Altered sleep and affect in the neurotensin receptor 1 knockout mouse

Abstract

Study objective: Sleep and mood disorders have long been understood to have strong genetic components, and there is considerable comorbidity of sleep abnormalities and mood disorders, suggesting the involvement of common genetic pathways. Here, we examine a candidate gene implicated in the regulation of both sleep and affective behavior using a knockout mouse model.

Design: Previously, we identified a quantitative trait locus (QTL) for REM sleep amount, REM sleep bout number, and wake amount in a genetically segregating population of mice. Here, we show that traits mapping to this QTL correlated with an expression QTL for neurotensin receptor 1 (Ntsr1), a receptor for neurotensin, a ligand known to be involved in several psychiatric disorders. We examined sleep as well as behaviors indicative of anxiety and depression in the NTSR1 knockout mouse.

Measurements and results: NTSR1 knockouts had a lower percentage of sleep time spent in REM sleep in the dark phase and a larger diurnal variation in REM sleep duration than wild types under baseline conditions. Following sleep deprivation, NTSR1 knockouts exhibited more wake and less NREM rebound sleep. NTSR1 knockouts also showed increased anxious and despair behaviors.

Conclusions: Here we illustrate a link between expression of the Ntsr1 gene and sleep traits previously associated with a particular QTL. We also demonstrate a relationship between Ntsr1 and anxiety and despair behaviors. Given the considerable evidence that anxiety and depression are closely linked with abnormalities in sleep, the data presented here provide further evidence that neurotensin and Ntsr1 may be a component of a pathway involved in both sleep and mood disorders.

Keywords: NTSR1; Sleep; anxiety; depression; neurotensin.

Figure 1

Significant differences in baseline sleep amounts between wild type B6 controls and NTSR1 knockouts. %REM/TS, percentage of REM sleep over total sleep. Results are expressed as mean ± SEM; P-values were obtained using the Student t test. (A) Percentage of total sleep spent in REM sleep in the dark (active) phase, *P < 0.05. (B) Diurnal variation of REM sleep minutes (light – dark), *P < 0.05. (C) Diurnal variation of the percentage of total sleep spent in REM sleep (light – dark), *P < 0.05.

Figure 2

Significant differences in rebound sleep amounts as compared to baseline. Results are expressed as mean ± SEM; P-values were obtained using the Student t test. (A) Wake rebound after 6-h sleep deprivation period (ZT2-8), separated out into light phase (inactive, left) and dark phase (active, right), *P < 0.05. (B) NREM sleep rebound after 6-h sleep deprivation period (ZT2-8), separated out into light phase (inactive, left) and dark phase (active, right), *P < 0.05.

Figure 3

Significant differences in open field activity. Results are expressed as mean ± SEM; P-values were obtained using the Student t test. (A) Total distance traveled (cm) in the open field, **P < 0.01. (B) Percentage of time spent in the center portion of the open field, *P < 0.05. (C) Percentage of time spent in the corners of the open field, **P < 0.01.

Figure 4

Time course of number of bouts of immobility on the second day in the tail suspension test. Results are expressed as mean ± SEM; P-values were obtained using the Student t test; **P < 0.01.

Figure S1

Total Immobility in seconds over the 6-minute tail suspension test. Two-way repeated measures ANOVA F_1,36 = 6.180, P = 0.0262.

Figure S2

Total Immobility by minute over the 6-minute tail suspension test. Two-way repeated measures ANOVA F_1,36 = 6.180, P = 0.0262.