The organization of interconnections between the mediodorsal nucleus of the thalamus (MD) and the orbital and medial prefrontal cortex and the agranular insular cortex in the monkey was studied by retrograde and anterograde tracing techniques. In addition to the magnocellular and parvicellular divisions of MD, three other subdivisions can be recognized on the basis of myeloarchitecture, cytoarchitecture, and connections. The first two of these represent a parcellation of the magnocellular division into a lateral, fiber-rich MD pars fibrosa and a medial, poorly myelinated MD pars paramediana adjacent to the midline. The third is a small, poorly myelinated area located at the caudomedial and dorsal edges of MD; it is referred to as MD pars caudodorsalis. MD pars fibrosa is reciprocally interconnected primarily with areas 11, 12 and 13 in the central and lateral part of the orbital cortex. There is a general organization within this projection, with the rostrocaudal axis of the cortex represented from dorsal to ventral in the pars fibrosa, and the mediolateral cortical axis represented from medial to lateral. Cells that project to area 12 also extend laterally into the adjacent pars parvicellularis. MD pars paramediana is more heavily interconnected with the caudal and medial portions of the orbital region, particularly the agranular insular areas and the caudal parts of areas 13 and 14. Cells that project to two caudal areas, 13a and Iad, do not fit with the general organization, in that they are located in the dorsomedial parts of the pars fibrosa and pars paramediana, where they overlap with cells that project to area 14. The pars fibrosa and pars paramediana receive inputs from areas of the ventral forebrain such as the amygdala, piriform (olfactory) cortex, and entorhinal cortex, which project directly to the orbital and agranular insular cortex, as well as from the ventral pallidum. MD pars caudodorsalis is reciprocally interconnected with areas 14, 24, and 32 on the medial surface of the prefrontal cortex. In this part of the nucleus the dorsoventral axis of the medial prefrontal cortex is represented from caudal to rostral in the thalamus. The amygdala and other ventral forebrain structures do not send fibers into the pars caudodorsalis, even though some of these structures project directly to the medial prefrontal cortex. Ventral to MD, and separated from it by the internal medullary lamina, a small region was recognized that appears to be comparable to the anteroventral part of the submedial nucleus previously defined in the rat and cat.(ABSTRACT TRUNCATED AT 400 WORDS)

The medial and central segments of the mediodorsal nucleus of the thalamus (MD) receive afferents from the ventral forebrain, including the piriform cortex, the ventral pallidum, and the amygdaloid complex. Because MD is reciprocally interconnected with prefrontal and agranular insular cortical areas, it provides a relay of ventral forebrain activity to these cortical areas. However, there are also direct projections from the piriform cortex and the amygdala to the prefrontal and agranular insular cortices. This study addresses whether this system has a "triangular" organization, such that structures in the ventral forebrain project to interconnected areas in MD and the prefrontal/insular cortex. The thalamocortical projections of MD have been studied in experiments with injections of retrograde tracers into prefrontal or agranular insular cortical areas. In many of the same experiments, projections from the ventral forebrain to MD and to the prefrontal/insular cortex have been demonstrated with anterograde axonal tracers. The connections of the piriform cortex (PC) with MD and the prefrontal/insular cortex form an organized triangular system. The PC projections to the central and medial segments of MD and to the lateral orbital cortex (LO) and the ventral and posterior agranular insular cortices (AIv and AIp) are topographically organized, such that more caudal parts of PC tend to project more medially in MD and more caudally within the orbital/insular cortex. The central and medial portions of MD also send matching, topographically organized projections to LO, AIv and AIp, with more medial parts of MD projecting further caudally. The anterior cortical nucleus of the amygdala (COa) also projects to the dorsal part of the medial segment of MD and to its cortical targets, the medial orbital area (MO) and AIp. The projections of the basal/accessory basal amygdaloid nuclei to MD and to prefrontal cortex, and from MD to amygdaloceptive parts of prefrontal cortex, are not as tightly organized. Amygdalothalamic afferents in MD are concentrated in the dorsal half of the medial segment. Cells in this part of the nucleus project to the amygdaloceptive prelimbic area (PL) and AIp. However, other amygdaloceptive prefrontal areas are connected to parts of MD that do not receive fibers from the amygdala. Ventral pallidal afferents are distributed to all parts of the central and medial segments of MD, overlapping with the fibers from the amygdala and piriform cortex. Fibers from other parts of the pallidum, or related areas such as the substantia nigra, pars reticulata, terminate in the lateral and ventral parts of MD, where they overlap with inputs from the superior colliculus and other brainstem structures.(ABSTRACT TRUNCATED AT 400 WORDS)

