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Neuronal growth regulator 1 (NEGR1) belongs to the immunoglobulin (IgLON) superfamily of cell adhesion molecules involved in cortical layering. Recent functional and genomic studies implicate the role of NEGR1 in a wide spectrum of psychiatric disorders, such as major depression, schizophrenia and autism. Here, we investigated the impact of Negr1 deficiency on brain morphology, neuronal properties and social behavior of mice. In situ hybridization shows Negr1 expression in the brain nuclei which are central modulators of cortical-subcortical connectivity such as the island of Calleja and the reticular nucleus of thalamus. Brain morphological analysis revealed neuroanatomical abnormalities in Negr1 −/− mice, including enlargement of ventricles and decrease in the volume of the whole brain, corpus callosum, globus pallidus and hippocampus. Furthermore, decreased number of parvalbumin-positive inhibitory interneurons was evident in Negr1 −/− hippocampi. Behaviorally, Negr1 −/− mice displayed hyperactivity in social interactions and impairments in social hierarchy. Finally, Negr1 deficiency resulted in disrupted neurite sprouting during neuritogenesis. Our results provide evidence that NEGR1 is required for balancing the ratio of excitatory/inhibitory neurons and proper formation of brain structures, which is prerequisite for adaptive behavioral profiles. Therefore, Negr1 −/− mice have a high potential to provide new insights into the neural mechanisms of neuropsychiatric disorders.

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Genetic deletion of cannabinoid CB1 receptors or diacylglycerol lipase alpha (DAGLa), the main enzyme involved in the synthesis of the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG), produced profound phenotypes in animal models of depression-related behaviors. Furthermore, clinical studies have shown that antagonists of CB1 can increase the incidence and severity of major depressive episodes. However, the underlying pathomechanisms are largely unknown. In this study, we have focused on the possible involvement of astrocytes. Using the highly sensitive RNAscope technology, we show for the first time that a subpopulation of astrocytes in the adult mouse brain expresses Dagla, albeit at low levels. Targeted lipidomics revealed that astrocytic DAGLa only accounts for a minor percentage of the steadystate brain 2-AG levels and other arachidonic acid derived lipids like prostaglandins. Nevertheless, the deletion of Dagla in adult mouse astrocytes had profound behavioral consequences with significantly increased depressive-like behavioral responses and striking effects on maternal behavior, corresponding with increased levels of serum progesterone and estradiol. Our findings therefore indicate that lipids from the DAGLa metabolic axis in astrocytes play a key regulatory role in affective behaviors.

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Psychosocial stress is one of the main environmental factors contributing to the development of psychiatric disorders. In humans and rodents, chronic stress is associated with elevated inflammatory responses, indicated by increased numbers of circulating myeloid cells and activation of microglia, the brain-resident immune cells. The endocannabinoid system (ECS) regulates neuronal and endocrine stress responses via the cannabinoid receptor 1 (CB1). CB1-deficient mice (Cnr1−/−) are highly sensitive to stress, but if this involves altered inflammatory responses is not known. To test this, we exposed Cnr1+/+ and Cnr1−/− mice to chronic social defeat stress (CSDS). Cnr1−/− mice were extremely sensitive to a standard protocol of CSDS, indicated by an increased mortality rate. Therefore, a mild CSDS protocol was established, which still induced a behavioural phenotype in susceptible Cnr1−/− mice. These mice also showed altered glucocorticoid levels after mild CSDS, suggesting dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. Mild CSDS induced weak myelopoiesis in the periphery, but no recruitment of myeloid cells to the brain. In contrast, mild CSDS altered microglial activation marker expression and morphology in Cnr1−/− mice. These microglial changes correlated with the severity of the behavioural phenotype. Furthermore, microglia of Cnr1−/− mice showed increased expression of Fkbp5, an important regulator of glucocorticoid signalling. Overall, the results confirm that CB1 signalling protects the organism from the physical and emotional harm of social stress and implicate endocannabinoid-mediated modulation of microglia in the development of stress-related pathologies.

Aim Since foods with high hedonic value are often consumed in excess of energetic needs, this study was designed to identify the mechanisms that may counter anorexigenic signalling in the presence of hedonic foods in lean animals. Methods Mice, in different states of satiety (fed/fasted, or fed/fasted and treated with ghrelin or leptin, respectively), were allowed to choose between high‐fat/high‐sucrose and standard foods. Intake of each food type and the activity of hypothalamic neuropetidergic neurons that regulate appetite were monitored. In some cases, food choice was monitored in leptin‐injected fasted mice that received microinjections of galanin receptor agonists into the lateral hypothalamus. Results Appetite‐stimulating orexin neurons in the lateral hypothalamus are rapidly activated when lean, satiated mice consume a highly palatable food (PF); such activation (upregulated c‐Fos expression) occurred even after administration of the anorexigenic hormone leptin and despite intact leptin signalling in the hypothalamus. The ability of leptin to restrain PF eating is restored when a galanin receptor 2 (Gal2R) agonist is injected into the lateral hypothalamus. Conclusion Hedonically‐loaded foods interrupt the inhibitory actions of leptin on orexin neurons and interfere with the homeostatic control of feeding. Overeating of palatable foods can be curtailed in lean animals by activating Gal2R in the lateral hypothalamus.