Morphine- and foot shock-responsive neuronal ensembles in the VTA possess different connectivity and biased GPCR signaling pathway.

Background: Neurons in the ventral tegmental area (VTA) are sensitive to stress and their maladaptation have been implicated in the psychiatric disorders such as anxiety and addiction, etc. The cellular properties of the VTA neurons in response to different stressors related to different emotional processing remain to be investigated. Methods: By combining immediate early gene (IEG)-dependent labeling, rabies virus tracing, ensemble-specific transcriptomic analysis and fiber photometry recording in the VTA of male mice, the spatial distribution, brain-wide connectivity and cellular signaling pathways in the VTA neuronal ensembles in response to morphine (Mor-Ens) or foot shock (Shock-Ens) stimuli were investigated. Results: Optogenetic activation of the Mor-Ens drove approach behavior, whereas chemogenetic activation of the Shock-Ens increased the anxiety level in mice. Mor-Ens were clustered and enriched in the ventral VTA, contained a higher proportion of dopaminergic neurons, received more inputs from the dorsal medial striatum and the medial hypothalamic zone, and exhibited greater axonal arborization in the zona incerta and ventral pallidum. Whereas Shock-Ens were more dispersed, contained a higher proportion of GABAergic neurons, and received more inputs from the ventral pallidum and the lateral hypothalamic area. The downstream targets of the G protein and ß-arrestin pathways, PLCß3 and phosphorylated AKT1Thr308, were relatively enriched in the Mor-Ens and Shock-Ens, respectively. Cariprazine, the G-protein-biased agonist for the dopamine D2 receptor, increased the response of Mor-Ens to sucrose water and decreased the anxiety-like behavior during morphine withdrawal, whereas the ß-arrestin-biased agonist UNC9994 decreased the response of Shock-Ens to tail suspension. Conclusions: Taken together, these findings reveal the heterogeneous connectivity and signaling pathways of the VTA neurons in response to morphine and foot shock, providing new insights for development of specific interventions for psychiatric disorders caused by various stressors associated with different VTA neuronal functions.

Environmental eustress improves postinfarction cardiac repair via enhancing cardiac macrophage survival.

Macrophages play a vital role in cardiac repair following myocardial infarction (MI). An enriched environment (EE) is involved in the regulation of macrophage-related activities and disease progression; however, whether EE affects the phenotype and function of macrophages to improve postinfarction cardiac repair remains unknown. In this study, we found that EE improved cardiac function, decreased mortality, and ameliorated adverse ventricular remodeling in mice after MI, with these outcomes closely related to the increased survival of Ly6Clow macrophages and their CCR2-MHCIIlow subsets. EE increased the expression of brain-derived neurotrophic factor (BDNF) in the hypothalamus, leading to higher circulating levels of BDNF, which, in turn, regulated the cardiac macrophages. BDNF bound to tropomyosin receptor kinase B to activate downstream ERK1/2 and AKT pathways, promoting macrophage survival. These findings demonstrate that EE optimizes postinfarction cardiac repair and highlights the significance of EE as a previously unidentified strategy for impeding adverse ventricular remodeling.

Sex differences in morphine-induced behavioral sensitization and social behaviors in ICR mice.

Gender and genetic strain are two prominent variants that influence drug abuse. Although certain sex-related behavioral responses have been previously characterized in ICR mice, little is known about the effects of sex on morphine-induced behavioral responses in this outbred strain. Therefore, in this study, we investigated the sex differences of morphine-induced locomotion, anxiety-like and social behaviors in ICR mice. After morphine or saline exposure for four consecutive days (twice daily), increased locomotion, more time spent in the central area, as well as attenuated rearing and self-grooming behaviors were found in morphine-treated females in an open field; no differences were found in locomotion and the time spent in the central area between male and female controls. When interacting with the same-sex individuals, female controls were engaged in more social investigation, following, body contacting and self-grooming behaviors than controls; morphine exposure reduced contacting and self-grooming behaviors in females; in contrast, these effects were not found in males. These results indicate that female ICR mice are more prosocial and are more susceptible to morphine exposure than males.