A translational bridge between mouse and human models of learned safety

Abstract

Background. Learned safety is established by negatively correlating the occurrence of a neutral stimulus and a noxious stimulus, which renders the previously neutral stimulus a ‘safety signal’. While the neurophysiological and molecular mechanisms have been characterized in mice, it is currently not known how the neural substrates involved compare between mice and people.

Methods. Here we attempt to adapt the original animal protocol to humans and use functional magnetic resonance imaging to examine neural responses to the conditioned stimulus in safety conditioned and fear conditioned subjects. Diffusion tensor imaging (DTI) was used in a parallel group of subjects as a first approach to delineate the underlying neural circuitry.

Results. Learned safety is associated with dampened amygdala and increased dorsolateral prefrontal cortex and caudate responses and paralleled by pupillary constriction. A neural connection between the amygdala and the dorsolateral prefrontal cortex is suggested by DTI.

Conclusion. We present a translational bridge between mouse and human models of learned safety in which cellular and molecular insights from animal experiments are extended to the human neural circuitry. This study provides an example of how animal experiments can be used to inform and target human studies, which in turn can corroborate results obtained in experimental animals.

Key words::

• Amygdala
• dorsolateral prefrontal cortex
• functional magnetic resonance imaging (fMRI)
• learned safety
• translational research

Acknowledgements

Daniela D. Pollak was supported by the Austrian Academy of Science (Max-Kade-Fellowship) and the Austrian Science Fund (Erwin-Schroedinger-Fellowship). Tobias Egner was supported by a Columbia University fMRI Research Fellowship. Ted Yanagihara was supported by the Medical Scientist Training Program, Columbia University Medical School. Imaging funds were provided by education grants to Joy Hirsch, Director, fMRI Research Center, Columbia University (now PICS, Program for Imaging & Cognitive Sciences) for translational and applied studies. The extremely skillful and dedicated expertise of Stephen Dashnaw in carrying out the imaging experiments is highly appreciated.

Declaration of interest: The authors report no biomedical financial interests or other conflicts of interest.