Y1 receptors regulate aggressive behavior by modulating serotonin pathways

Abstract

Neuropeptide Y (NPY) is pivotal in the coordinated regulation of food intake, growth, and reproduction, ensuring that procreation and growth occur only when food is abundant and allowing for energy conservation when food is scant. Although emotional and behavioral responses from the higher brain are known to be involved in all of these functions, understanding of the coordinated regulation of emotion/behavior and physiological functions is lacking. Here, we show that the NPY system plays a central role in this process because ablation of the Y1 receptor gene leads to a strong increase in territorial aggressive behavior. After exposure to the resident-intruder test, expression of c-fos mRNA in Y1-knockout mice is significantly increased in the medial amygdala, consistent with the activation of centers known to be important in regulating aggressive behavior. Expression of the serotonin [5-hydroxytryptamine (5-HT)] synthesis enzyme tryptophan hydroxylase is significantly reduced in Y1-deficient mice. Importantly, treatment with a 5-HT-1A agonist, (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide, abolished the aggressive behavior in Y1-knockout mice. These results suggest that NPY acting through Y1 receptors regulates the 5-HT system, thereby coordinately linking physiological survival mechanisms such as food intake with enabling territorial aggressive behavior.

Fig. 1.

Territorial aggression and its reduction after 5-HT1A agonist treatment. (a and b) Territorial aggression in group-housed (a) and individually housed (b) mice after being tested in the RI paradigm. Frequencies [n] of aggressive behaviors such as tail rattling, aggressive grooming, and biting in control and Y1^-/- mice are shown. Data represent means ± SEM (n = 9-12 mice). Significant post hoc effects vs. control animals are indicated by asterisks (^*, P < 0.05; ^**, P < 0.01; ^***, P < 0.001). (c) Territorial aggression in individually housed mice after being tested in the RI paradigm. Latencies [s] of aggressive behaviors such as tail rattling, aggressive grooming, and biting in control and Y1^-/- mice are shown. Data represent means ± SEM (n = 10-12 mice). Significant post hoc effects vs. control animals are indicated by asterisks (^*, P < 0.05; ^***, P < 0.001). (d) Reduction in territorial aggressive behavior in the RI paradigm 25 min after s.c. treatment with different doses (saline, 0.1 or 1.0 mg/kg) of a 5HT-1A agonist (8-OH-DPAT). Latencies [s] of aggressive behaviors such as tail rattling, aggressive grooming, and biting in control and Y1^-/- mice are shown, dependent on different drug doses (mg/kg of body weight). Data represent means ± SEM (n = 9-10 mice). Significant post hoc effects vs. control animals are indicated by asterisks (^*, P < 0.05; ^**, P < 0.01).

Fig. 2.

Neuropeptide mRNA expression in the CNS. Altered neuropeptide mRNA levels in areas involved in aggression and feeding in Y1-deficient mice. High-power photomicrographs of photo emulsion-dipped sections obtained from control (a, c, e, g, i, and k) and Y1^-/- (b, d, f, h, j, and l) mice after in situ hybridization for neuropeptide mRNAs. NPY in the accessory olfactory bulb (a and b), GnRH in scattered neurons of the medial septal nucleus (c and d), CART in the medial (e and f) and central (g and h) amygdaloid nucleus and the arcuate nucleus (i and j), and POMC in the arcuate nucleus (k and l) are depicted. (Scale bar = 100 μm.)

Fig. 3.

TPH mRNA and c-fos mRNA expression in CNS. (a-d) Photomicrographs of photo emulsion-dipped sections obtained from Y1^-/- (a and c) and control (b and d) mice after in situ hybridization for TPH mRNA. The dorsal raphe nucleus is depicted in a and b, and the pontine nucleus is shown in c and d. Aq, aqueduct. (e and f) c-fos mRNA expression in the central nucleus of the amygdala of Y1^-/- and control mice, respectively, after exposure to the RI test. (Scale bar = 40 μm.)