Involvement of the Nucleus Accumbens in Chocolate-induced Cataplexy

Abstract

Happiness is key for both mental and physical well-being. To further understand the brain mechanisms involved, we utilized the cataplexy that occurs in narcoleptic animal models as a quantitative behavioral measure because it is triggered by actions associated with happiness, such as laughter in humans and palatable foods in mice. Here we report that the rostral part of the nucleus accumbens (NAc) shell is strongly activated during the beginning of chocolate-induced cataplexy in orexin neuron-ablated mice. We made a local lesion in the NAc using ibotenic acid and observed the animals' behavior. The number of cataplexy bouts was negatively correlated to the lesion size. We also examined the hedonic response to palatable food by measuring the number of tongue protrusions in response to presentation of honey, which was also found to be negatively correlated to the lesion size. Next, we used clozapine N-oxide to either activate or inactivate the NAc through viral DREADD expression. As expected, the number of cataplexy bouts increased with activation and decreased with inactivation, and saline control injections showed no changes. Hedonic response in the DREADD experiment varied and showed both increases and decreases across mice. These results demonstrated that the rostral part of the NAc plays a crucial role in triggering cataplexy and hedonic orofacial movements. Since the NAc is also implicated in motivated behavior, we propose that the NAc is one of the key brain structures involved in happiness and is a driving force for positive emotion-related behaviors.

Sexual excitation induces courtship ultrasonic vocalizations and cataplexy-like behavior in orexin neuron-ablated male mice

“…In these double transgenic mice (called ORX-AB in this paper), doxycycline is removed from their chow starting from birth so by 4 weeks of age, almost all (>97%) of orexin neurons are ablated 14 . Ablation of orexin neurons was confirmed in our previous studies 10 , 29 and in the current study. Although both male and female ORX-AB mice show cataplexy, we used only male ORX-AB mice in this study because most vocalizations are produced by the male and the vocal contribution of the female is very limited in male–female courtship behaviors 23 , 30 , 31 .…”

“…For the animal model of narcolepsy, 24 male ORX-AB mice 10 , 14 that were 8–12 weeks old at the start of the experiment and weighed 24–32 g were used. The original mating pairs were a generous gift from Prof. Yamanaka at Nagoya University and were bred in Kagoshima University’s animal facility.…”

“…Apart from the positive emotional context, there are many studies pertaining to cataplexy as a symptom of narcolepsy 6 – 14 . Deficiency of the neuropeptide orexin in the hypothalamus is one of the causes of this symptom 7 and activation of the NAc and the prefrontal cortex is thought to be an upstream trigger 9 , 10 . Studies have also shown that the amygdala is a key brain structure involved in the occurrence of cataplexy 6 , 11 , 12 .…”

Activity of putative orexin neurons during cataplexy

“…Orexin neurons express opioid receptors, and activation of the receptor inhibits orexin neuronal activity at least in vitro [ 28 ]. Positive emotions induce both cataplexy [ 21 , 29 ] and opioid release [ 30 ]. Sympathetic activation, a role of orexin neurons [ 31 ], is not as strong during negative emotions as during positive emotions [ 32 ].…”

Positive memory increases cataplexy-like behaviors in narcolepsy mice as revealed using conditioned place preference test

“…Cataplexy is triggered by positive emotions, such as laughter, in human patients [ 5 , 6 ]. Narcolepsy model mice also show cataplexy, and its frequency increases in response to positive emotion-inducing stimuli such as chocolate and female courtship [ 7 – 9 ]. Chocolate increased the incidence of cataplexy by ~ 60% compared to regular food in orexin neuron-ablated mice [ 9 ].…”