SYK-623, a δ Opioid Receptor Inverse Agonist, Mitigates Chronic Stress-Induced Behavioral Abnormalities and Disrupted Neurogenesis.

The δ opioid receptor (DOR) inverse agonist has been demonstrated to improve learning and memory impairment in mice subjected to restraint stress. Here, we investigated the effects of SYK-623, a new DOR inverse agonist, on behavioral, immunohistochemical, and biochemical abnormalities in a mouse model of imipramine treatment-resistant depression. Male ddY mice received daily treatment of adrenocorticotropic hormone (ACTH) combined with chronic mild stress exposure (ACMS). SYK-623, imipramine, or the vehicle was administered once daily before ACMS. After three weeks, ACMS mice showed impaired learning and memory in the Y-maze test and increased immobility time in the forced swim test. SYK-623, but not imipramine, significantly suppressed behavioral abnormalities caused by ACMS. Based on the fluorescent immunohistochemical analysis of the hippocampus, ACMS induced a reduction in astrocytes and newborn neurons, similar to the reported findings observed in the postmortem brains of depressed patients. In addition, the number of parvalbumin-positive GABA neurons, which play a crucial role in neurogenesis, was reduced in the hippocampus, and western blot analysis showed decreased glutamic acid decarboxylase protein levels. These changes, except for the decrease in astrocytes, were suppressed by SYK-623. Thus, SYK-623 mitigates behavioral abnormalities and disturbed neurogenesis caused by chronic stress.

Microglial subpopulations with distinct transcriptome signatures vary across brain regions in the resting mouse brain.

Microglia are crucial for tissue homeostasis and its disturbance. However, microglial heterogeneity and its relationship with microglial activation in physiological conditions remain elusive. Using single-cell RNA sequencing, we identified microglial subpopulations with distinct transcriptome signatures in the resting brain. The distribution of two major, continuous subpopulations varied across brain regions, especially between cerebral cortices and the hypothalamus. Lipopolysaccharide and chronic social defeat stress, both of which involve the innate immune receptor TLR4, upregulate the marker genes of selective microglial subpopulations. These findings suggest that microglial subpopulations contribute to the heterogeneity of microglial transcriptome and responsiveness within and across brain regions.