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Topographic Organization of Serotonergic Dorsal Raphe Neurons Projecting to the Superior Colliculus in the Mongolian Gerbil (Meriones Unguiculatus)

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Topographic Organization of Serotonergic Dorsal Raphe Neurons Projecting to the Superior Colliculus in the Mongolian Gerbil (Meriones Unguiculatus) THE JOURNAL OF COMPARATIVE NEUROLOGY 413:342–355 (1999) Topographic Organization of Serotonergic Dorsal Raphe Neurons Projecting to the Superior Colliculus in the Mongolian Gerbil (Meriones unguiculatus) SKIRMANTAS JANUSˇ ONIS,1* KATHERINE V. FITE,1 AND WARREN FOOTE,2 1Neuroscience and Behavior Program, University of Massachusetts, Amherst, Massachusetts 01003 2Massachusetts General Hospital, Boston, Massachusetts 02114 ABSTRACT Recent evidence suggests that the dorsal raphe nucleus (DRN) of the brainstem is a collection of neuronal clusters having different neurochemical characteristics and efferent projection patterns. To gain further insight into the neuroanatomic organization of the DRN, neuronal populations projecting to the superior colliculus (SC) were mapped in a highly visual rodent, the Mongolian gerbil (Meriones unguiculatus). Retrograde tracers Fluoro-Gold (FG) or cholera toxin subunit-B (CTB) were injected into the superficial layers of the SC, and serotonin (5-hydroxytryptamine, 5-HT) -positive cells were identified by using immunocyto- chemistry in the FG-injected animals. Based on its projections to the SC, the DRN was divided into five rostrocaudal levels. In the rostral and middle levels of the DRN, virtually all FG-filled cells occurred in the lateral DRN, and 36–55% of 5-HT-immunoreactive (5-HT-ir) cells were also double-labeled with FG. Caudally, FG-filled cells occurred in the lateral, ventromedial, and interfascicular DRN; and 44, 12, and 31% of 5-HT-ir cells, respectively, were also FG-filled. The dorsomedial DRN contained only a small proportion of FG-filled cells at its most caudal level and was completely devoid of FG-filled cells more rostrally. The CTB-injected animals showed a similar distribution of retrogradely labeled cells in the DRN. Topographi- cally, the dorsal tegmental nucleus and the laterodorsal tegmental nucleus appeared to be closely associated with 5-HT-ir cells in the caudal DRN. These results suggest that the lateral DRN and the ventromedial/interfascicular DRN may be anatomically, morphologically, and neurochemically unique subdivisions of the gerbil DRN. J. Comp. Neurol. 413:342–355, 1999. ௠ 1999 Wiley-Liss, Inc. Indexing terms: dorsal raphe nucleus; serotonin (5-HT); visual system; dorsal tegmental nucleus; laterodorsal tegmental nucleus; topography The raphe nuclei of the brainstem contain most of the behaviors (Van Bockstaele et al., 1993; Jacobs and Fornal, serotonin (5-hydroxytryptamine, 5-HT) -producing neu- 1993; Shiromani and Schwartz, 1995; Cassel and Jeltsch, rons in the brain and are subdivided into superior and 1995; Montgomery, 1995; Harvey, 1996). inferior groups. The inferior nuclei send descending projec- Several lines of evidence in different species suggest tions to the brainstem, whereas the four superior, mesence- that the mesencephalic raphe system may be topographi- phalic nuclei (dorsal raphe nucleus, DRN; median raphe cally organized, such that different target nuclei are nucleus, MRN; caudal linear nucleus, CLN; and the B9 group) project to mesencephalic, diencephalic, and telence- phalic targets (Vertes, 1991; Jacobs and Azmitia, 1992; Grant sponsor: Whitehall Foundation; Grant sponsor: UMass-Baystate Vertes et al., 1999). The raphe nuclei are involved in the Collaborative Biomedical Research Program. *Correspondence to: Skirmantas Janusˇonis, Neuroscience and Behavior regulation, modulation, or both, of a broad range of Program, Tobin Hall, University of Massachusetts, Amherst, MA 01003. systems, including sensory and motor functions, arousal E-mail: [email protected] and the sleep-wake cycle, and cognitive and affective Received 1 January 1999; Revised 14 May 1999; Accepted 30 June 1999 ௠ 1999 WILEY-LISS, INC. TOPOGRAPHIC ORGANIZATION OF THE DORSAL RAPHE 343 innervated by anatomically distinct subpopulations of the superior colliculus are serotonergic, whereas, in the raphe neurons. In rats, neurons projecting to the caudate- cat, they seem to be exclusively serotonergic (Mize and putamen and substantia nigra are located in the rostral Horner, 1989). portion of the DRN, whereas neurons projecting to the To provide further insight into the organization of the hippocampus and locus coeruleus are more caudal (Imai et DRN, the present study has focused on the anatomic al., 1986). Neurons projecting to the medial prefrontal localization of serotonergic DRN neurons projecting to the cortex are clustered in the medial DRN (Van Bockstaele et superior colliculus in the Mongolian gerbil. Unlike rats, al., 1993). The anterior thalamic nucleus receives a seroton- gerbils are crepuscular/diurnal in their habits and have a ergic projection from the ventromedial and ventrolateral well-developed visual system (Pietrewicz et al., 1982; part of the ipsilateral DRN (Gonzalo-Ruiz et al., 1995), Susic and Masirevic, 1986; Govardovskii et al., 1992). Also, whereas the piriform cortex is innervated by neurons in a direct projection