Cross-species studies enable rapid translational discovery and produce the broadest impact when both mechanism and phenotype are consistent across organisms. We developed a knock-in mouse that biologically recapitulates a common human mutation in the gene for fatty acid amide hydrolase (FAAH) (C385A; rs324420), the primary catabolic enzyme for the endocannabinoid anandamide. This common polymorphism impacts the expression and activity of FAAH, thereby increasing anandamide levels. Here, we show that the genetic knock-in mouse and human variant allele carriers exhibit parallel alterations in biochemisty, neurocircuitry, and behavior. Specifically, there is reduced FAAH expression associated with the variant allele that selectively enhances fronto-amygdala connectivity and fear extinction learning, and decreases anxiety-like behaviors. These results suggest a gain-of-function in fear regulation and may indicate for whom and for what anxiety symptoms FAAH inhibitors or exposure-based therapies will be most efficacious, bridging an important translational gap between the mouse and human.

Secretion of glucocorticoid hormones during stress produces an array of physiological changes that are adaptive and beneficial in the short term. In the face of repeated stress exposure, however, habituation of the glucocorticoid response is essential as prolonged glucocorticoid secretion can produce deleterious effects on metabolic, immune, cardiovascular, and neurobiological function. Endocannabinoid signaling responds to and regulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis that governs the secretion of glucocorticoids; however, the role this system plays in adaptation of the neuroendocrine response to repeated stress is not well characterized. Herein, we demonstrate a divergent regulation of the two endocannabinoid ligands, N-arachidonylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), following repeated stress such that AEA content is persistently decreased throughout the corticolimbic stress circuit, whereas 2-AG is exclusively elevated within the amygdala in a stress-dependent manner. Pharmacological studies demonstrate that this divergent regulation of AEA and 2-AG contribute to distinct forms of HPA axis habituation. Inhibition of AEA hydrolysis prevented the development of basal hypersecretion of corticosterone following repeated stress. In contrast, systemic or intra-amygdalar administration of a CB 1 receptor antagonist before the final stress exposure prevented the repeated stress-induced decline in corticosterone responses. The present findings demonstrate an important role for endocannabinoid signaling in the process of stress HPA habituation, and suggest that AEA and 2-AG modulate different components of the adrenocortical response to repeated stressor exposure.corticosterone | endocannabinoid | habituation | hypothalamic-pituitaryadrenal axis | amygdala

Research on the development of face recognition in infancy has shown that infants respond to faces as if they are special and recognize familiar faces early in development. Infants also show recognition and differential attachment to familiar people very early in development. We tested the hypothesis that infants' responses to familiar and unfamiliar faces differ at different ages. Specifically, we present data showing age-related changes in infants' brain responses to mother's face versus a stranger's face in children between 18 and 54 months of age. We propose that these changes are based on age-related differences in the perceived salience of the face of the primary caregiver versus strangers.Keywords face recognition; social behavior; attachment; stranger anxiety; event-related potentials Interest in relations between brain and behavioral development has grown substantially in recent years. Of special interest is the development of the brain basis of social behavior. Although researchers interested in the role of experience in brain development have proposed that experience can alter brain areas involved in social development (e.g., Greenough, Black, & Wallace, 1987), there are very little data that address this issue. Indeed, we still have little knowledge about the development of brain systems underlying the development of social behavior and cognition. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptWe describe age-related differences in the neural correlates of face recognition and suggest ways that these differences may be related to changes in social development that arise through the child's interaction with the environment. We examined the neural correlates of the response to the mother's versus a stranger's face throughout the toddler and preschool years. We sought to better understand the development of the recognition of familiar and unfamiliar faces during a period of great developmental change in a number of cognitive and social domains.Infants have an inherent interest in faces, which may play a pivotal role in the development of relationships with others and in the ability to recognize the emotional states and intentions of others. A substantial body of literature makes it clear that very young infants are able to discriminate familiar from unfamiliar faces. For example, behavioral measures such as looking time and habituation have shown that, from a few days of age, infants prefer to look at a familiar versus an unfamiliar face (e.g., Pascalis & de Schonen, 1994;Pascalis, de Schonen, Morton, Derulle, & Fabre-Grenet, 1995), imitate selected facial movements (Meltzoff & Moore, 1977, 1997, and by 6 weeks of age, differentially imitate familiar versus unfamiliar people (Meltzoff & Moore, 1992, 1998.Evidence from electrophysiological studies shows that by about 6 months of age infants exhibit differential brain activity to familiar faces versus unfamiliar faces, and that infants' patterns of brain activity can be influenced by how similar the un...

Variations in environmental aversiveness influence emotional memory processes in rats. We have previously shown that cannabinoid effects on memory are dependent on the stress level at the time of training as well as on the aversiveness of the environmental context. Here, we investigated whether the hippocampal endocannabinoid system modulates memory retrieval depending on the trainingassociated arousal level. Male adult Sprague Dawley rats were trained on a water maze spatial task at two different water temperatures (19°C and 25°C) to elicit either higher or lower stress levels, respectively. Rats trained under the higher stress condition had better memory and higher corticosterone concentrations than rats trained at the lower stress condition. The cannabinoid receptor agonist WIN55212-2 (10 -30 ng/side), the 2-arachidonoyl glycerol (2-AG) hydrolysis inhibitor JZL184 (0.1-1 g/side), and the anandamide (AEA) hydrolysis inhibitor URB597 (10 -30 ng/side) were administered bilaterally into the hippocampus 60 min before probe-trial retention testing. WIN55212-2 or JZL184, but not URB597, impaired probe-trial performances only of rats trained at the higher stressful condition. Furthermore, rats trained under higher stress levels displayed an increase in hippocampal 2-AG, but not AEA, levels at the time of retention testing and a decreased affinity of the main 2-AG-degrading enzyme for its substrate. The present findings indicate that the endocannabinoid 2-AG in the hippocampus plays a key role in the selective regulation of spatial memory retrieval of stressful experience, shedding light on the neurobiological mechanisms involved in the impact of stress effects on memory processing.