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Urine scent marking (USM): a novel test for depressive-like behavior and a predictor of stress resiliency in mice.

Lehmann ML, Geddes CE, Lee JL, Herkenham M - PLoS ONE (2013)

Bottom Line: The expression of this behavior is highly sensitive and adaptive to environmental cues and social status.We demonstrated that 1) adult male mice displayed a strong preference for marking proestrous female urine with a high degree of specificity, 2) exposure to chronic social defeat profoundly decreased USM whereas exposure to environmental enrichment increased USM, 3) the standard antidepressant fluoxetine reversed declines in USM induced by social defeat, 4) USM behavior closely correlated with other hedonic measures, and 5) USM scores in non-stressed mice predicted behavioral outcomes after defeat exposure such that mice displaying high preference for marking female urine prior to social defeat showed behavioral resiliency after social defeat.The findings indicate that the USM test is a sensitive, validated measure of psychosocial stress effects that has high predictive value for examination of stress resiliency and vulnerability and their neurobiological substrates.

View Article: PubMed Central - PubMed

Affiliation: Section on Functional Neuroanatomy, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America. Michael.lehmann@nih.gov

ABSTRACT
Decreased interest in pleasurable stimuli including social withdrawal and reduced libido are some of the key symptomatic criteria for major depression, and thus assays that measure social and sexual behavior in rodents may be highly appropriate for modeling depressive states. Here we present a novel approach for validating rodent models of depression by assessing male urine scent marking (USM) made in consequence to a spot of urine from a proestrous female. USM is an ethologically important form of sexual communication expressed by males to attract females. The expression of this behavior is highly sensitive and adaptive to environmental cues and social status. We hypothesized that male USM behavior offers a naturalistic measure of social motivation that can be used to evaluate hedonic behaviors relevant to the study of mood disorders. We demonstrated that 1) adult male mice displayed a strong preference for marking proestrous female urine with a high degree of specificity, 2) exposure to chronic social defeat profoundly decreased USM whereas exposure to environmental enrichment increased USM, 3) the standard antidepressant fluoxetine reversed declines in USM induced by social defeat, 4) USM behavior closely correlated with other hedonic measures, and 5) USM scores in non-stressed mice predicted behavioral outcomes after defeat exposure such that mice displaying high preference for marking female urine prior to social defeat showed behavioral resiliency after social defeat. The findings indicate that the USM test is a sensitive, validated measure of psychosocial stress effects that has high predictive value for examination of stress resiliency and vulnerability and their neurobiological substrates.

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Fluoxetine prevents a decline in urine scent marking (USM) preferences induced by social defeat.a) Diagram illustrates experimental groups and study design. Fluoxetine (Flx) or saline vehicle (Sal) was administered once a day for the duration of the experiment. b) Saline treated defeated mice show substantial reductions in USM preferences compared to all other groups. Mice treated with fluoxetine show USM preferences similar to non-defeated groups. c–d) Fluoxetine completely reverses the decline in the area of urine marks in the arena (c) and in the female urine quadrant (d) induced by social defeat. e–h) Time spent in each quadrant for each treatment condition is shown. All groups show significant preference for the female urine quadrant during the first trial min. i) Interest for sniffing female urine was elevated early in the trial period (Time effect; F 9,216 = 4.89, p<0.0001), no effect of treatment was observed. (HC; homecage, SD; social defeat) Bars represent mean+SE (n = 7 for HC groups, 8 for SD groups) *P<0.05, **P<0.01.
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pone-0069822-g005: Fluoxetine prevents a decline in urine scent marking (USM) preferences induced by social defeat.a) Diagram illustrates experimental groups and study design. Fluoxetine (Flx) or saline vehicle (Sal) was administered once a day for the duration of the experiment. b) Saline treated defeated mice show substantial reductions in USM preferences compared to all other groups. Mice treated with fluoxetine show USM preferences similar to non-defeated groups. c–d) Fluoxetine completely reverses the decline in the area of urine marks in the arena (c) and in the female urine quadrant (d) induced by social defeat. e–h) Time spent in each quadrant for each treatment condition is shown. All groups show significant preference for the female urine quadrant during the first trial min. i) Interest for sniffing female urine was elevated early in the trial period (Time effect; F 9,216 = 4.89, p<0.0001), no effect of treatment was observed. (HC; homecage, SD; social defeat) Bars represent mean+SE (n = 7 for HC groups, 8 for SD groups) *P<0.05, **P<0.01.

