Fine mapping of QTL for prepulse inhibition in LG/J and SM/J mice using F(2) and advanced intercross lines.

Prepulse inhibition (PPI) of the startle response is a measure of sensorimotor gating, a process that filters out extraneous sensory, motor and cognitive information. Humans with neurological and psychiatric disorders, including schizophrenia, obsessive-compulsive disorder and Huntington's disease, exhibit a reduction in PPI. Habituation of the startle response is also disrupted in schizophrenic patients. In order to elucidate the genes involved in sensorimotor gating, we phenotyped 472 mice from an F(2) cross between LG/J × SM/J for PPI and genotyped these mice genome-wide using 162 single nucleotide polymorphism (SNP) markers. We used prepulse intensity levels that were 3, 6 and 12 dB above background (PPI3, PPI6 and PPI12, respectively). We identified a significant quantitative trait locus (QTL) on chromosome 12 for all three prepulse intensities as well as a significant QTL for both PPI6 and PPI12 on chromosome 11. We identified QTLs on chromosomes 7 and 17 for the startle response when sex was included as an interactive covariate and found a QTL for habituation of the startle response on chromosome 4. We also phenotyped 135 mice from an F(34) advanced intercross line (AIL) between LG/J × SM/J for PPI and genotyped them at more than 3000 SNP markers. Inclusions of data from the AIL mice reduced the size of several of these QTLs to less than 5 cM. These results will be useful for identifying genes that influence sensorimotor gaiting and show the power of AIL for fine mapping of QTLs.

Latent inhibition and conditioning in rat strains which show differential prepulse inhibition.

Latent inhibition (LI) is the retardation of associative conditioning resulting from preexposure of the conditioned stimulus (CS) alone prior to conditioning. Schizophrenic patients show deficient prepulse inhibition (PPI) and, at least acutely, deficient LI as well. We recently found that Brown Norway (BN) rats show a PPI deficit compared to Wistar-Kyoto (WKY) rats. If PPI and LI depend on neural processes with common genetic substrates, then LI should be deficient in BN rats as well. Here, LI of a conditioned taste aversion was examined in BN and WKY rats. One group from each strain was preexposed to a saccharin-flavored solution (CS) the day prior to conditioning. For taste aversion conditioning, these two groups again consumed saccharin and were injected with lithium chloride (unconditioned stimulus) 10 min later. A second group from each strain was not preexposed to the CS and was treated identically during conditioning, while a third group was not conditioned (injected with sodium chloride). To test for taste aversion conditioning, saccharin was offered for 20 min/day for 3 days. Nonconditioned BN and WKY rats consumed equal amounts of saccharin on test days. In both strains, conditioned rats showed a saccharin aversion. However, conditioning was less robust in BN than in WKY rats. WKY rats showed good LI of the conditioned taste aversion in that preexposed WKY rats consumed significantly more saccharin on test days than conditioned, nonpreexposed WKY rats. Preexposed BN rats did not consume significantly more saccharin on test days than conditioned, nonpreexposed BN rats. The previously reported deficiency in PPI in the BN rats was confirmed here 1 week after the taste aversion experiment. These results suggest that BN rats show deficient LI as well as PPI and display poor associative learning, a trait also reported in schizophrenia.

Strain differences in Fos expression following airpuff startle in Spontaneously Hypertensive and Wistar Kyoto rats.

The airpuff startle stimulus elicits both a behavioral and a concurrent sympathetic and parasympathetic activation, which have been shown to differ between inbred normotensive Wistar Kyoto and Spontaneously Hypertensive rat strains. Neither the brain sites responsible for the cardiovascular and motor responses, nor the origins of the strain differential responses, have yet been elucidated. The goals of the present study were (i) to define the neuronal pattern of immunoreactive Fos expression to the airpuff stimulus, and (ii) to determine whether this pattern of expression differed between the two contrasting inbred rat strains, thereby relating to observed differences in response. The airpuff stimulus induced Fos protein expression in discrete nuclei within the hypothalamus, thalamus, midbrain, pons and medulla of both strains, with strain-dependent differences evident in the hypothalamus (lateral, ventromedial and dorsomedial), pons (locus coeruleus) and medulla (rostroventrolateral medulla and solitary tract nuclei). To remove Fos expression arising from test chamber novelty, which was observed in both strains, a subset of animals was habituated to the test chamber for four days prior to testing. Habituation reduced Fos expression in several brain regions in the Wistar Kyoto, but failed to do so in the Spontaneously Hypertensive rat. The present results are the first to identify a set of brain regions likely to be responsible for the mediation of the cardiovascular and motor responses associated with the airpuff startle stimulus. Several of the identified areas contain neurotransmitters implicated by prior pharmacological studies. Further, these data identify differences in the degree of activation of specific neuronal structures that probably underlie strain differences in the cardiovascular response to the airpuff. Additionally, the results provide a cellular correlate to reported deficits in behavioral habituation by the Spontaneously Hypertensive rat and suggest a potentially profound difference between the ability of these two strains to adapt to repeated mild stress stimuli.

Attenuation of Fos expression to airpuff startle stimuli following tympanic membrane rupture.

The airpuff startle stimulus consists of two modalities, tactile and acoustic. Tympanic membrane rupture (TMR) effectively deafens a rat, thus preventing it from perceiving the acoustic component of the airpuff and permitting study of the tactile component in isolation. Previous studies have shown that the tactile modality is sufficient to drive the cardiovascular response to the airpuff, but cannot elicit the full behavioral startle response. In the present study Fos protein was used as a marker of neuronal activation to identify brain regions activated by the airpuff in both intact and TMR rats. Results show an attenuation of Fos expression following TMR in the dorsal and ventral cochlear nuclei, ventral nucleus of the lateral lemniscus and medial geniculate nucleus. In contrast, Fos expression following TMR was unchanged in the locus coeruleus, the laterodorsal tegmental nucleus, the supramammilary nucleus, and the ventromedial hypothalamic nucleus. Analysis of behavioral data confirmed that the startle response to the airpuff was diminished following TMR. These data are the first of which we know to employ an immediate early gene approach to discriminate between brain regions activated by the tactile and acoustic startle stimulus modalities. The results are discussed in terms of the classical acoustic startle circuit, and the central autonomic pathways activated by the tactile component of the airpuff.