A locus coeruleus to dentate gyrus noradrenergic circuit modulates aversive contextual processing.

Dysregulation in contextual processing is believed to affect several forms of psychopathology, such as post-traumatic stress disorder (PTSD). The dentate gyrus (DG), a subregion of the hippocampus, is thought to be an important brain region for disambiguating new experiences from prior experiences. Noradrenergic (NE) neurons in the locus coeruleus (LC) are more tonically active during stressful events and send dense projections to the DG, yet an understanding of their function in DG-dependent contextual discrimination has not been established. Here, we isolate a key function of the LC-NE-DG circuit in contextual aversive generalization using selective manipulations and in vivo single-cell calcium imaging. We report that activation of LC-NE neurons and terminal activity results in contextual generalization. We found that these effects required ß-adrenergic-mediated modulation of hilar interneurons to ultimately promote aversive generalization, suggesting that disruption of noradrenergic tone may serve as an important avenue for treating stress-induced disorders.

Contemporary strategies for dissecting the neuronal basis of neurodevelopmental disorders.

Great efforts in clinical and basic research have shown progress in understanding the neurobiological mechanisms of neurodevelopmental disorders, such as autism, schizophrenia, and attention-deficit hyperactive disorders. Literature on this field have suggested that these disorders are affected by the complex interaction of genetic, biological, psychosocial and environmental risk factors. However, this complexity of interplaying risk factors during neurodevelopment has prevented a complete understanding of the causes of those neuropsychiatric symptoms. Recently, with advances in modern high-resolution neuroscience methods, the neural circuitry analysis approach has provided new solutions for understanding the causal relationship between dysfunction of a neural circuit and behavioral alteration in neurodevelopmental disorders. In this review we will discuss recent progress in developing novel optogenetic and chemogenetic strategies to investigate neurodevelopmental disorders.

A GABAergic Projection from the Centromedial Nuclei of the Amygdala to Ventromedial Prefrontal Cortex Modulates Reward Behavior.

The neural circuitry underlying mammalian reward behaviors involves several distinct nuclei throughout the brain. It is widely accepted that the midbrain dopamine (DA) neurons are critical for the reward-related behaviors. Recent studies have shown that the centromedial nucleus of the amygdala (CeMA) has a distinct role in regulating reward-related behaviors. However, the CeMA and ventromedial PFC (vmPFC) interaction in reward regulation remains poorly understood. Here, we identify and dissect a GABAergic projection that originates in the CeMA and terminates in the vmPFC (VGat-CreCeMA-vmPFC) using viral-vector-mediated, cell-type-specific optogenetic techniques in mice. Pathway-specific optogenetic activation of the VGat-CreCeMA-vmPFC circuit in awake, behaving animals produced a positive, reward-like phenotype in real-time place preference and increased locomotor activity in open-field testing. In sucrose operant conditioning, the photoactivation of these terminals increased nose-poking effort with no effect on licking behavior and robustly facilitated the extinction of operant behavior. However, photoactivation of these terminals did not induce self-stimulation in the absence of an external reward. The results described here suggest that the VGat-CreCeMA-vmPFC projection acts to modulate existing reward-related behaviors. SIGNIFICANCE STATEMENT: Many studies have shown that the interactions between the centromedial nucleus of the amygdala (CeMA) and ventromedial PFC (vmPFC) have critical roles for emotional regulation. However, most studies have associated this circuit with fear and anxiety behaviors and emphasized top-down processing from vmPFC to CeMA. Here, we provide new evidence for bottom-up CeMA to vmPFC influence on reward-related behaviors. Although previous work implicated the CeMA in incentive salience, our results isolate the investigation to a specific CeMA GABAergic projection to the vmPFC. This long-range GABAergic interaction between amygdala and frontal cortex adds a new dimension to the complex regulation of reward-related behaviors.