Aversive experiences can lead to complex behavioral adaptations including increased levels of anxiety and fear generalization. The neuronal mechanisms underlying such maladaptive behavioral changes, however, are poorly understood. Here, using a combination of behavioral, physiological and optogenetic approaches in mouse, we identify a specific subpopulation of central amygdala neurons expressing protein kinase C δ (PKCδ) as key elements of the neuronal circuitry controlling anxiety. Moreover, we show that aversive experiences induce anxiety and fear generalization by regulating the activity of PKCδ+ neurons via extrasynaptic inhibition mediated by α5 subunit-containing GABAA receptors. Our findings reveal that the neuronal circuits that mediate fear and anxiety overlap at the level of defined subpopulations of central amygdala neurons and demonstrate that persistent changes in the excitability of a single cell type can orchestrate complex behavioral changes.

Background and Purpose-Activation of NMDA subtypes of glutamate receptors is implicated in cell damage induced by ischemia as well as for the establishment of ischemic tolerance after ischemic preconditioning in animal models. We investigated the contributions of NR2A-and NR2B-containing NMDA receptors to ischemic cell death and ischemic tolerance in a rat model of transient global ischemia. Methods-Transient global ischemia was produced in rats by 4-vessel occlusion. Neuronal injury was analyzed by Fluoro-Jade B and Nissl staining. Phosphorylation of CREB was detected by Western blotting and immunohistochemistry. In situ hybridization and reverse transcriptase-polymerase chain reaction were used to evaluate the mRNA level of cpg15 and bdnf. Results-NR2A subtype-specific antagonist NVP-AAM077 enhanced neuronal death after transient global ischemia and abolished the induction of ischemic tolerance. In contrast, NR2B subtype-specific antagonist ifenprodil attenuated ischemic cell death and enhanced preconditioning-induced neuroprotection. Furthermore, selectively blocking NR2A-, but not NR2B-, containing NMDA receptors inhibited ischemia-induced phosphorylation of CREB and the subsequent upregulation of CREB target genes such as cpg15 and bdnf. Conclusions-We found that NR2A-and NR2B-containing NMDA receptor subtypes play differential roles in ischemic neuronal death and ischemic tolerance, suggesting attractive new strategies for the development of drugs for patients with stroke. (Stroke. 2008;39:3042-3048.)

Internal states, including affective or homeostatic states, are important behavioral motivators. The amygdala regulates motivated behaviors, yet how distinct states are represented in amygdala circuits is unknown. By longitudinally imaging neural calcium dynamics in freely moving mice across different environments, we identified opponent changes in activity levels of two major, nonoverlapping populations of basal amygdala principal neurons. This population signature does not report global anxiety but predicts switches between exploratory and nonexploratory, defensive states. Moreover, the amygdala separately processes external stimuli and internal states and broadcasts state information via several output pathways to larger brain networks. Our findings extend the concept of thalamocortical “brain-state” coding to include affective and exploratory states and provide an entry point into the state dependency of brain function and behavior in defined circuits.