A PHA-L analysis of ascending projections of the dorsal raphe nucleus in the rat

“…b; Gabbott et al. 2006) and brainstem inputs to AC (Swanson 1982; Foote et al. 1983; Waterhouse et al. 1983; Vertes and Martin 1988; Herrero et al. 1991a; Vertes 1991; Cameron et al. 1995; Morin and Meyer-Bernstein 1999; Vertes et al. 1999; Carr and Sesack 2000a, b; Berridge and Waterhouse 2003).”

“These nuclei have slightly different anatomical targets (Azmitia, 1978; Azmitia & Segal, 1978; Vertes, 1991; Vertes, Fortin, & Crane, 1999), with the dorsal raphe making connections to those areas also innervated by the dopamine system (such as the amygdala and the striatum), and the median raphe…”

“A similar effect was reported for rats with dorsal raphe lesions (Maier et al., 1993), suggesting possible interactions between these two interconnected (e.g., Peyron et al., 1998; Vertes, 1991) structures.”

“These neurons are critical in the mediation of the behavioral sequelae of IS, likely because of the unique projections of these neurons (Vertes, 1991).”

“5) (Kosofsky and Molliver, 1987; Vertes, 1991; Jacobs and Azmitia, 1992; Kazakov et al., 1993).”

“…1982; LeDoux et al., 1991; Turner and Herkenham, 1991; Yasui et al., 1991; Canteras et al., 1992), afferents related to the state of arousal (Vertes, 1991), input about planning of viscero- and somato-motor aspects of behaviors (Price et al., 1987), and cognitive input from several…”

“…et al., 1999; Delfs et al., 2000; Georges and Aston-Jones, 2000), serotonergic inputs from the dorsal nucleus of the raphé (Eiden et al., 1985; Vertes, 1991), and presumably dopaminergic inputs from the ventral tegmental area (Moore, 1978; Hökfelt et al., 1980; Phelix et al., 1992b;…”

“…nuclei (Andén et al., 1964, 1965, 1966; Fallon et al., 1978; Fallon and Moore, 1978; Lindvall and Björklund, 1983; Björklund and Lindvall, 1984; Swanson, 1982; Deutch et al., 1988; Hallanger and Wainer, 1988; Cornwall et al., 1990; Vertes, 1991; Gritti et al., 1997, 2003; Vertes et al., 1999).”

“Direct serotonergic input to the dorsal striatum has been previously described (Pan et al., 2010; Vertes, 1991), but its potential functional roles are only beginning to be explored (Di Matteo et al.”

“Notably, many known targets of DR serotonin neurons (Allen Brain Atlas, 2017; Azmitia and Segal, 1978; Vertes, 1991) were not inner- (E) Sagittal brain atlas image (10 mm) from the Allen Institute that encompasses Ce (C) and (D).”

“Inputs from Thalamus Projections from DR preferentially target thalamic nuclei that are important for cognitive or emotional behaviors, in particular anterior nuclei, mediodorsal nucleus, and the midline and intralaminar nuclei, while avoiding principal nuclei (Vertes, 1991; Vertes et al., 2010).”

“The dorsal raphe nucleus (DRN) projects extensively to several reward-related brain areas, and this structure is themajor source of serotonin (5-HT) in the forebrain (Jacobs and Azmitia, 1992; Vertes, 1991).”

“1, the connections in the model are based on the following studies (Araki et al., 1988; Bester et al., 1997; Cameron et al., 1995a,b; Chiba and Murata, 1985; Cornwall et al., 1990; Dong and Swanson, 2003, 2006b; Eberhart et al., 1985; Gaykema et al., 1990, 1991a,b; Goto et al., 2005; Gritti et al., 1994; Groenewegen e…”

“…locus coeruleus (Loughlin et al., 1982; Jones and Yang; 1985; Jones and Cuello, 1989), the serotoninergic dorsal and median raphe nuclei (Sobel and Corbett, 1984; Vertes, 1991; Tillet, 1992), the dopaminergic neurons in the ventral periaqueductal gray matter (Lu J. and Saper C.B., unpubl. obs.)”

“This small population of neurons (approximately 9000 in the mouse dorsal raphe; Ishimura et al., 1988) projects to almost the entire forebrain (Azmitia and Segal, 1978; Moore et al., 1978; Steinbusch, 1981; O’Hearn and Molliver, 1984; Vertes, 1991; Gagnon and Parent, 2014).”

“All divisions of MD receive common inputs from several sites including the reticular nucleus of thalamus, the mesopontine reticular formation, PPT, LDT, LC and the dorsal and median raphe nuclei of the brainstem (Groenewegen, 1988; Vertes, 1991; Vertes et al., 1999; Krout et al., 2002).”

