Activation of the rostral nucleus accumbens shell by optogenetics induces cataplexy-like behavior in orexin neuron-ablated mice

Abstract

Cataplexy is one of the symptoms of type 1 narcolepsy, characterized by a sudden loss of muscle tone. It can be seen as a behavioral index of salience, predominantly positive emotion, since it is triggered by laughter in humans and palatable foods in mice. In our previous study using chemogenetic techniques in narcoleptic mice (orexin neuron-ablated mice), we found that the rostral nucleus accumbens (NAc) shell is needed for chocolate-induced cataplexy. In this study, we investigated whether a short-lasting stimulation/inhibition of the NAc by optogenetics led to a similar result. Photo-illumination to the NAc in the channel rhodopsin-expressing mice showed a higher incidence (34.9 ± 5.1%) of cataplexy-like behavior than the control mice (17.8 ± 3.1%, P = 0.0056). Meanwhile, inactivation with archaerhodopsin did not affect incidence. The episode duration of cataplexy-like behavior was not affected by activation or inactivation. Immunohistochemical analysis revealed that photo-illumination activated channel rhodopsin-expressing NAc shell neurons. Thus, activation of the NAc, whether transient (light stimulation) or longer-lasting (chemical stimulation in our previous study), facilitates cataplexy-like behaviors and contributes to the induction but not maintenance in them. On the other hand, our study's result from optogenetic inhibition of the NAc (no effect) was different from chemogenetic inhibition (reduction of cataplexy-like behavior) in our previous study. We propose that the initiation of cataplexy-like behavior is facilitated by activation of the NAc, while NAc-independent mechanisms determine the termination of the behavior.

Dopamine release in the nucleus accumbens promotes REM sleep and cataplexy

“…The limbic system has a documented role in regulating cataplexy; 2 , 53 , 58 , 59 , 60 however, the involvement of the striatum has garnered only modest attention. 35 , 61 In agreement with hypothesized roles for DA release in the striatum, we show that DA release in the DLS is suppressed during cataplexy, perhaps due to the suppression of movement. In the NAcc and NAcSh, robust increases in DA release were observed prior to cataplexy onset, consistent with the positively valenced states that often precede both human and murine cataplexy.…”

“…As opto-/chemogenetic activation of the NAcSh is sufficient to increase cataplexy frequency in OX KO mice, 35 , 61 it remains unclear what mechanisms, if not DA, are responsible for this effect. While the NAcc and NAcSh share functional similarities, anatomically, the NAcSh has characteristics not present in the NAcc, such as a flipped patch-matrix, increased D1/D2-receptor co-expression, and differences in where DA axons synapse.…”

International Union of Basic and Clinical Pharmacology CXIV: Orexin Receptor Function, Nomenclature and Pharmacology

“…Moreover, activation of the nucleus accumbens, by optogenetic or chemogenetic stimulation, facilitates induction, but not maintenance of cataplectic events in rodents (Su et al, 2020). However, chemogenetic inhibition of the nucleus accumbens inhibits cataplexy while optogenetic inhibition does not (Su et al, 2020;Kawashima et al, 2023). Orexin neurons have been shown to increase their firing rate before initiation of cataplectic episode but to decrease their firing rate below the baseline during the episode in PPO-KO mice (Zhou et al, 2022).…”

Striatal dopamine regulates sleep states and narcolepsy-cataplexy

“…The limbic system has a documented role in regulating cataplexy 2,53,58-60 , however, the involvement of the striatum has garnered only modest attention 35,61 . In agreement with hypothesized roles for DA release in the striatum, we show that DA release in the DLS is suppressed during cataplexy, perhaps due to the suppression of movement.…”

“…As opto-/chemogenetic activation of the NAcSh is sufficient to increase cataplexy frequency in OX KO mice 35,61 , it remains unclear what mechanisms, if not DA, are responsible for this effect. While the NAcc and NAcSh share functional similarities, anatomically, the NAcSh has characteristics not present in the NAcc, such as a flipped patch-matrix, increased D1/D2receptor co-expression, and differences in where DA axons synapse 27 .…”