Measuring animal behavior in the context of experimental manipulation is critical for modeling, and understanding neuropsychiatric disease. Prepulse inhibition of the acoustic startle response (PPI) is a behavioral phenomenon studied extensively for this purpose, but the results of PPI studies are often inconsistent. As a result, the utility of this phenomenon remains uncertain. Here, we deconstruct the phenomenon of PPI and confirm several limitations of the methodology traditionally utilized to describe PPI, including that the underlying startle response has a non-Gaussian distribution, and that the traditional PPI metric changes with different stimuli. We then develop a novel model that reveals PPI to be a combination of the previously appreciated scaling of the startle response, as well as a scaling of sound processing. Using our model, we find no evidence for differences in PPI in a rat model of Fragile-X Syndrome (FXS) compared with wild-type controls. These results in the rat provide a reliable methodology that could be used to clarify inconsistent PPI results in mice and humans. In contrast, we find robust differences between wild-type male and female rats. Our model allows us to understand the nature of these differences, and we find that both the startle-scaling and sound-scaling components of PPI are a function of the baseline startle response. Males and females differ specifically in the startle-scaling, but not the sound-scaling, component of PPI. These findings establish a robust experimental and analytical approach that has the potential to provide a consistent biomarker of brain function.

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Measuring animal behavior in the context of experimental manipulation is critical for modeling and understanding neuro-psychiatric disease. Prepulse inhibition of the acoustic startle response (PPI) is a behavioral paradigm used extensively for this purpose, but the results of PPI studies are often inconsistent. As a result, the utility of this metric remains uncertain. Here we deconstruct the phenomenon of PPI. We first confirm several limitations of the traditional PPI metric, including that the underlying startle response has a non-Gaussian distribution and that the traditional PPI metric changes with different stimulus condition. We then develop a novel model that reveals PPI to be a combination of the previously appreciated scaling of the startle response, as well as a scaling of sound perception. Using our model, we find no evidence for differences in PPI in a rat model of Fragile-X Syndrome (FXS) compared to wild-type controls. These results in the rat provide a reliable methodology that could be used to clarify inconsistent PPI results in mice and humans. In addition, we find robust differences between wild-type male and female rats. Our model allows us to understand the nature of these differences, and we find that both the startle-scaling and sound-scaling components of PPI are a function of the baseline startle response. Males and females differ specifically in the startle-scaling, but not the sound-scaling, component of PPI. These findings establish a robust experimental and analytical approach that has the potential to provide a consistent biomarker of brain function.state 41 , habituation 42 , socialization 43,44 , and the baseline startle response 45 . Consequently, there is a pressing need for an approach that could consistently identify real differences among groups. We therefore sought to deconstruct the phenomenon of PPI to develop a more accurate methodology for capturing the way in which a prepulse stimulus modifies the acoustic startle response.The traditional methodology for PPI makes four assumptions: 1) the startle response can be accurately measured with a small number of trials per animal; 2) the startle response has an approximately Gaussian distribution, allowing the use of the mean startle response as the basis of the PPI metric; 3) PPI is stable across startle sound levels, enabling the measurement of PPI at a single startle level instead of necessitating a full measurement of the startle function; and 4) PPI is independent of the baseline startle response, allowing for a direct combination of PPI results between animals.Using data from 72 rats across more than 100 stimulus conditions, for a total of over 300,000 trials, we replicated previous work demonstrating that the aforementioned assumptions do not hold. Specifically, our findings confirm: 1) the startle response is highly variable 46 ; 2) the startle response has a non-Gaussian distribution that is better represented by a log-normal distribution 47 ; 3) the traditional metric used for PPI systematically decreases as a functio...