from the retina to the DRN has been the ventromedial DRN (Datiche et al., 1995). Rat raphe described in gerbils (Fite et al., 1998), which is more neurons innervating the ventricular system appear to be extensive than has been previously reported in rats (Shen distributed in the intermediate dorsomedial DRN (Simp- and Semba, 1994). son et al., 1998). Specific visual nuclei also receive differential projections from anatomically distinct neuronal subpopulations in the MATERIALS AND METHODS mesencephalic raphe system. In hamsters and rats, the Animals MRN projects to the suprachiasmatic nucleus (Meyer- Adult gerbils weighing 60–75 g were anesthetized with a Bernstein and Morin, 1996; Moga and Moore, 1997; Lean- mixture of ketamine (100 mg/kg) and xylazine (10 mg/kg). der et al., 1998), whereas in hamsters, the DRN sends All experiments were approved by the Institutional Ani- axons to the intergeniculate leaflet (Meyer-Bernstein and mal Care and Use Committee of the University of Massa- Morin, 1996). The caudal DRN projects to the pineal gland chusetts at Amherst in accordance with National Insti- in the golden hamster (Leander et al., 1998). In rats, tutes of Health and United States Department of neurons projecting to the visual cortex are clustered in the Agriculture guidelines. ventromedial portion of the rostral two-thirds of the DRN, between the medial longitudinal fasciculi (Waterhouse et Tracer injections al., 1993). Koh et al. (1991) obtained somewhat different By using a 10 µl-Hamilton syringe, a 5% Fluoro-Gold results, with most of the neurons projecting to the visual (FG; Fluorochrome, Inc., Englewood, CO) solution in dis- cortex being localized in the midcaudal region of the DRN. tilled water was pressure-injected stereotaxically into the If the tracer injection was restricted to the superficial and superficial layers of both superior colliculi in three animals intermediate layers of the rat superior colliculus, retro- (0.4–0.5 µl on each side) and into the superficial layers of gradely labeled serotonergic neurons occurred predomi- the right superior colliculus in one animal (0.5 µl). The nantly in the DRN (Beitz et al., 1986). Similar results have stereotaxic coordinates were (with respect to the lambda been obtained in the cat (Mize and Horner, 1989). In rats, point) 1.0 mm anterior, 1.0 mm lateral, and 3.0 mm below injections into the superior colliculus and lateral genicu- the dura. The needle was left in place for at least 10 late nucleus (LGN) retrogradely labeled neurons in the minutes after the injection was complete. After injections, ipsilateral lateral wings of the DRN (Villar et al., 1988; the skull was sealed with bone wax and the incision was Waterhouse et al., 1993). Also, the same serotonergic closed with stainless steel wound clips. neuron may send axonal branches both to the superior In three additional animals, a solution of 2% cholera colliculus and to the lateral geniculate nucleus (Villar et toxin subunit B (CTB low salt; List Biological Laborato- al., 1988). ries, Inc., Campbell, CA) dissolved in 2% dimethyl sulfox- The data on the neurochemical identity of DRN neurons ide was injected bilaterally into the superficial layers of innervating different target nuclei are sparse and incom- the superior colliculi (1.5 µl on each side). The CTB plete. Neurons in the DRN contain a large variety of injections were performed in the same manner as the FG neurotransmitters, some of which may be colocalized. injections. Most DRN neurons produce 5-HT, and 5-HT–immunoreac- tive neurons are conventionally used to delineate the DRN Histology and immunocytochemistry itself. However, it is estimated that approximately 30% of After a 7- to 9-day survival period, both FG- and the neurons in the cat DRN are not serotonergic (Wiklund CTB-injected animals were deeply anesthetized with Nem- et al., 1981). Neurons in the DRN may produce GABA butal. The exposed heart immediately was injected with (Stamp and Semba, 1995), glutamate (Clements and Grant, 0.2 ml of heparin (5,000 USP U/ml), and the animal was 1990), enkephalins (Leger et al., 1986), substance P (SP) perfused with saline followed by 400 ml of chilled 4% (Chan-Palay et al., 1978), and other neurotransmitters paraformaldehyde in 0.1 M phosphate buffer (PB, pH 7.2). and neuromodulators. It is likely that neuronal subpopula- The brains were removed, post-fixed in the same fixative tions revealed by tracing studies may contain a specific overnight at 4°C, and transferred to 30% sucrose in PB. subset of these neurotransmitters. For example, squirrel- The following day, serial, coronal sections were cut on a monkey DRN neurons have been shown to be segregated freezing microtome at 40 µm thickness and were stored in according to their neurotransmitter immunoreactivity cryoprotectant. The plane of sectioning was comparable to (Charara and Parent, 1998). In rats, vasoactive intestinal that shown in the Paxinos and Watson (1998) rat brain polypeptide (VIP)–immunoreactive neurons are located in atlas. the dorsal part of the DRN (Petit et al., 1995). Approxi- CTB immunocytochemistry was performed by using a mately half of rat DRN neurons projecting to the visual highly sensitive protocol (Angelucci et al., 1996). Free- cortex are serotonergic (Koh et al., 1991).
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