Expression of serotonin 1A and 2A receptors in molecular- and projection-defined neurons of the mouse insular cortex

Abstract

The serotonin (5-HT) system is the target of multiple anxiolytics, including Buspirone, which is a partial agonist of the serotonin 1A receptor (5-HT1A). Similarly, ligands of the serotonin 2A receptor (5-HT2A) were shown to alter anxiety level. The 5-HT1A and 2A receptors are widely expressed across the brain, but the target region(s) underlying the influence of those receptors on anxiety remain unknown. Interestingly, recent studies in human and non-human primates have shown that the 5-HT1A and 5-HT2A binding potentials within the insular cortex (insula) are correlated to anxiety. As an initial step to define the function of 5-HT transmission in the insula, we quantified the proportion of specific neuronal populations of the insula expressing 5-HT1A or 5-HT2A. We analyzed seven neural populations, including three defined by a molecular marker (putative glutamate, GABA or parvalbumin), and four defined by their projections to different downstream targets. First, we found that more than 70% of putative glutamatergic neurons, and only 30% of GABAergic neurons express the 5-HT1A. Second, within insular projection neurons, 5-HT1A is highly expressed (75–80%) in the populations targeting one sub-nuclei of the amygdala (central or basolateral), or targeting the rostral or caudal sections of the lateral hypothalamus (LH). Similarly, 70% of putative glutamatergic neurons and only 30% of insular GABAergic neurons contain 5-HT2A. Finally, the 5-HT2A is present in a majority of insula-amygdala and insula-LH projection neurons (73–82%). These observations suggest that most glutamatergic neurons can respond to 5-HT through 5-HT1A or 5-HT2A in the insula, and that 5-HT directly affects a limited number of GABAergic neurons. This study defines a molecular and neuroanatomical map of the 5-HT system within the insular cortex, providing ground knowledge to identify the potential role of serotonergic modulation of selective insular populations in anxiety.

Synthesis, docking studies, and pharmacological evaluation of 2‐hydroxypropyl‐4‐arylpiperazine derivatives as serotoninergic ligands

“…numerous biological effects of the endogenous ligand; serotonin is mainly involved in impulsivity and alcoholism, and in the different phases of sleep, sexual behavior, appetite control, thermoregulation, and cardiovascular function. [2] In addition, it is already known that 5-HT plays a fundamental role as a growth factor in several types of nontumoral and tumoral cells, differentiation, and gene expression also related to oncogenes. [3] Consequently, pharmacological manipulation of the 5-HT system is assumed to have therapeutic potential, and therefore it has been the subject of intense research.…”

Cannabinoids regulate an insula circuit controlling water intake

“…Importantly, there was no expression of CB 1 receptors in the control mice ( Figures S2B-S2F ). These data reveal that CB 1 receptors on axonal terminals of IC neurons are highly expressed in the BLA, but not in the CeA, although IC neurons intensively project to both BLA and CeA [12, 13, 30–32].…”

“…Both aIC and pIC neurons send projections to the BLA [30][31][32]. A recent study reported that CB1 receptors are expressed in IC glutamatergic neurons [42], but the distribution of CB1 receptors in axonal terminals of IC neurons is unclear.…”

“…Since CB1 receptors are mainly located at the presynaptic terminals [26][27][28][29] and IC sends intense projections to BLA and CeA [12,13,[30][31][32], we next examined the distribution of insula CB1 receptors on axonal terminals in the amygdala including the BLA and CeA. To observe CB1 receptors of IC neurons specifically, we took advantage of a rescue approach to selectively re-express CB1 receptors in IC cells in Stop-CB1 mutant mice, where CB1 receptor expression is prevented by a "floxed-stop" cassette, except in the presence of the Cre recombinase [16,33,34] (Figure 2A).…”

Action mechanism of Roman chamomile in the treatment of anxiety disorder based on network pharmacology

“…5-HT2A is mainly located in hippocampal glutamate neurons. The activation of 5-HT2A receptor increases anxiety behavior in stress response to environmental changes (Ju et al, 2020). It is known from the KEGG results that the drug participates in the 5-HT pathway, 5-HT is considered to be an important substance that induces anxiety, and it is an important detection indicator in anxiety diseases (Bellia et al, 2020;Wang et al, 2019).…”