The anterior insular cortex associates temporally discontiguous stimuli during threat learning

Learning about potential threats in the environment is indispensable for survival. Deficits in threat learning constitute a key dimension of multiple brain disorders, which include posttraumatic stress disorder and anxiety disorder. While human brain imaging studies have highlighted a reliable engagement of the anterior insular cortex (AIC) in threat learning, its precise role remains elusive partly due to the lack of animal studies that can address causality and mechanistic questions. Filling in this gap, the present mouse study proposes a novel AICmediated mechanism underlying the association of temporally discontiguous stimuli during threat learning. We identified that activity of AIC layer 5 (L5) pyramidal neurons is required for associating temporally discontiguous stimuli, specifically during a time interval between them. Notably, the AIC is not required for associating temporally contiguous stimuli during threat learning. The AIC not only sends the essential information, via its L5 pyramidal neurons, to the basolateral amygdala (BLA) during the time interval, but also receives from the BLA. We also identified a modulatory role of AIC dopamine D1 receptor (D1R)-mediated dopamine signaling in associating temporally discontiguous stimuli during the time interval.

Chronic Distress in Male Mice Impairs Motivation Compromising Both Effort and Reward Processing With Altered Anterior Insular Cortex and Basolateral Amygdala Neural Activation

In humans and mammals, effort-based decision-making for monetary or food rewards paradigms contributes to the study of adaptive goal-directed behaviours acquired through reinforcement learning. Chronic distress modelled by repeated exposure to glucocorticoids in rodents induces suboptimal decision-making under uncertainty by impinging on instrumental acquisition and prompting negative valence behaviours. In order to further disentangle the motivational tenets of adaptive decision-making, this study addressed the consequences of enduring distress on relevant effort and reward-processing dimensions. Experimentally, appetitive and consummatory components of motivation were evaluated in adult C57BL/6JRj male mice experiencing chronic distress induced by oral corticosterone (CORT), using multiple complementary discrete behavioural tests. Behavioural data (from novelty suppressed feeding, operant effort-based choice, free feeding, and sucrose preference tasks) collectively show that behavioural initiation, effort allocation, and hedonic appreciation and valuation are altered in mice exposed to several weeks of oral CORT treatment. Additionally, data analysis from FosB immunohistochemical processing of postmortem brain samples highlights CORT-dependent dampening of neural activation in the anterior insular cortex (aIC) and basolateral amygdala (BLA), key telencephalic brain regions involved in appetitive and consummatory motivational processing. Combined, these results suggest that chronic distress-induced irregular aIC and BLA neural activations with reduced effort production and attenuated reward value processing during reinforcement-based instrumental learning could result in maladaptive decision-making under uncertainty. The current study further illustrates how effort and reward processing contribute to adjust the motivational threshold triggering goal-directed behaviours in versatile environments.

Chronic distress in male mice impairs motivation compromising both effort and reward processing with altered anterior insular cortex and basolateral amygdala neural activation

In humans and mammals, effort-based decision-making for monetary or food rewards paradigms contribute to the study of adaptive goal-directed behaviours acquired through reinforcement learning. Chronic distress modelled by repeated exposure to glucocorticoids in rodents induces suboptimal decision-making under uncertainty by impinging on instrumental acquisition and prompting negative valence behaviours. In order to further disentangle the motivational tenets of adaptive decision-making, this study addressed the consequences of enduring distress on relevant effort and reward processing dimensions. Experimentally, appetitive and consummatory components of motivation were evaluated in adult C57BL/6JRj male mice experiencing chronic distress induced by oral corticosterone (CORT), using multiple complementary discrete behavioural tests. Behavioural data (from Novelty Supressed Feeding, operant effort-based choice, Free Feeding and Sucrose Preference tasks) collectively show that behavioural initiation, effort allocation and hedonic appreciation and valuation are altered in mice exposed to several weeks of oral CORT treatment. Additionally, data analysis from FosB immunohistochemical processing of postmortem brain samples highlight a CORT-dependent dampening of neural activation in the anterior insular cortex (aIC) and basolateral amygdala (BLA), key telencephalic brain regions involved in cue appetitive and consummatory motivational processing. Combined, these results suggest that chronic distress-induced irregular aIC and BLA neural activations with reduced effort production and attenuated reward value processing during reinforcement-based instrumental learning could result in maladaptive decision-making under uncertainty. The current study further illustrates how the stoichiometry of effort and reward processing contributes to dynamically adjust the motivational threshold triggering goal-directed behaviours in versatile environments.

Primate anterior insular cortex represents economic decision variables postulated by Prospect theory

In humans, risk attitude is highly context-dependent, varying with wealth levels or for different potential outcomes, such as gains or losses. These behavioral effects are well described by Prospect Theory, with the key assumption that humans represent the value of each available option asymmetrically as gain or loss relative to a reference point. However, it remains unknown how these computations are implemented at the neuronal level. Using a new token gambling task, we found that macaques, like humans, change their risk attitude across wealth levels and gain/loss contexts. Neurons in their anterior insular cortex (AIC) encode the ‘reference point’ (i.e. the current wealth level of the monkey) and the ‘asymmetric value function’ (i.e. option value signals are more sensitive to change in the loss than in the gain context) as postulated by Prospect Theory. In addition, changes in the activity of a subgroup of AIC neurons are correlated with the inter-trial fluctuations in choice and risk attitude. Taken together, we find that the role of primate AIC in risky decision-making is to monitor contextual information used to guide the animal’s willingness to accept risk.