Cell migration is fundamental for both physiological and pathological processes. Migrating cells usually display high dynamics in morphology, which is orchestrated by an integrative array of signalling pathways. Here we identify a novel pathway, we term lateral signalling, comprised of the planar cell polarity (PCP) protein Pk1 and the RhoGAPs, Arhgap21/23. We show that the Pk1–Arhgap21/23 complex inhibits RhoA, is localized on the non-protrusive lateral membrane cortex and its disruption leads to the disorganization of the actomyosin network and altered focal adhesion dynamics. Pk1-mediated lateral signalling confines protrusive activity and is regulated by Smurf2, an E3 ubiquitin ligase in the PCP pathway. Furthermore, we demonstrate that dynamic interplay between lateral and protrusive signalling generates cyclical fluctuations in cell shape that we quantify here as shape volatility, which strongly correlates with migration speed. These studies uncover a previously unrecognized lateral signalling pathway that coordinates shape volatility during productive cell migration.

Substance use disorders (SUDs) are a growing public health concern with only a limited number of approved treatments. However, even approved treatments are subject to limited efficacy with high long-term relapse rates. Current treatment approaches are typically a combination of pharmacotherapies and behavioral counselling. Growing evidence and technological advances suggest the potential of brain stimulation techniques for the treatment of SUDs. There are three main brain stimulation techniques that are outlined in this review: transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS). The insula, a region of the cerebral cortex, is known to be involved in critical aspects underlying SUDs, such as interoception, decision making, anxiety, pain perception, cognition, mood, threat recognition, and conscious urges. This review focuses on both the preclinical and clinical evidence demonstrating the role of the insula in addiction, thereby demonstrating its promise as a target for brain stimulation. Future research should evaluate the optimal parameters for brain stimulation of the insula, through the use of relevant biomarkers and clinical outcomes for SUDs.

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Substance-related and addictive disorders, in particular gambling disorder, are known to be associated with risky decision-making behavior. Several neuroimaging studies have identified the involvement of the insular cortex in decision-making under risk. However, the extent of this involvement remains unclear and the specific contributions of two distinct insular subregions, the rostral agranular (RAIC) and the caudal granular (CGIC), have yet to be examined. Animals were trained to perform a rat gambling task (rGT), in which subjects chose between four options that differed in the magnitude and probability of rewards and penalties. In order to address the roles of the RAIC and CGIC in established choice behavior, pharmacological inactivations of these two subregions via local infusions of GABA receptor agonists were performed following 30 rGT training sessions. The contribution made by the RAIC or CGIC to the acquisition of choice behavior was also determined by lesioning these areas before behavioral training. Inactivation of the RAIC, but not of the CGIC, shifted rats' preference toward options with greater reward frequency and lower punishment. Before rGT acquisition, lesions of the RAIC, but not the CGIC, likewise resulted in a higher preference for options with greater reward frequency and lower punishment, and this persisted throughout the 30 training sessions. Our results provide confirmation of the involvement of the RAIC in rGT choice behavior and suggest that the RAIC may mediate detrimental risky decision-making behavior, such as that associated with addiction and gambling disorder.