Ablation of the hypothalamic neuropeptide melanin concentrating hormone is associated with behavioral abnormalities that reflect impaired olfactory integration

Abstract

Melanin-concentrating hormone (MCH) is an orexigenic hypothalamic neuropeptide. At least one receptor, MCH receptor 1 (MCHR1), is present in all mammals and is expressed widely throughout the brain, including cortex, striatum and structures implicated in the integration of olfactory cues such as the piriform cortex and olfactory bulb. Consistent with a potential role for MCH in mediating olfactory function, MCH knockout mice demonstrate abnormal olfactory behaviors. These behaviors include impaired food seeking by both genders in the context of normal levels of exploratory behavior, suggesting impaired olfaction. Males also exhibit increased aggression while females show defects in several olfactory mediated behaviors including mating, estrous cycle synchronization and maternal behavior. These findings suggest that hypothalamic inputs through MCH play an important role in regulating sensory integration from olfactory pathways.

Figure 1

A. The percentage of mice in each group able to locate the PB tube during the testing period was significantly higher in the WT mice than in the MCHKO mice further reinforcing the apparent olfactory deficit we see in the total time spent in the odorant zone. B. Wild type mice (Open bars) spend a significantly longer time (% of total test time) in the PB (Odorant zone) of the cage when compared to the placebo zone consistent with the attractive odor of the PB. However, in the MCHKO mice (Black bars) there is no significant zone preference exhibited indicating an inherent inability to locate a buried food odorant. C. In an open field test WT and MCHKO mice both explored to a similar extent, furthermore, the activity decreased at a similar rate over the course of the trial (WT vs. MCHKO, Repeated measures ANOVA, NS). D. There was also no significant difference in the total distance moved over the duration of the testing sessions between genotypes (10777 ± 781 vs. 11742 ± 740; NS).

Figure 2

A. The percentage of mice in the MCHKO group which displayed aggressive behavior during the testing period was significantly greater than in the WT group (75% vs. 25%). B. The time until mice displayed aggression towards an intruder mouse placed in their cage was found to be significantly higher in WT mice when compared to their MCHKO counterparts (789.5s ± 73.4s vs. 334.5s ± 98.3s, p=<0.001), indicating a significantly heightened level of aggression towards intruder mice in the MCHKO mice.

Figure 3

A. During video recording sessions WT males were found to attempt significantly less mountings of females than that of the MCHKO males with their respective partners (10±3 vs. 28±6, p=<0.05). This difference may in part explain the reduced fertility of the MCHKO mice when bred in a homozygous manner. B. In accordance with the number of failed mounting attempts the efficacy of the mating was found to be significantly higher in WT females when compared to MCHKO females (80% vs. 20% resulted in subsequent pregnancy respectively).

Figure 4

A. Numbers of pups were not different between WT and MCHKO litters immediately following birth on day 0 (7.1±0.4 vs. 7.1±1, NS). However, at the end of the study period on day 14 WT litters trended to be larger than MCHKO litters (6.5±0.4 vs. 5±1.2, NS). B. Mean weight of pups was found to diverge throughout the measurement period with WT mice being trending to be heavier on day 14 when compared to MCHKO pups (6.3g±0.49g vs.5.8g±0.5g, NS). C. Concordant with the reduced litter size at the end of the monitoring period mortality was significantly higher in the MCHKO litters when compared to WT (7.3%±4.2% vs. 31.1%±13.6%, p=<0.05).