SUBCORTICAL AFFERENTS TO THE LATERAL MEDIODORSAL THALAMUS IN CYNOMOLGUS MONKEYS S. L. ERICKSON, a * D. S. MELCHITZKY b AND D. A. LEWIS a,b a Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, USA b Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA Abstract—The mediodorsal (MD) nucleus of the thalamus has long been known to provide the principal source of subcor- tical input to the primate prefrontal cortex, as well as to other areas of the frontal lobe that are thought to contribute to higher-order cognitive functions. In this study, we used in- jections of retrograde tracers in the lateral portion of the monkey MD to assess the locations of labeled cells in sub- cortical structures. Three main patterns were identified in the distribution of subcortical connections. We found that the claustrum, superior colliculus and ventral midbrain regions were heavily labeled in the cases with injections in caudoven- tral MD. In these cases, labeled cells were also found in either the periaqueductal gray or zona incerta, depending on the specific case. In one case with an injection in anterodorsal MD, labeled cells were most numerous in the structures of the ventral midbrain, especially the ventral tegmental area. Finally, the claustrum and superior colliculus contained the largest percentage of labeled subcortical cells in cases with injections in ventrolateral MD. These three patterns of sub- cortical label corresponded to three equally distinctive trends in the distribution of MD connections with the cortex in these same cases [J Comp Neurol 473 (2004) 107]. Very few labeled cells were found in other areas such as the amygdala, globus pallidus and deep cerebellar nuclei, suggesting that path- ways leading from these structures to dorsolateral and dor- somedial frontal cortices are not likely to include the lateral divisions of MD. In concert, these findings show that partic- ular locales within lateral MD receive distinct profiles of sub- cortical afferents, and project into specific neocortical do- mains, suggesting that these different sites within lateral MD may participate in functionally distinct circuits of information processing. © 2004 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: ventral anterior nucleus, superior colliculus, sub- stantia nigra, claustrum, periaqueductal gray, ventral teg- mental area. The mediodorsal nucleus (MD) of the thalamus forms con- nections with most regions of the frontal cortex (FC) in primates (Giguere and Goldman-Rakic, 1988; Ray and Price, 1993; Erickson and Lewis, 2004), including areas that contribute to the selection, sequencing and execution of complex behavioral tasks and the motivational factors that impact on these processes (Fuster, 1997). Lesions of MD significantly increase the number of trials to reach criterion in delayed alternation and delayed response tasks (Isseroff et al., 1982), while transient inactivation of the nucleus results in errors in saccade vector calculation in a multistep saccade task (Sommer and Wurtz, 2002). Unit recording studies in MD showed that cellular activity is modified during different phases of a delayed response task, including visual cue presentation, delay and re- sponse (Fuster and Alexander, 1973). In addition, several more recent studies demonstrated neuronal activity in MD related to both visually and memory-guided saccades (Schlag and Schlag-Rey, 1986; Tanibuchi and Goldman- Rakic, 2003; Wyder et al., 2003). Previous anatomical studies demonstrated that robust inputs to MD arise from broadly distributed areas of the FC (De Vito and Smith, 1964; Nauta, 1964; Giguere and Goldman-Rakic, 1988; Siwek and Pandya, 1991; McFar- land and Haber, 2002; Erickson and Lewis, 2004). De- scending, corticothalamic connections are generally con- sidered to modulate a thalamic cell’s responsiveness to its principal, ascending inputs (Steriade et al., 1997). How- ever, a functional study that examined the role of prefrontal activity on the activity of MD neurons found that cooling the prefrontal cortex reversibly diminished the changes in cel- lular activity associated with delayed response perfor- mance (Alexander and Fuster, 1973). These authors con- cluded that task-related activity in MD was due to activa- tion of prefrontal units that project to MD. Indeed, it has been suggested that corticothalamic projections serve as “driving” inputs to MD based, in part, on the morphological resemblance of these terminals to the ascending afferents to principal relay thalamic nuclei (Miller, 1996; Sherman and Guillery, 1996; Guillery and Sherman, 2002). These reports minimized the significance of the subcortical affer- ents to MD (Sherman and Guillery, 1996; Fuster, 1997; Smith and Sherman, 2002), despite the fact that the sub- cortical afferents to the nucleus, particularly its lateral sub- divisions, remain largely unexplored in the monkey. *Correspondence to: S. L. Erickson, Department of Neurobiology, Uni- versity of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA. Tel: +1-412-648-9556, fax: +1-412-648-1441. E-mail address: ericksonsl@upmc.edu (S. L. Erickson). Abbreviations: AP, anteroposterior; CTb, cholera toxin b; FC, frontal cortex; GPi, globus pallidus internal segment; IP, interpeduncular nu- cleus; MD, mediodorsal nucleus; MDmf, mediodorsal thalamic nu- cleus, multiform division; MDpc, mediodorsal thalamic nucleus, parvi- cellular division; RRA, retrorubral area; SC, superior colliculus; SNc, substantia nigra pars compacta; SNcd, substantia nigra dorsal com- pacta; SNlat, substantia nigra pars lateralis; SNr, substantia nigra pars reticulata; VA, ventral anterior; VAmc, ventral anterior thalamic nu- cleus, magnocellular division; VTA, ventral tegmental area; ZI, zona incerta. Neuroscience 129 (2004) 675– 690 0306-4522/04$30.00+0.00 © 2004 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2004.08.016 675