Mentions: Chronic treatment with antidepressants can remediate maladaptive behaviors in socially defeated mice, and we tested whether USM preferences were similarly malleable (Fig. 5a). We observed that fluoxetine administered daily prior to and during SD protected against the emergence of depressive behaviors. Chronic fluoxetine completely reversed the decline in USM preference induced by SD (Fig. 5b; stress effect F 1,26 = 4.81, p<0.03 and drug effect F 1,26 = 7.31, p<0.01). USM preference was significantly attenuated in vehicle-treated defeated mice compared to all other groups (post hoc p<0.01). The strong differences in USM preferences in saline- vs. fluoxetine-treated defeated mice were seen in marking behavior: the area of urine marks in both the arena (Fig. 5c; stress effect F 1,26 = 4.43, p<0.05 and drug effect F 1,26 = 6.55, p<0.02) and within the female-urine quadrant (Fig. 5d; interaction effect F 1,26 = 4.37, p<0.04, stress effect F 1,26 = 5.25, p<0.03, and drug effect F 1,26 = 4.37, p<0.002) were substantially elevated in fluoxetine-treated compared to vehicle-treated defeated mice (post hoc p<0.01). In contrast, all treatment groups showed preference for the female urine quadrant during the first min of exposure (Fig. 5 e–h) (HC+Sal, Fig. 5e; Interaction effect F 27,216 = 1.67, p<0.02, quadrant preference F 3,27 = 21.7, p<0.0001) (HC+Flx, Fig. 5f; Interaction effect F 27,216 = 1.69, p<0.03, quadrant preference F 3,27 = 14.4, p<0.0001) (SD+Sal, Fig. 5g; quadrant preference F 3,27 = 24.1, p<0.0001) (SD+Flx, Fig. 5h; quadrant preference F 3,27 = 8.05, p<0.001)(All treatment groups; post hoc test, p<0.01 female urine quadrant vs. all other quadrants during 1st min.). In addition, all groups spent a similar amount of time sniffing female urine directly (Fig. 5i; p>0.05). Quadrant preferences and interest in female urine remained independent of USM behaviors (p>0.05 for all groups).


Urine scent marking (USM): a novel test for depressive-like behavior and a predictor of stress resiliency in mice.

Lehmann ML, Geddes CE, Lee JL, Herkenham M - PLoS ONE (2013)

Fluoxetine prevents a decline in urine scent marking (USM) preferences induced by social defeat.a) Diagram illustrates experimental groups and study design. Fluoxetine (Flx) or saline vehicle (Sal) was administered once a day for the duration of the experiment. b) Saline treated defeated mice show substantial reductions in USM preferences compared to all other groups. Mice treated with fluoxetine show USM preferences similar to non-defeated groups. c–d) Fluoxetine completely reverses the decline in the area of urine marks in the arena (c) and in the female urine quadrant (d) induced by social defeat. e–h) Time spent in each quadrant for each treatment condition is shown. All groups show significant preference for the female urine quadrant during the first trial min. i) Interest for sniffing female urine was elevated early in the trial period (Time effect; F 9,216 = 4.89, p<0.0001), no effect of treatment was observed. (HC; homecage, SD; social defeat) Bars represent mean+SE (n = 7 for HC groups, 8 for SD groups) *P<0.05, **P<0.01.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3713058&req=5

