉到了其融入适应性行为的过程。这种方法可能有助于完善视力恢复疗法的临床评估，弥合感觉恢复与现实世界功能结果之间的差距。
