Norepinephrine and second messenger encoding of temporal threat proximity

PROJECT SUMMARY
Individuals must predict threats in the environment in order to survive. However, maladaptive threat
computation processes can lead to psychiatric disorders such as post-traumatic stress disorder. For threat
predictions to be adaptive, they must be temporally accurate and capable of predicting threats which may be
distant in time. However, the mechanisms underlying predictions involving temporal distance are poorly
understood. The overall aim of this project is to determine the neural substrates underlying learned
encoding of temporal threat proximity and temporally accurate defensive responses to threat.
I have recently shown that the in the prefrontal cortex, norepinephrine represents a teaching signal
which also encodes proximity of incoming threat. Furthermore, threat-predictive stimuli evoke increases in
prefrontal cyclic AMP (cAMP) concentration that persist past the stimulus and to an aversive event, consistent
with temporal linkage of predictive stimulus to outcome. These results are consistent with both the encoding of
temporal information within prefrontal cortex (PFC) and the necessity of PFC for delayed threat prediction.
Taken together, current work on the prediction of distant threat suggests an interplay between norepinephrine
signaling of threat proximity during learning, second messenger linkage of predictive cue to distant
outcome across learning, and encoding of threat proximity in PFC in order to effect accurate defensive
behavior. The proposed project seeks to test this model of threat prediction.
The proposed project seeks to understand the roles of norepinephrine, second messengers, and
prefrontal neurons in encoding of and effecting behavioral responses to threat proximity. In Aim 1, I will
determine the role of norepinephrine time-to-danger signals in supporting temporally accurate threat
responding and encoding of threat proximity information by prefrontal cortex. I will do so by employing
behavioral optogenetics and in vivo calcium imaging, techniques essential to this work and my future systems
neuroscience studies. In Aim 2, I will determine whether cAMP links temporally distant events during
learning by determining whether sustained cAMP supports delayed threat preparation and elucidating the
effect of temporal distance on threat cAMP. I will use optogenetic manipulation and fluorometry of prefrontal
cAMP to complete these aims, as well as to gain personal expertise in future manipulation and measurement
of second messengers, which are key to learned behavior but highly understudied in vivo. In total, I seek to
understand the neural processes underlying the accurate prediction of threats across timescales.
The proposed project will accomplish the technical training goals aforementioned, and I will also use
this fellowship for my personal advancement in science communication, teaching, and mentorship within
an environment of technical experts. My sponsors, collaborators, contributors, and research environment are
technically and intellectually equipped to support the proposed training and research under this fellowship.

Grant Number: 5F31MH138088-02
NIH Institute/Center: NIH
Principal Investigator: Aakash Basu