Or in other words that the parabrachial nucleus (BPN) is directly or indirectly affected by serotonin (5-HT) coming from some of the nine serotonin-producing nuclei in the brain.
Off-topic: Of note, serotonin is also produced in the gastrointestinal tract (vast majority of it in the human body in fact) but it doesn't cross the blood brain barrier. And as a result, it doesn't concern us greatly in the brain (though peripheral - non-brain - serotonin may still affect the brain via affarent sensory neuronal pathways).
Details?By this I mean that the PBN most likely expresses both serotonin 1B and 2C receptors (5-HT1BRs and 5-HT2CRs).
The 5-HT1BR mRNA expression is detected in PBN by in-situ hybridisation histochemistry (ISHH) techniques (Bruinvels et al., 1993). cFos is a member of an immediate early gene family of transcription factors. As such it responds quickly and transiently to a vast range of neuronal stimuli. This allows us to use is as a marker of neuronal activation. Co come back to presence of 5-HT1BR in the BPN, more research shows that administration of a selective 5-HT1BR agonist such as CP-94253 induces cFos-immunoreactivity in the PBN (Lee et al., 1998). This further supports presence of functional 5-HT1BRs in the PBN.
Similarly to the 5-HT1BR, 5-HT2CR mRNA expression is detected in many brain regions including the PBN (Molineaux et al., 1989; Mengod et al., 1990), though the literature is not specific about the specific subdivisions of the nucleus; we know that the PBN is traditionally divided into medial and lateral: the formed composed of medial PBN 'proper' and lateral PBN, the latter composed of external, internal, waist, ventral, dorsal, superior and central. We also know that d-fenfluramine is a serotonin releaser and serotonin re-uptake inhibitor but also that it has affinity for all three serotonin 2 receptor subtypes in the order of 2C > 2B > 2A, i.e. with highest affinity for 5-HT2CR (Knight et al., 2004). Furthermore, d-fenfluramine induces cFos-IR in rat lateral and dorsal PBN. From that we can infer that 5-HT2CR is expressed mostly in the lateral and dorsal subdivisions of the lateral PBN.
This was the long way to support the claim that the PBN most likely expresses both 5-HT1BRs and 5-HT2CRs. We also know that the PBN receives axonal projections from the dorsal raphae (Petrov et al., 1992), which synthetise and secrete serotonin. Therefore, we can propose that the PBN may be directly stimulated by serotonin.
As for the indirect stimulation of the PBN by serotonin, we need to delve into the model of serotonin-mediated anorexia via two distinct populations of neurons in the arcuate nucleus of the hypothalamus (ARC). In the ARC, serotonin activates Gq-coupled 5-HT2CRs on proopriomelanocortin(POMC)-expressing neurons and inhibits Gi-coupled 5-HT1BRs on agouti-related peptide(AgRP)-expressing neurons. The product of POMC, alpha-melanocyte stimulating hormone (alpha-MSH), and AgRP are endogenous ligands of melanocortin 4 receptors (MC4Rs); the former activates and the latter inhibits MC4R-expressing neurons. Therefore, upon serotonin stimulation of the two populations of neurons, the release of alpha-MSH and AgRP can be altered, leading to increased likelihood of activation of MC4R-expressing neurons. This ultimately results in the serotonin-mediated anorexia, i.e. reduction of food intake. We know that MC4Rs are essential (though not necessarily the only) for the effect of serotonin on food intake because the serotonin-induced anorexia is abolished in MC4R-knockout mice as it is for that matter in 5-HT1BR- and 5-HT2CR-knockout mice.
We also know that MC4Rs are expressed widely throughout the central nervous system (CNS) and among other sites also in the PBN (Kishi et al., 2003; Liu et al., 2003; Mountjoy et al., 1994). Furthermore, we know that the ARC projects directly to the PBN (Wu et al., 2008; Bromberger et al., 1998; Moga et al., 1990a&b; Sim et al., 1991). From that we can imply that the PBN can be also indirectly affected by serotonin via the ARC 5-HT1BR- and 5-HT2CR-expressing AgRP and POMC neurons.
Significance?From previous research, we already know that in the brain serotonin stimulates 5-HT2CRs on POMC neurons in the ARC, which project to the paraventricular nucleus of the hypothalamus (PVH), where they stimulate MC4R-expressing neurons to ultimately reduce food intake and cause weight reduction. But the above things that I learned today have brought the PBN much more into the picture for me, expanding the complexity of the neural pathways that control appetite and body weight.
