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.

Elucidation of The Behavioral Program and Neuronal Network Encoded by Dorsal Raphe Serotonergic Neurons

“…Brain serotonergic neurons are distributed in a series of predominantly midline raphe nuclei extending from the midbrain to the caudal medulla and projecting widely throughout the brain and spinal cord (Jacobs and Azmitia, 1992). The midbrain dorsal raphe nucleus (DRN) is the largest of the raphe nuclei, and DRN serotonergic neurons project rostrally to provide the predominant serotonergic innervation of the forebrain (Vertes, 1991;Jacobs and Azmitia, 1992;Waselus et al, 2012). Dysregulation of DRN serotonergic neurotransmission has been implicated in many psychiatric illnesses, such as anxiety and depressive disorders (Graeff et al, 1996;Underwood et al, 1999;Lowry et al, 2008).…”

Dorsal raphe nucleus and harm avoidance: A resting-state investigation

“…It has been hypothesized that HA levels and anxiety are directly influenced by activity levels within the ascending serotonergic system, which predominantly originates within the dorsal raphe nucleus (DR; Waselus, Valentino, & Van Bockstaele, 2011). Recent neuroimaging studies support this hypothesis by suggesting that anxiety is regulated by serotonergic activity and that activity within the ascending serotonergic system plays a crucial role in the pathogenesis of anxiety disorders (Vertes & Linley, 2007;Westlye et al, 2011).…”

Connections of the lateral hypothalamic area juxtadorsomedial region in the male rat

“…The above regions, each of which connect with the MRN, are indicated to have involvement in a very wide range of functions, including behavioral state control (dorsal raphe) (Nitz and Siegel, 1997;Millan, 2003;Waselus et al, 2011), parasympathetic control (PSTN) (Goto and Swanson, 2004;Ciriello et al, 2008), gustation and viscerosensation (PB, PSTN) (Spector, 1995;Goto and Swanson, 2004;Geerling and Loewy, 2008), thermogenesis (PB) (Morrison and Nakamura, 2011), orofacial motor control (PSTN, RR, STN, SN) (Goto and Swanson, 2004;Hamani et al, 2004;Mascaro et al, 2009), locomotion (SN, STN) (Blandini et al, 2000;Hamani et al, 2004), motivational value (VTA, LH) (Ikemoto, 2007;Matsumoto and Hikosaka, 2007;Jhou et al, 2009;Ikemoto, 2010), and ingestive behavior and energy homeostasis (anterior BST) (Dong and Swanson, 2003, 2004, 2006a.…”

“…An exhaustive review of the extensive connections of the midbrain reticular formation is beyond the scope of this study; nevertheless, some pertinent observations can be made. At least one previous tracing study appears to show a connection from the MRNm to the MRNp (Steininger et al, 1992), and several previous studies appear to show that the MRNm and/or MRNp connect to several interrelated regions, including the following: output to the ventral tegmental area (VTA) (Geisler and Zahm, 2005;Jhou et al, 2009) and substantia nigra (SN) (Rye et al, 1987;Jhou et al, 2009); input from the medial half of the retrorubral area (RR; termed the mesopontine rostromedial tegmental nucleus) (Jhou et al, 2009), VTA (Becksstead et al, 1979, SN (Beckstead et al, 1979), parasubthalamic nucleus (PSTN; to MRNp) (Goto and Swanson, 2004), dorsal raphe (Vertes, 1991), lateral habenula (LH) (Herkenham and Nauta, 1979; Araki et al, 1988;Steininger et al, 1992;Jhou et al, 2009), and all subdivisions of the anterior BST (especially from the BST rhomboid and dorsomedial nuclei) (Dong and Swanson, 2003, 2004, 2006a; bidirectional connections with the parabrachial nucleus (PB) (Saper and Loewy, 1980;Moga et al, 1990;Steininger et al, 1992) and subthalamic nucleus (mostly MRNp) (Kita and Kita, 2011).The above regions, each of which connect with the MRN, are indicated to have involvement in a very wide range of functions, including behavioral state control (dorsal raphe) (Nitz and Siegel, 1997;Millan, 2003;Waselus et al, 2011), parasympathetic control (PSTN) (Goto and Swanson, 2004;Ciriello et al, 2008), gustation and viscerosensation (PB, PSTN) (Spector, 1995;Goto and Swanson, 2004;Geerling and Loewy, 2008), thermogenesis (PB) (Ikemoto, 2007;Matsumoto and Hikosaka, 2007;Jhou et al, 2009;Ikemoto, 2010), and ingestive behavior and energy homeostasis (anterior BST) …”