Making predictions about future rewards or pun-1 ishments is fundamental to adaptive behavior. 2 These processes are influenced by prior experi-3 ence. For example, prior exposure to aversive 4 stimuli or stressors changes behavioral responses 5 to negative-and positive-value predictive cues.6Here, we demonstrate a role for medial pre-7 frontal cortex (mPFC) neurons projecting to the 8 paraventricular nucleus of the thalamus (PVT; 9 mPFC→PVT) in this process. We found that a 10 history of punishments negatively biased behav-11 ioral responses to motivationally-relevant stim-12 uli in mice and that this negative bias was asso-13 ciated with hyperactivity in mPFC→PVT neu-14 rons during exposure to those cues. Further-15 more, artificially mimicking this hyperactive re-16 sponse with selective optogenetic excitation of 17 the same pathway recapitulated the punishment-18 induced negative behavioral bias. Together, our 19 results highlight how information flow within the 20 mPFC→PVT circuit is critical for making pre-21 dictions about imminent motivationally-relevant 22 outcomes as a function of prior experience. 23 vated by multiple forms of stressors (Chastrette et al., 75 1991; Sharp et al., 1991; Cullinan et al., 1995; Bubser 76 and Deutch, 1999; Spencer et al., 2004) and coordinate 77 behavioral responses to stress (Hsu et al., 2014; Do-78 Monte et al., 2015; Penzo et al., 2015; Zhu et al., 2016; 79 Do-Monte et al., 2017; Beas et al., 2018). On the other 80 hand, under conditions of opposing emotional valence, 81 PVT plays a role in multiple forms of stimulus-reward 82 learning and PVT neurons have been reported to show 83 reward-modulated responses (Schiltz et al., 2005; Igel-84 strom et al. , 2010; Martin-Fardon and Boutrel, 2012; 85 James and Dayas, 2013; Browning et al., 2014; Haight 86 and Flagel, 2014; Li et al., 2016; Choi et al., 2019).
87Activity in mPFC neurons projecting to the PVT also 88 suppresses both the acquisition and expression of condi-89 tioned reward seeking (Otis et al., 2017).
90Taken together, these studies place the mPFC to PVT 91 projection in a unique position to integrate information 92 about positive and negative motivationally-relevant cues 93 and translate it into adaptive behavioral responses. How 94 these projection-specific prefrontal neurons regulate be-95 115 phase, four odor cues (A, B, C and D, counterbalanced) 116 were presented. Odor A predicted an appetitive sweet 117 solution (3 µl of 5% sucrose water). Odor B predicted 118 an aversive bitter solution (3 µl of 10 mM denatonium 119 water). Odor C was associated with no reinforcement. 120 Odor D predicted a punishment (an unavoidable air puff 121 delivered to the mouse's right eye) in mice assigned to 122 the air puff group and was associated with no reinforce-123 ment in mice assigned to the no air puff group. Each 124 behavioral trial began with an odor (1 s; conditioned 125 stimulus, CS), followed by a 1-s delay and an outcome 126 (unconditioned stimulus, US). Mice showed essentially 127 binary respo...