Early Auditory Event Related Potentials Distinguish Higher-Order From First-Order Aversive Conditioning.

Stimuli in reality rarely co-occur with primary reward or punishment to allow direct associative learning of value. Instead, value is thought to be inferred through complex higher-order associations. Rodent research has demonstrated that the formation and maintenance of first-order and higher-order associations are supported by distinct neural substrates. In this study, we explored whether this pattern of findings held true for humans. Participants underwent first-order and subsequent higher-order conditioning using an aversive burst of white noise or neutral tone as the unconditioned stimuli. Four distinct tones, initially neutral, served as first-order and higher-order conditioned stimuli. Autonomic and neural responses were indexed by pupillometry and evoked response potentials (ERPs) respectively. Conditioned aversive values of first-order and higher-order stimuli led to increased autonomic responses, as indexed by pupil dilation. Distinct temporo-spatial auditory evoked response potentials were elicited by first-order and high-order conditioned stimuli. Conditioned first-order responses peaked around 260 ms and source estimation suggested a primary medial prefrontal and amygdala source. Conversely, conditioned higher-order responses peaked around 120 ms with an estimated source in the medial temporal lobe. Interestingly, pupillometry responses to first-order conditioned stimuli were diminished after higher order training, possibly signifying concomitant incidental extinction, while responses to higher-order stimuli remained. This suggests that once formed, higher order associations are at least partially independent of first order conditioned representations. This experiment demonstrates that first-order and higher-order conditioned associations have distinct neural signatures, and like rodents, the medial temporal lobe may be specifically involved with higher-order conditioning.

Adversity in early adolescence promotes an enduring anxious phenotype and increases serotonergic innervation of the infralimbic medial prefrontal cortex.

Stress during early development produces lasting effects on psychopathological outcomes. We analysed the impact of prior intermittent, physical stress (IPS) during early adolescence (PD 22-33) on anxiety-like behaviour of female rats in adulthood. After behavioural testing, we used immunohistochemistry for the 5-HT transporter (SERT) to evaluate 5-HT innervation profiles in the medial prefrontal cortex (mPFC) and ventral hippocampus (VH). Administration of IPS (i.e., water immersion, elevated platform, foot shock) in early adolescence increased rats' anxiety-like behaviour in the elevated plus-maze but had no effects in the shock-probe burying test. In the social interaction test, IPS decreased social interaction, and this effect was driven by selective decreases in the frequency of playfighting with no evident changes in contact and investigative behaviours. Selective stress-induced increases in the density of SERT-ir positive fibres were found in the infralimbic (IL) subregion of the mPFC but not in the cingulate or prelimbic (PL) subregions. IPS in early adolescence did not affect 5-HT innervation profiles in any sub-fields of the VH. Our findings confirm and extend on earlier evidence that stress during early adolescence promotes the emergence of an anxious phenotype and provide novel evidence that these effects are associated with increased 5-HT innervation of the IL mPFC.