pone-0069822-g005: Fluoxetine prevents a decline in urine scent marking (USM) preferences induced by social defeat.a) Diagram illustrates experimental groups and study design. Fluoxetine (Flx) or saline vehicle (Sal) was administered once a day for the duration of the experiment. b) Saline treated defeated mice show substantial reductions in USM preferences compared to all other groups. Mice treated with fluoxetine show USM preferences similar to non-defeated groups. c–d) Fluoxetine completely reverses the decline in the area of urine marks in the arena (c) and in the female urine quadrant (d) induced by social defeat. e–h) Time spent in each quadrant for each treatment condition is shown. All groups show significant preference for the female urine quadrant during the first trial min. i) Interest for sniffing female urine was elevated early in the trial period (Time effect; F 9,216 = 4.89, p<0.0001), no effect of treatment was observed. (HC; homecage, SD; social defeat) Bars represent mean+SE (n = 7 for HC groups, 8 for SD groups) *P<0.05, **P<0.01.
Mentions: Chronic treatment with antidepressants can remediate maladaptive behaviors in socially defeated mice, and we tested whether USM preferences were similarly malleable (Fig. 5a). We observed that fluoxetine administered daily prior to and during SD protected against the emergence of depressive behaviors. Chronic fluoxetine completely reversed the decline in USM preference induced by SD (Fig. 5b; stress effect F 1,26 = 4.81, p<0.03 and drug effect F 1,26 = 7.31, p<0.01). USM preference was significantly attenuated in vehicle-treated defeated mice compared to all other groups (post hoc p<0.01). The strong differences in USM preferences in saline- vs. fluoxetine-treated defeated mice were seen in marking behavior: the area of urine marks in both the arena (Fig. 5c; stress effect F 1,26 = 4.43, p<0.05 and drug effect F 1,26 = 6.55, p<0.02) and within the female-urine quadrant (Fig. 5d; interaction effect F 1,26 = 4.37, p<0.04, stress effect F 1,26 = 5.25, p<0.03, and drug effect F 1,26 = 4.37, p<0.002) were substantially elevated in fluoxetine-treated compared to vehicle-treated defeated mice (post hoc p<0.01). In contrast, all treatment groups showed preference for the female urine quadrant during the first min of exposure (Fig. 5 e–h) (HC+Sal, Fig. 5e; Interaction effect F 27,216 = 1.67, p<0.02, quadrant preference F 3,27 = 21.7, p<0.0001) (HC+Flx, Fig. 5f; Interaction effect F 27,216 = 1.69, p<0.03, quadrant preference F 3,27 = 14.4, p<0.0001) (SD+Sal, Fig. 5g; quadrant preference F 3,27 = 24.1, p<0.0001) (SD+Flx, Fig. 5h; quadrant preference F 3,27 = 8.05, p<0.001)(All treatment groups; post hoc test, p<0.01 female urine quadrant vs. all other quadrants during 1st min.). In addition, all groups spent a similar amount of time sniffing female urine directly (Fig. 5i; p>0.05). Quadrant preferences and interest in female urine remained independent of USM behaviors (p>0.05 for all groups).

Bottom Line: The expression of this behavior is highly sensitive and adaptive to environmental cues and social status.We demonstrated that 1) adult male mice displayed a strong preference for marking proestrous female urine with a high degree of specificity, 2) exposure to chronic social defeat profoundly decreased USM whereas exposure to environmental enrichment increased USM, 3) the standard antidepressant fluoxetine reversed declines in USM induced by social defeat, 4) USM behavior closely correlated with other hedonic measures, and 5) USM scores in non-stressed mice predicted behavioral outcomes after defeat exposure such that mice displaying high preference for marking female urine prior to social defeat showed behavioral resiliency after social defeat.The findings indicate that the USM test is a sensitive, validated measure of psychosocial stress effects that has high predictive value for examination of stress resiliency and vulnerability and their neurobiological substrates.

View Article: PubMed Central - PubMed

Affiliation: Section on Functional Neuroanatomy, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America. Michael.lehmann@nih.gov

ABSTRACT
Decreased interest in pleasurable stimuli including social withdrawal and reduced libido are some of the key symptomatic criteria for major depression, and thus assays that measure social and sexual behavior in rodents may be highly appropriate for modeling depressive states. Here we present a novel approach for validating rodent models of depression by assessing male urine scent marking (USM) made in consequence to a spot of urine from a proestrous female. USM is an ethologically important form of sexual communication expressed by males to attract females. The expression of this behavior is highly sensitive and adaptive to environmental cues and social status. We hypothesized that male USM behavior offers a naturalistic measure of social motivation that can be used to evaluate hedonic behaviors relevant to the study of mood disorders. We demonstrated that 1) adult male mice displayed a strong preference for marking proestrous female urine with a high degree of specificity, 2) exposure to chronic social defeat profoundly decreased USM whereas exposure to environmental enrichment increased USM, 3) the standard antidepressant fluoxetine reversed declines in USM induced by social defeat, 4) USM behavior closely correlated with other hedonic measures, and 5) USM scores in non-stressed mice predicted behavioral outcomes after defeat exposure such that mice displaying high preference for marking female urine prior to social defeat showed behavioral resiliency after social defeat. The findings indicate that the USM test is a sensitive, validated measure of psychosocial stress effects that has high predictive value for examination of stress resiliency and vulnerability and their neurobiological substrates.

Show MeSH
Related in: MedlinePlus