Collateralized dorsal raphe nucleus projections: a mechanism for the integration of diverse functions during stress

Abstract

The midbrain dorsal raphe nucleus (DR) is the origin of the central serotonin (5-HT) system, a key neurotransmitter system that has been implicated in the expression of normal behaviors and in diverse psychiatric disorders, particularly affective disorders such as depression and anxiety. One link between the DR-5-HT system and affective disorders is exposure to stressors. Stress is a major risk factor for affective disorders, and stressors alter activity of DR neurons in an anatomically specific manner. Stress-induced changes in DR neuronal activity are transmitted to targets of the DR via ascending serotonergic projections, many of which collateralize to innervate multiple brain regions. Indeed, the collateralization of DR efferents allows for the coordination of diverse components of the stress response. This review will summarize our current understanding of the organization of the ascending DR system and its collateral projections. Using the neuropeptide corticotropin-releasing factor (CRF) system as an example of a stress-related initiator of DR activity, we will discuss how topographic specificity of afferent regulation of ascending DR circuits serves to coordinate activity in functionally diverse target regions under appropriate conditions.

Figure 1. Ascending collateral projections of DR neurons

DR schematics through representative caudal (−8.72mm bregma), middle (−8.00mm bregma), and rostral (−7.30mm bregma) levels. Collateral projections occurring along the midline (in pink) are represented in the schematics on the left. On the right are depicted collaterals known to originate in specific DR subregions (dmDR in blue, vmDR in green, dlDR in orange, or lateral in purple) at the three rostrocaudal levels.

Figure 2. Differential distribution of CRF-immunoreactive fibers in the DR with respect to DR efferent projections

A–C) DR neurons projecting to the lateral septum (green) or caudate-putamen (red) are topographically distributed at different rostrocaudal DR levels (adapted from Waselus et al., 2006). DR-LS neurons are primarily located at caudal DR levels (A). At mid-DR levels (B), both DR-LS and DR-CPu neurons are present, with DR-LS neurons located in the vmDR and DR-CPu neurons mostly in the dmDR. DR-CPu neurons are enriched at rostral levels (C) in both the dmDR and vmDR, with some neurons located laterally, ispilateral to the injection site. Shaded area in gray indicates the location of the medial longitudinal fasciculus (mlf). D–F) The overlap of CRF-immunohistochemistry (black fibers/puncta) with DR-LS (magenta) or DR-CPu (cyan) neurons indicates a distinct distribution of CRF immunoreactivity related to DR neurons projecting to each of these regions, dependent on the rostrocaudal DR level examined. At caudal levels (D), CRF-containing fibers are enriched just below the aqueduct, and also in regions dorsal and lateral to the primarily midline distributed DR-LS neurons. At mid-DR levels, CRF fibers are enriched in the dlDR, where few (if any) DR-LS or DR-CPu neurons are detected (E). At rostral DR levels (F), CRF is enriched in more medial locations, especially in the vmDR where there are a large number of DR-CPu neurons. (*) 4^th ventricle or cerebral aqueduct; (mlf) medial longitudinal fasciculus. Scale bars: D–F=100μm. Schematics in A–C adapted from Paxinos and Watson (Paxinos and Watson, 1997) and (Waselus et al., 2006).

Figure 3. Functional models for complex effects in the DR mediated by a stress-related peptide

Direct and indirect regulation of DR-5-HT neurons can produce opposing behavioral outcomes (active vs passive coping) and differential effects in forebrain regions based on the specific underlying biological substrates. Evidence exists for the inhibition of DR-5-HT circuits (A,B) mediating active coping behaviors (i.e., swimming on Day 1 of forced swim test), as well as the excitation of DR-5-HT circuits (C,D) which mediate passive coping behaviors (i.e., learned helplessness). CRF effects on DR-5-HT neurons can occur by both direct (A,C) or indirect mechanisms involving non-5-HT neurons (B,D). A hypothetical circuit for CRF actions on DR-5-HT neurons in subjects with prior stress exposure is illustrated (E). Elevated CRF levels that occur subsequent to stress act on CRF₂ receptors that have been recruited to the plasma membrane of DR-5-HT neurons, resulting in neuronal activation and increased forebrain release of 5-HT. Elucidating the mechanisms (F), either direct or indirect, by which DR projection neurons (possibly collateral projections) are regulated by CRF_r will contribute to the understanding of stress-related DR activity.