The distribution of presumptive glutamatergic and/or aspartatergic neurons retrogradely labeled following injections of 3HD-aspartate into the mediodorsal nucleus of the thalamus (MD) in the rat was compared to the distribution of neurons labeled by comparable injections of the nonspecific retrograde tracer wheat germ agglutinin conjugated horseradish peroxidase (WGA-HRP). Cells retrogradely labeled by WGA-HRP were found in the prefrontal and agranular insular cortices; in forebrain structures such as the amygdaloid complex, the piriform cortex, the ventral pallidum and the reticular nucleus of the thalamus; and in several different parts of the brainstem, such as the superior colliculus, central grey, and substantia nigra, pars reticulata. Some, but not all, of these projections are presumably glutamatergic and/or aspartatergic. The projections to MD from the prefrontal and agranular insular cortices are well labeled with 3H-D-aspartate, as are projections from the anterior cortical amygdaloid nucleus. Projections from the superior colliculus to the lateral portion of MD also label with this tracer. However, other forebrain and brainstem projections to MD are not labeled with 3H-D-aspartate, and apparently do not use glutamate or aspartate as a neurotransmitter. These include the projections from the basal and accessory basal amygdaloid nuclei, as well as possibly GABAergic projections from the ventral pallidum and the substantia nigra, pars reticulata. A small fraction of the cells in the piriform cortex that project to MD label with 3H-D-aspartate, suggesting that this projection may be heterogeneous. In other experiments, presumptive GABAergic projections to MD were studied by using 3H-GABA as a retrograde tracer. Although in these cases the thalamic reticular nucleus is well labeled, the ventral pallidum and the substantia nigra, pars reticulata are only poorly labeled. Pallidal projections to the ventromedial thalamic nucleus (VM), which are likely to be GABAergic, were also studied with this technique. After injections of 3H-GABA into VM, only a few cells in the substantia nigra, pars reticulata, or entopeduncular nucleus were labeled. This result suggests 3H-GABA has limited usefulness as a transmitter-specific retrograde tracer.

A previous report (Inagaki et al., Brain Res. 260:143-146, '83) suggested that the peptide neurotensin is contained in neurons of the piriform cortex that project to the mediodorsal thalamic nucleus (MD) in young rats. To confirm this, we have studied the distribution of neurotensin-like immunoreactive (NTIR) fibers in MD during development, using three antisera directed at different parts of the neurotensin molecule (Emson et al., J. Neurochem. 38:992-999, '82). In adult rats, NTIR fibers in MD are sparse. They are located mostly at the medial edge of MD and in the adjacent midline thalamic nuclei, with a few poorly stained NTIR fibers in the central part of MD. In contrast, during the first postnatal week, both the medial and central portions of MD stain heavily for neurotensin. The density of NTIR fibers in MD then progressively decreases until the density typical of adult rats is reached, at about 5 weeks. Changes in the distribution of NTIR fibers in MD also occur. In 7-day-old rats, the patches of NTIR fibers in the medial and central parts of MD are contiguous, but by 10 days a sparsely immunoreactive zone forms between them. With maturation, this zone enlarges as the density of neurotensin staining decreases, until the medial contingent of NTIR fibers reaches its adult position at the medial edge of MD. From a comparison of the distribution of NTIR cells with that of cells that can be retrogradely labeled from MD or the midline thalamus, the probable source of the NTIR fibers to the central part of MD is in the deep layer of the piriform cortex, while the NTIR fibers to the medial edge of MD and the midline nuclei may arise from the preoptic region and the medial amygdala. In neonatal rats, neurons are found in the piriform cortex, the preoptic region, and the medial amygdala, which can be double-labeled both for neurotensin and with a retrograde tracer injected into MD and the midline thalamus. Projections of the preoptic region to the thalamus have a distribution similar to that of the medial population of NTIR fibers, whereas the distribution of piriform cortical afferents in central MD matches the central patch of NTIR fibers.

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