Glutamatergic synapses from the insular cortex to the basolateral amygdala encode observational pain.

Empathic pain has attracted the interest of a substantial number of researchers studying the social transfer of pain in the sociological, psychological, and neuroscience fields. However, the neural mechanism of empathic pain remains elusive. Here, we establish a long-term observational pain model in mice and find that glutamatergic projection from the insular cortex (IC) to the basolateral amygdala (BLA) is critical for the formation of observational pain. The selective activation or inhibition of the IC-BLA projection pathway strengthens or weakens the intensity of observational pain, respectively. The synaptic molecules are screened, and the upregulated synaptotagmin-2 and RIM3 are identified as key signals in controlling the increased synaptic glutamate transmission from the IC to the BLA. Together, these results reveal the molecular and synaptic mechanisms of a previously unidentified neural pathway that regulates observational pain in mice.

Robo4 regulates the radial migration of newborn neurons in developing neocortex.

During the morphogenesis of neocortex, newborn neurons undergo radial migration from the ventricular zone toward the surface of the cortical plate to form an "inside-out" lamina structure. The spatiotemporal signals that control this stereotyped radial migration remain elusive. Here, we report that a recently identified Robo family member Robo4 (Magic Roundabout), which was considered to be solely expressed in endothelial cells, is expressed in developing brain and regulates the radial migration of newborn neurons in neocortex. Downregulation of Robo4 expression in cortical newborn neurons by using in utero electroporation, with either specific siRNAs in wild-type rodents or with Cre recombinase in floxed-robo4 mutant mice, led to severe defects in the radial migration of newborn neurons with misorientation of these neurons. Moreover, newborn neurons transfected with Robo4 siRNAs exhibited significantly lower motility in a transwell migration assay (Boyden chamber) in the absence of Slit and significantly higher sensitivity to the repulsive effect of Slit in both transwell migration assay and growth cone collapse assay. Overall, our results showed an important role of Robo4 in the regulation of cortical radial migration through Slit-dependent and -independent mechanisms.

PKCdelta regulates cortical radial migration by stabilizing the Cdk5 activator p35.

Cyclin-dependent kinase 5 (Cdk5) and its activator p35 are critical for radial migration and lamination of cortical neurons. However, how this kinase is regulated by extracellular and intracellular signals during cortical morphogenesis remains unclear. Here, we show that PKCdelta, a member of novel PKC expressing in cortical neurons, could stabilize p35 by direct phosphorylation. PKCdelta attenuated the degradation of p35 but not its mutant derivative, which could not be phosphorylated by PKCdelta. Down-regulation of PKCdelta by in utero electroporation of specific small interference RNA (siRNA) severely impaired the radial migration of cortical neurons. This migration defect was similar to that caused by down-regulation of p35 and could be prevented by cotransfection with the wild-type but not the mutant p35. Furthermore, PKCdelta could be activated by the promigratory factor brain-derived neurotrophic factor (BDNF) and was required for the activation of Cdk5 by BDNF. Both PKCdelta and p35 were required for the promigratory effect of BDNF on cultured newborn neurons. Thus, PKCdelta may promote cortical radial migration through maintaining the proper level of p35 in newborn neurons.