“Fear conditioning taxes a well-defined neural circuit within the amygdala, which in turn interacts with the hippocampus, anterior cingulate, or the PFC, depending on the elements of the conditioning session and the stage of memory processing (Zelikowsky et al., 2014).”

“Furthermore, the DRN is a primary source of 5-HT projections to regions implicated in affective and behavioral responses (Imai et al., 1986; Ma et al., 1991; Vertes, 1991; Kazakov et al., 1993).”

“, 2000], which in turn sends serotoninergic projections to most of the cerebral cortex [Conrad et al., 1974; Steinbusch, 1984; Vertes, 1991].”

“They include the locus coeruleus (Jones and Yang, 1985), dorsal nucleus of the raphé (Eiden et al., 1985; Vertes, 1991; Phelix et al., 1992), ventral tegmental area (Moore, 1978; Hökfelt et al., 1980; Phelix et al., 1992; Freedman and Cassell, 1994), and dorsal lateral hypothalamic area (Peyron…”

“…of the SP=NK1 receptor system with monoaminergic sys- tems: In the dorsal raphe nucleus, the major source of 5-HT projections to forebrain areas (Vertes, 1991), both SP immunoreactive cells=fibers (Warden and Young, 1988; Nakaya et al., 1994) as well as NK1 receptors have been described…”

“…projections from the DR and PAG to the EAc have been documented with retrograde (Ottersen, 1981; Weller and Smith, 1982; Grove, 1988; Rizvi et al., 1991; Shammah-Lagnado et al., 1999) and anterograde tracing techniques (Eberhart et al., 1985; Rizvi et al., 1991; Vertes, 1991; Cameron et al., 1995).”

“The MR serotonin neurons project to structures near the midline, whereas the DR serotonin neurons target more lateral regions (Jacobs and Azmitia, 1992; Muzerelle et al., 2016; Vertes, 1991; Vertes et al., 1999).”

“More precise anterograde anatomical tracing, obtained with phaseolus (Vertes 1991; Vertes et al. 1999), allowed to describe the main terminal domains of the DR and the MR, and indicated the complementarity of these innervations.”

“…each of the REM sleep sign-generators in the brainstem (Bobillier et al., 1976;Morrison and Foote, 1986;Parent et al., 1981;Pierce et al., 1976;Semba and Fibiger, 1992;Steinbusch, 1981;Steininger et al., 1992;Vertes, 1991;Vertes et al., 1999;Vertes and Kocsis, 1994;Vertes and Martin, 1988).”

“…systems of the brainstem and diencephalon, prominently including orexin/ hypocretin cells of the lateral hypothalamus (Chen and Su, 1990; Vertes, 1991; Freedman and Cassell, 1994; Otake and Ruggiero, 1995; Peyron et al., 1998; Cutler et al., 1999; Vertes et al., 1999; Bhatnagar et al.,…”

“…noradrenergic fibers probably arise at least in part from the locus ceruleus (Jones and Yang, 1985); serotonergic fibers arise from the raphé nuclei (Vertes, 1991; Vertes et al., 1999); histaminergic fibers arise from the tuberomammillary nucleus (Inagaki et al., 1988); hypocretin/orexin fibers…”

“Finally, previous reports have also demonstrated significant projections from the dorsal raphe nucleus (Vertes, 1991; Morin and Meyer-Bernstein, 1999; Goto et al., 2001; Krout et al., 2002), median raphe nucleus (Vertes and Martin, 1988; Vertes et al., 1999; Morin and Meyer-Bernstein, 1999), LDT…”

“For example, recent studies [40,43,44] have demonstrated that the terminations of projections of the DRN include sites that are believed to mediate the linkage between vestibular dysfunction and anxiety disorders [23], such as the medial and lateral PBN, the infralimbic, frontal, and insular cortex, the bed nucleus of…”

“…which contain the majority of 5-HT neurones, give rise to serotonergic projections that are widely distributed throughout the brain notably in areas critical for cognitive functions such as septum, frontal cortex, temporal cortex and the hippocampal formation (Vertes, 1991; Vertes et al., 1999).”

“MR and DR project to many of the same forebrain regions but also have distinct projections; additionally DR subfields project to different brain regions (Azmitia and Segal, 1978; Datiche et al., 1995; Imai et al., 1986a, 1986b; Johnson et al., 2008; Lowry, 2002; Vertes, 1991; Vertes et al., 1999; Vertes and Martin, 19…”

“5-HT neurons in the dorsal raphé nucleus project to thalamic, cortical, and other structures involved in sleep/wake transitions (7), and 5-HT can convert the firing patterns of thalamic reticular and thalamocortical neurons in slices from a bursting pattern seen in NREM to a tonic single-spiking pattern seen in W (8).”

