Identifying Genes in Monoamine Nuclei that may Determine Stress Vulnerability and Depressive Behavior in Wistar–Kyoto Rats

Abstract

The Wistar-Kyoto (WKY) rat is stress sensitive and exhibits depressive-like behavior. The locus coeruleus (LC)-norepinephrine and dorsal raphe (DR)-serotonin systems mediate certain aspects of the stress response and have been implicated in depression. Microarray technology was used to identify gene expression differences in the LC and DR between WKY vs Sprague-Dawley (SD) rats that might account for the WKY phenotype. RNA was isolated from microdissected LC and DR, amplified, and hybridized to microarrays (1 array/ subject, n ¼ 4/group). Significance of microarray (SAM) analysis revealed increased expression of 66 genes in the LC and 19 genes in the DR and decreased expression of 33 genes in the DR of WKY rats. Hierarchical clustering identified differences in gene expression profiles of WKY vs SD rats that generally concurred with SAM. Notably, genes that encoded for enzymes involved in norepinephrine turnover, amino-acid receptors, and certain G-protein-coupled receptors were elevated in the LC of WKY rats. The DR of WKY rats showed decreased expression of genes encoding several potassium channels and neurofilament genes. The chromosomal locations of 15 genes that were differentially expressed in WKY rats were near loci identified as contributing to depressive-like behaviors in the rat. The specific genes revealed by the present analysis as being differentially expressed in WKY rats may contribute to their unique behavioral profile and suggest targets that confer susceptibility to stress-related psychiatric disorders.

Presynaptic Inhibition of Diverse Afferents to the Locus Ceruleus by -Opiate Receptors: A Novel Mechanism for Regulating the Central Norepinephrine System

“…In this regard, previous studies have implicated the dynorphin--OR system in depression and suggest that -OR antagonists may be useful antidepressants (Pliakas et al, 2001;Mague et al, 2003;McLaughlin et al, 2003McLaughlin et al, , 2006bShirayama et al, 2004). Although these studies focused on -OR actions in forebrain, findings of increased -OR gene expression in the LC of the Wistar-Kyoto rat (a strain that exhibits a depressive phenotype) support a role for -OR in the LC in depression (Pearson et al, 2006). In other clinical conditions that are characterized by excessive responses to sensory stimuli, the ability of -OR agonists to blunt these responses without altering the state of arousal might be therapeutically useful.…”

“…This is of particular interest as dynorphin and -ORs are implicated in stress-related disorders (Pliakas et al, 2001;Mague et al, 2003;McLaughlin et al, 2006a). Moreover, elevated -OR gene expression in the LC of Wistar-Kyoto (WKY) rats, a strain that has been used to model stress-related depression, suggests that -OR activation in this nucleus may have clinically relevant consequences (Pearson et al, 2006).…”

Genotype-dependent responsivity to inflammatory pain: A role for TRPV1 in the periaqueductal grey

“…Gene expression studies with the help of microarray technology identified the differential gene expression between WKY rats and SD rats in the locus coeruleus (LC) and dorsal raphe (DR) which are key sites of origin for noradrenergic and serotonergic pathways, respectively (Pearson et al, 2006). Differences in gene expression in LC or DR neurons could underlie differential responses of these systems to stress and account for the stress-sensitive phenotype of the WKY strain.…”

“…Along with the genetic impairment of noradrenergic systems, an increased expression of genes encoding opioids, and orexin (hypocretin) which regulates the neurotransmitters that convey afferent information to the LC was reported. The low expression of genes encoding cytoskeletal proteins that are important for structural plasticity and several potassium channels, suggests that the excitability and synaptic integration of DR neurons may be altered in WKY rats (Pearson et al, 2006).…”

Animal Models of Anxiety Vulnerability - The Wistar Kyoto Rat

“…Several QTL (Imm 1 D2Rat188, Imm3 D5Rat40, Imm6 D16Arb5, Climb2 D1Rat147, FST1 D16Rat75) were identified for climbing, immobility and swimming in WKY rats, sharing common target regions with susceptibility loci mapped by genome scan analyses for emotionality QTL in rodents and human genetic linkage to emotional disorder (Solberg et al, 2004). Significance of microarray analysis (SAM) revealed that expression of 66 genes was increased in the locus coeruleus (LC) of WKY compared to SD rats (Pearson et al, 2006), including genes that encoded for enzymes involved in NE turnover. Moreover, the mRNA of catechol-O-methyltransferase (COMT), a key enzyme in the catabolism of catecholamines, was found at levels four-to sevenfold higher in the cerebral cortex in WKYs than SDs (Walker et al, 2004).…”