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.

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ObjectiveTo evaluate the safety and assess the different symptom improvements found after a combined low-frequency primary motor cortex and high-frequency prefrontal cortex (PFC) stimulation using the deep TMS (dTMS) H-coil, as an add-on treatment for Parkinson’s disease (PD).MethodsForty-five PD patients underwent 14 dTMS sessions; each consisting of 1 Hz stimulation of the primary motor cortex for 15 min, followed by 10 Hz stimulation of the PFC for 15 min. Clinical assessments were performed, BEFORE, at the MIDDLE, and END of therapy as well as at FOLLOW-UP after 30 days, using Movement Disorder Society-Unified Parkinson’s Disease Rating Scale, TINETTI, UP&GO, SCOPA, HDRS21, Beck Depression Inventory, and self-applied daily motor assessment scales.ResultsTreatment was well-tolerated, without serious adverse effects. dTMS-induced significant PD symptom improvements at END and at FOLLOW-UP, in all subscales of the UPDRS, gait speed, depressive symptoms, balance, autonomic symptoms, and a 73% increase in daily ON time.ConclusionIn the cohort of PD patients treated, dTMS was well-tolerated with only minor adverse effects. The dTMS-induced significant improvements in motor, postural, and motivational symptoms of PD patients and may potentiate concurrent levodopa treatment.SignificanceThe present study demonstrates that dTMS may have a much wider spectrum of beneficial effects than previously reported for TMS, including enhancement of levodopa effects, suggesting that future clinical trials with dTMS should include a broader range of symptom measurements.

Astrocytes release gliotransmitters via connexin 43 (Cx43) hemichannels into neighboring synapses, which can modulate synaptic activity and are necessary for fear memory consolidation. However, the gliotransmitters released, and their mechanisms of action remain elusive. Here, we report that fear conditioning training elevated Cx43 hemichannel activity in astrocytes from the basolateral amygdala (BLA). The selective blockade of Cx43 hemichannels by microinfusion of TAT‐Cx43L2 peptide into the BLA induced memory deficits 1 and 24 h after training, without affecting learning. The memory impairments were prevented by the co‐injection of glutamate and D‐serine, but not by the injection of either alone, suggesting a role for NMDA receptors (NMDAR). The incubation with TAT‐Cx43L2 decreased NMDAR‐mediated currents in BLA slices, effect that was also prevented by the addition of glutamate and D‐serine. NMDARs in primary neuronal cultures were unaffected by TAT‐Cx43L2, ruling out direct effects of the peptide on NMDARs. Finally, we show that D‐serine permeates through purified Cx43 hemichannels reconstituted in liposomes. We propose that the release of glutamate and D‐serine from astrocytes through Cx43 hemichannels is necessary for the activation of post‐synaptic NMDARs during training, to allow for the formation of short‐term and subsequent long‐term memory, but not for learning per se.

The amygdala has a central role in anxiety responses to stressful and arousing situations. Pharmacological and lesion studies of the basolateral, central, and medial subdivisions of the amygdala have shown that their activation induces anxiogenic effects, while their inactivation produces anxiolytic effects. Many neurotransmitters and stress mediators acting at these amygdalar nuclei can modulate the behavioral expression of anxiety. These mediators may be released from different brain regions in response to different types of stressors. The amygdala is in close relationship with several brain regions within the brain circuitry that orchestrates the expression of anxiety. Recent developments in optogenetics have begun to unveil details on how these areas interact.