Reversing anterior insular cortex neuronal hypoexcitability attenuates compulsive behavior in adolescent rats

Abstract

Significance Clinical evidence suggests that adolescents engage in dangerous activities despite understanding the risks involved, questioning the theory of decreased top-down control of the immature prefrontal cortex promoting adolescent disinhibited behaviors. In the present study, we report that adolescent rats show a much higher degree of inflexible behavior when making decisions under conflict compared to adults. Unexpectedly, we identified a lower excitability of layer 5 pyramidal neurons in the anterior insular cortex (AIC) of adolescent rats and smaller synaptic glutamatergic inputs to these cells but no difference in layer 5 prefrontal cortex pyramidal neurons. Chemogenetic activation of AIC neurons reduced persistent reward-seeking despite punishment, suggesting that the delayed maturation of the insula may promote inflexible reward-related behaviors in adolescent rats.

Propensity for risky choices despite lower cue reactivity in adolescent rats

“…Interestingly, sign tracking was also associated with premature nosepoke entries in adults ( Swintosky et al, 2021 ) but not adolescents, and adults performed more premature entries than adolescents overall. This finding is at odds with the idea that adolescents are more impulsive than adults in general, although this is certainly the case on a number of tasks ( Burton and Fletcher, 2012 ; Jadhav et al, 2022 ). There may be situations, including the current task, when reward-associated cues elicit impulsive actions from adults more readily than from adolescents.…”

Early-onset smoking theory of compulsivity development: a neurocognitive model for the development of compulsive tobacco smoking

“…Another study ( 29 ) conducted on rodents using a foot-shock-punished cocaine self-administration procedure reported rats with compulsive cocaine intake (punishment-resistant state) to present increased neural activity in the anterior insular cortex compared with non-compulsive rats. Jadhav and colleagues ( 30 ) reported adolescent rats to be more persistent in lever pressing during a reward (saccharine)-delivery foot-shock administration procedure compared with adult rats. As stated by the authors, “ lever presses decreased with increased shock intensity from 0.22 to 0.33 mA in all rats, but to a significantly lesser extent in adolescents.…”

“…As stated by the authors, “ lever presses decreased with increased shock intensity from 0.22 to 0.33 mA in all rats, but to a significantly lesser extent in adolescents. Strikingly, the adolescents persisted in lever pressing despite the 0.22 mA mild electrical foot shock, suggesting a compulsive-like reward-seeking behavior” ( 30 ). The same authors also observed a decrease in mRNA expression of the zif268 protein, as well as a lower excitability of L5 pyramidal neurons, and a weaker glutamatergic synaptic input to the anterior insular cortex of adolescent rats showing compulsive saccharine intake ( 30 ).…”