Heterogeneous distribution of the serotonin 5‐HT_1A receptor mRNA in chemically identified neurons of the mouse rostral brainstem: Implications for the role of serotonin in the regulation of wakefulness and REM sleep

Abstract

The 5-HT(1A) receptor (5-HT(1A)R) plays a key role in the inhibitory influence of serotonin (5-HT) on rapid eye movement (REM) sleep in rodents. However, the neuronal networks mediating such influence are mostly unknown, notably in the mouse. This led us to map 5-HT(1A)R mRNA, by in situ hybridization histochemistry (ISHH), and to characterize the neuronal phenotype of 5-HT(1A)R mRNA-positive neurons by dual ISHH and ISHH combined with immunohistochemistry, throughout the mouse rostral brainstem, a pivotal region for the generation of REM sleep and cortical activation. 5-HT(1A)R mRNA was found in most 5-HT neurons in the dorsal raphe (DR), the median raphe (MnR), the B9, and the interpeduncular (IP) nuclei. 5-HT(1A)R mRNA-positive neurons were also identified in individualized clusters of gamma-aminobutyric acid (GABA)ergic neurons in the DR and in neurons of an undetermined phenotype in the MnR. In addition, 1) GABAergic neurons of the ventral portion of Gudden's dorsal tegmental nucleus (DTg), the IP, and the caudal portion of the deep mesencephalic nucleus (DpMe), and 2) glutamatergic neurons scattered in the caudal pontine reticular nucleus (PnC) and densely packed in the internal lateral parabrachial subnucleus (PBil) also expressed 5-HT(1A)R mRNA. In contrast, no specific 5-HT(1A)R-related ISHH signal was generally detected in brainstem cholinergic and catecholaminergic neurons. These results emphasize the role of 5-HT(1A)R as an autoreceptor and the phenotypical heterogeneity of 5-HT(1A)R-expressing neurons within the DR and the MnR in the mouse brain. They also provide a neuroanatomical basis for understanding the influence of 5-HT(1A)R on REM sleep and wakefulness.

Optogenetic activation of cholinergic neurons in the PPT or LDT induces REM sleep

“…In addition, it is possible that serotonin inhibition of cholinergic PPT occurs through other receptor subtypes or that selectivity for the 5-HT 1A receptor by 8-OH-DPAT is lost at high concentrations. Also, 5HT 1A serotonin receptor mRNA has only been found in GABAergic but not cholinergic neurons in the PPT of the mouse (38). Taken together, these data suggest that it is possible Grace et al (20) inhibited GABAergic or glutamatergic REM-on neurons to get an increase in REM sleep, whereas we selectively activated cholinergic REM-on neurons to get an increase in REM sleep.…”

Cellular profile of the dorsal raphe lateral wing sub-region: Relationship to the lateral dorsal tegmental nucleus

“…Serotonergic regulation of NOS cells within this region could influence local circuit operations in response to stressor exposure. Prior investigations have demonstrated weak expression of the excitatory 5HT 2A receptor on cells of the LDT (Fay and Kubin, 2000), but beyond this study the 5HT receptor complement of this structure is not clear (Bonnavion et al, 2010). …”

5-HT1AReceptor-Responsive Pedunculopontine Tegmental Neurons Suppress REM Sleep and Respiratory Motor Activity

“…Although 5-HT 1A receptor mRNA is present in the PPTn (Wright et al, 1995) it was not detected in rodent cholinergic PPTn neurons but was expressed by PPTn GABAergic neurons (Bonnavion et al, 2010). Although a previous study has shown that 5-HT inhibits cholinergic PPTn neurons in vitro (Leonard and Llinás, 1994), (Ϯ)8-OH-DPAT produced no effect in four of four cholinergic neurons tested whereas two neurons were hyperpolarized by (ϩ)8-OH-DPAT.…”