“…tegmental and adjacent retrorubral areas (Deutch et al., 1988; Hasue and Shammah-Lagnado, 2002), 5) serotonergic neurons of the raphé nuclei (Vertes, 1991) and noradrenergic neurons of the locus ceruleus and nucleus of the solitary tract (Swanson and Hartman, 1975; Ricardo and Koh, 1978;…”

“Reward processing in the DRN: outputs Among the widespread efferent projections of the DRN (Lavoie and Parent, 1990; Vertes, 1991), those to the basal ganglia structures, especially, the striatum and the substantia nigra (van der Dopamine DRN large>small”

“In the brainstem, tracer studies in the rat have shown that the rostral and caudal portions of the dorsal raphé send projections that innervate the PPN (Vertes, 1991), where they preferentially target non-cholinergic neurons in the caudal PPN (Steininger et al., 1997).”

“1994) are the dorsal and median raphe nuclei, the source nuclei of forebrain serotonergic innervation (Azmitia and Segal 1978; Kellar et al. 1977; Vertes 1991).”

“Our PHA-L evidence also indicates that the caudal region of the dorsal raphé nucleus embedded in the pontine periventricular gray has a distinct though somewhat complementary projection pattern to that observed for rostral areas of the nucleus lying in the PAG (Vertes, 1991).”

“DRN efferents target the striatum at caudal to midlevels (Vertes, 1991).”

“…may be attributable to sampling of more rostral dorsal raphe serotonergic neurons (27.5 mm Bregma; Kirby et al., 2000) that are known to project preferentially to neocortical areas (Vertes, 1991), as well as to the substantia nigra and caudate putamen (Steinbusch et al., 1981; Imai et al., 1986).”

“Finally, it is noteworthy that anterogradely labeled fibers were sparse in other brain regions that typically exhibit substantial labeling from larger Pha-L injections into the DR (Vertes, 1991; Vertes and Kocsis, 1994), suggesting that injections Figure 3 NK1 receptor and CRF immunolabeling define the dorsomedial DR.”

“Serotonergic neurons in the dorsal raphe nucleus, as well as noradrenergic neurons in the brainstem and the locus coeruleus are important afferents for the regulation of hypothalamic CRH secretion (Cunningham et al., 1990; Vertes, 1991; Valentino et al., 1993; Calogero, 1995; Dayas et al., 2001).”

“…of efferent projections arising from the DR. Anatomical studies have provided evidence for an encephalotopy within the DR, such that different brain regions are targeted by distinct cell groups within the DR (Kohler and Steinbusch, 1982; O’Hearn and Molliver, 1984; Imai et al., 1986; Vertes, 1991).”

“It has been shown that the DRN sends projections tomesolimbic circuitry, with the VTA receiving notably stronger innervation than nucleus accumbens (Vertes, 1991).”

“Vertes (1991) used the retrograde tracer PHA-L in rats and DeVito et al. (1980) used the anterograde tracer HRP in macaque monkeys.”

“(43), and I, from Vertes (46), 2000, 1991, with permission of Wiley-Liss, Inc.”

“The efferent projection targets of the DRN neurons that are synaptically innervated by the PFC are not known but may include the PFC itself, other cortical areas, the nucleus accumbens, the amygdala, and other subcortical regions innervated by the DRN (Vertes, 1991).”

“For example, under conditions of acute administration, opioids including morphine depolarize 5-HT DRN neurons (Jolas and Aghajanian, 1997) and elevate extracellular levels of 5-HT in the DRN as well as those areas of the forebrain that are innervated at least in part by 5-HT fibers from the DRN (i.e. NAc, amygdala, fr…”

“Furthermore, beaded serotonergic axons with large, spherical varicosities are also found in hippocampus; median raphe nucleus predominantly innervate the stratum lacunosum moleculare of the CA1 and CA3 regions and the dentate hilus [26, 28, 30, 31].”

“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 (R. P. Vertes, 1991; B. L. Jacobs and E. C. Azmitia, 1992; M. Waselus et al., 2012).”

“Different groups of these neurons supply the ventral and dorsal hippocampus and the medial septum, which innervates the hippocampus extensively (Azmitia, 1981; Köhler and Steinbusch, 1982; Imai et al., 1986; Vertes, 1991; Acsady et al., 1996).”

“…nuclei, median raphe, parabrachial nucleus, cuneiform nucleus, oral and caudal pontine reticular nuclei and the nucleus of the solitary tract (Vertes, 1991; Oakman et al., 1995; Charara et al., 1996; Zahm et al., 2001; Geisler and Zahm, 2005; Geisler et al., 2006; Geisler et al., 2007;…”