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Gene expression profiles in the periaqueductal gray (PAG) of adult Long-Evans rats as a function of a stressful social defeat in inter-male fighting encounters were examined. This social subordination model mimics prototypical behavioral changes that parallel aspects of clinical depression, has been postulated to simulate early changes in the onset of depression in the losers, and has been successfully utilized for the evaluation of antidepressant activity. 22-kHz ultrasonic vocalizations (USVs) have been shown to reflect negative emotional states akin to anxiety and depression. Social defeat is the most robust and reliable method of eliciting these calls. The PAG has been shown to be a key brain region for the generation of 22-kHz ultrasonic vocalizations, and 22-kHz USVs have been shown to be controlled by the mesolimbic cholinergic system. In this present study we examined gene expression changes in the PAG of social subordinate rats compared to dominant rats (that do not exhibit 22-kHz USVs). We found that social defeat significantly altered the genes associated with cholinergic synaptic transmission in the PAG. The most robust of these were the increased expression of the β2 subunit of the nicotinic acetylcholine receptor (CHRNB2) and the T-subunit of acetylcholinesterase (ACHE) in the subordinate animals. These changes were corroborated by qRT-PCR and found to be exclusive to the PAG compared to seven other brain regions examined. These data suggest that cholinergic transmission in the PAG is involved in the generation of 22-kHz USVs and provide potential therapeutic targets for the treatment of affective disorders.

A central problem in neurobiology is the elucidation of the mechanisms that underlie left-right asymmetries in brain structure and function. Using a transcriptome screening approach, we found asymmetric gene expression patterns in the right when compared with the left hippocampal formation at postnatal days (P) 6, 9, and 60 in the rat. Of those genes that were differentially expressed, most were predominantly expressed in the right hippocampus at P6, whereas most were predominantly expressed in the left at P9 and P60. Real-time PCR analysis of genes associated with synaptic vesicle trafficking confirmed this pattern. At P6, 9 of 13 such genes were more robustly expressed in the right hippocampus, while only 1 gene was predominantly expressed in the left. Conversely, at P9, 5 of the 13 genes were more highly expressed in the left hippocampus and only 1 gene was predominantly expressed in the right. This pattern persisted at P60: eight genes were more robustly expressed in the left hippocampus, and the remaining five showed no hemispheric preference. These data demonstrate a pattern of early lateralized gene expression that is likely to underlie the establishment of functional asymmetry in the adult hippocampus.

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