Selection for contextual fear conditioning affects anxiety-like behaviors and gene expression.

Conditioned fear and anxiety-like behaviors have many similarities at the neuroanatomical and pharmacological levels, but their genetic relationship is less well defined. We used short-term selection for contextual fear conditioning (FC) to produce outbred mouse lines with robust genetic differences in FC. The high and low selected lines showed differences in fear learning that were stable across various training parameters and were not secondary to differences in sensitivity to the unconditioned stimulus (foot shock). They also showed a divergence in fear potentiated startle, indicating that differences induced by selection generalized to another measure of fear learning. However, there were no differences in performance in a Pavlovian approach conditioning task or the Morris water maze, indicating no change in general learning ability. The high fear learning line showed greater anxiety-like behavior in the open field and zero maze, confirming a genetic relationship between FC and anxiety-like behavior. Gene expression analysis of the amygdala and hippocampus identified genes that were differentially expressed between the two lines. Quantitative trait locus (QTL) analysis identified several chromosomal regions that may underlie the behavioral response to selection; cis-acting expression QTL were identified in some of these regions, possibly identifying genes that underlie these behavioral QTL. These studies support the validity of a broad genetic construct that includes both learned fear and anxiety and provides a basis for further studies aimed at gene identification.

Drug reward and intake in lines of mice selectively bred for divergent exploration of a hole board apparatus.

Individuals characterized as high-novelty seekers are more likely to abuse drugs than are low-novelty seekers, and it is possible that the biological substrates underlying novelty seeking and drug abuse are similar. We selectively bred replicate lines of mice from a B6D2 F3 hybrid stock for high exploratory behavior (HEB) or low exploratory behavior (LEB) as measured by the number of head dips on a hole board. To determine whether common genes might influence exploratory behavior and behaviors relevant to drug abuse, we tested HEB and LEB mice for conditioned place preference produced by ethanol and d-amphetamine and also examined oral methamphetamine intake. After four generations of selection, HEB and LEB mice did not differ in the magnitude of place preference for ethanol, but LEB mice showed a greater place preference for an amphetamine-paired location than did HEB mice. However, this difference did not replicate in mice tested from the fifth generation of selection. The selected lines also did not differ in sensitization to the locomotor stimulant effects of d-amphetamine that developed across the conditioning trials. Finally, HEB and LEB mice consumed equivalently low amounts of methamphetamine. These results suggest that common genes do not influence head dipping and several behaviors potentially relevant to drug abuse.

Anxiety-like behavior in mice in two apparatuses during withdrawal from chronic ethanol vapor inhalation.

BACKGROUND: Anxiety during ethanol withdrawal may be a factor in relapse to alcohol abuse and dependence. Animal models of ethanol withdrawal have typically used forced consumption of an ethanol-containing liquid diet to induce dependence. Ethanol vapor inhalation offers an advantage over liquid diet consumption in that the onset of withdrawal can be temporally controlled more precisely, allowing studies of the development of withdrawal symptoms. METHODS: The purpose of the current study was to induce ethanol dependence in mice using an inhalation procedure and to assess withdrawal anxiety symptoms behaviorally in the elevated zero maze and in the light/dark box. Male and female mice were exposed to 3 days of ethanol vapors. Anxiety-like behavior was measured on the elevated zero maze and light/dark box at multiple time points during withdrawal. RESULTS: Mice experiencing ethanol withdrawal demonstrated increased anxiety-like behaviors relative to control animals in both apparatuses. However, this finding was specific to the procedure used with the elevated zero maze and was strongly influenced by sex in the light/dark box. CONCLUSIONS: Ethanol vapor inhalation appears to be a valid tool for the study of withdrawal-induced anxiety.