The insula mediates the effects of glucocorticoids in anxiety.

Increased activity in the insula has been consistently reported to be associated with anxiety and anxiety-related disorders. However, little is known on how the insula regulates anxiety. The present study aims at determining the role of the insula on the effects of glucocorticoids in anxiety. A combination of pharmacological manipulations, including blockade of adrenal GC synthesis by metyrapone and intra-insular microinjections of corticosterone, corticosterone-BSA, mineralocorticoid receptor (MR) antagonist spironolactone and glucocorticoid receptor (GR) antagonist mifepristone, were used to assess the short-term (5 min) effects of intra-insular corticosterone in two anxiety-like behaviors in male Sprague-Dawley rats. The elevated plus maze (EPM) and Novelty Suppressed Feeding (hyponeophagia) were utilized. We found that corticosterone in the insula is sufficient to prevent the anxiolytic effects corticosterone synthesis blockade in anxiety, and that intra-insular corticosterone has anxiolytic or anxiogenic effects depending on the amount of corticosterone microinjected and the arousal associated to the test, without affecting the HPA axis. Glucocorticoid anxiolytic effects in the insula are mediated by MRs, while its anxiogenic effects are dependent on a mifepristone-sensitive membrane-bound mechanism. Anxiety appears to be modulated at the insula through a competition between fast MR-dependent anxiolytic and membrane-associated anxiogenic signaling pathways that orchestrate the behavioral response to stress and determines the resulting level of anxiety.

The Role of the Rodent Insula in Anxiety.

The human insula has been consistently reported to be overactivated in all anxiety disorders, activation which has been suggested to be proportional to the level of anxiety and shown to decrease with effective anxiolytic treatment. Nonetheless, studies evaluating the direct role of the insula in anxiety are lacking. Here, we set out to investigate the role of the rodent insula in anxiety by either inactivating different insular regions via microinjections of glutamatergic AMPA receptor antagonist CNQX or activating them by microinjection of GABA receptor antagonist bicuculline in rats, before measuring anxiety-like behavior using the elevated plus maze. Inactivation of caudal and medial insular regions induced anxiogenic effects, while their activation induced anxiolytic effects. In contrast, inactivation of more rostral areas induced anxiolytic effects and their activation, anxiogenic effects. These results suggest that the insula in the rat has a role in the modulation of anxiety-like behavior in rats, showing regional differences; rostral regions have an anxiogenic role, while medial and caudal regions have an anxiolytic role, with a transition area around bregma +0.5. The present study suggests that the insula has a direct role in anxiety.

Dopamine receptor D5 deficiency results in a selective reduction of hippocampal NMDA receptor subunit NR2B expression and impaired memory.

Pharmacological evidence associates type I dopamine receptors, including subtypes D1 and D5, with learning and memory. Analyses using genetic approaches have determined the relative contribution of dopamine receptor D1 (D1R) in cognitive tasks. However, the lack of drugs that can discriminate between D1R and D5R has made the pharmacological distinction between the two receptors difficult. Here, we aimed to determine the role of D5R in learning and memory. In this study we tested D5R knockout mice and wild-type littermates in a battery of behavioral tests, including memory, attention, locomotion, anxiety and motivational evaluations. Our results show that genetic deficiency of D5R significantly impairs performance in the Morris water maze paradigm, object location and object recognition memory, indicating a relevant role for D5R in spatial memory and recognition memory. Moreover, the lack of D5R resulted in decreased exploration and locomotion. In contrast, D5R deficiency had no impact on working memory, anxiety and depressive-like behavior, measured using the spontaneous alternation, open-field, tail suspension test, and forced swimming test. Electrophysiological analyses performed on hippocampal slices showed impairment in long-term-potentiation in mice lacking D5R. Further analyses at the molecular level showed that genetic deficiency of D5R results in a strong and selective reduction in the expression of the NMDA receptor subunit NR2B in the hippocampus. These findings demonstrate the relevant contribution of D5R in memory and suggest a functional interaction of D5R with hippocampal glutamatergic pathways.

The insula modulates arousal-induced reluctance to try novel tastes through adrenergic transmission in the rat.

Reluctance to try novel tastes (neophobia) can be exacerbated in arousing situations, such as when children are under social stress or in rodents, when the new taste is presented in a high arousal context (HA) compared to a low arousal context (LA). The present study aimed at determining whether adrenergic transmission at the Insula regulates the reluctance to try novel tastes induced by arousing contexts. To this end, a combination of systemic and intra-insular manipulations of adrenergic activity was performed before the novel taste (saccharin 0.1%) was presented either in LA or HA contexts in rats. Our results show that systemic adrenergic activity modulates reluctance to try novel tastes. Moreover, intra-insular microinjections of propranolol or norepinephrine (NE) were found to modulate the effects of arousing contexts on reluctance to try novel tastes. Finally, intra-insular propranolol blocked epinephrine-induced increased reluctance, while intra-insular NE blocked oral propranolol-induced decreases in reluctance and increased the reluctance to try novel tastes presented in low arousing contexts. In conclusion, our results suggest that the insula is a critical site for regulating the effects of arousal in the reluctance to try novel tastes via the adrenergic system.