The human cuneate nucleus contains discrete subregions whose neurochemical features match those of the relay nuclei for nociceptive information

Abstract

The present paper is aimed at defining distinctive subdivisions of the human cuneate nucleus (Cu), evident from prenatal to old life, whose occurrence has never been clearly formalized in the human brain, or described in other species so far. It extends our early observations on the presence of gray matter areas that host strong substance P (SP) immunoreactivity in the territory of the human Cu and adjacent cuneate fascicle. Here we provide a three-dimensional reconstruction of the Cu fields rich in SP and further identify those areas by means of their immunoreactivity to the neuropeptides SP, calcitonin gene-related peptide, methionine- and leucine-enkephalin, peptide histidine-isoleucine, somatostatin and galanin, to the trophins glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor, and to the neuroplasticity proteins polysialylated neural cell adhesion molecule and growth-associated protein-43. The presence, density and distribution of immunoreactivity for each of these molecules closely resemble those occurring in the superficial layers of the caudal spinal trigeminal nucleus (Sp5C). Myelin and Nissl stainings suggest that those Cu subregions and the Sp5C superficial layers share a similar histological aspect. This work establishes the existence of definite subregions, localized within the Cu territory, that bear the neurochemical and histological features of sensory nuclei committed to the neurotransmission of protopathic stimuli, including pain. These findings appear of particular interest when considering that functional, preclinical and clinical studies show that the dorsal column nuclei, classical relay station of fine somatic tactile and proprioceptive sensory stimuli, are also involved in pain neurotransmission.

TRPV1-Like Immunoreactivity in the Human Locus K, a Distinct Subregion of the Cuneate Nucleus

“…The results obtained provide evidence for the presence of TRPV1-LI, in the form of a network of nerve fibres and terminals, within a set of distinct subnuclear areas located in the territory of the human cuneate nucleus, which we designate as Locus Kalaris or, briefly, Locus K. In a previous study, we provided a three-dimensional reconstruction of those areas [ 92 ], showing that the Locus K spans longitudinally from the pyramidal decussation to the obex level, first appearing caudally at the level of the cuneate nucleus caudal pole, and being located along the dorsal border of the cuneate nucleus. Similarly to several other markers, such as neuropeptides and molecules indicative of trophism and neuroplasticity [ 70 , 71 , 92 , 93 , 94 , 95 , 96 , 97 ], TRPV1-LI is detectable in the Locus K throughout life, from fetal to adult age. The present study also provides the first description of the morphometric features of the Locus K and a comparative analysis between Locus K and a number of the human medulla oblongata sensory nuclei.…”

“…A similar, though reversed, trend among the same nuclei is maintained with regard to the mean cell density, which shows the highest value in the Locus K followed by the spinal trigeminal nucleus substantia gelatinosa, whereas it lessens in the spinal trigeminal nucleus magnocellular part and solitary nucleus, and is greatly reduced in the cuneate, external cuneate and gracile nuclei. Thus, the concurrent immunohistochemical labelling for TRPV1 and the neuropeptides CGRP and SP (this study), which in turn are codistributed with several other markers [ 92 ], and the outcome of the cyto- and myeloarchitectural analysis, display the remarkable similarity in the neurochemical and structural arrangement between the Locus K and the protopathic sensory nuclei of the human medulla oblongata. Moreover, the pattern of immunolabeling and relative distribution of TRPV1-, CGRP- and SP-LI uphold the possibility that the Locus K is structurally organized in a laminar pattern, likewise the spinal trigeminal nucleus substantia gelatinosa.…”

“…As a general rule, neuropeptide immunoreactive elements are less abundant in dorsal column nuclei than in regions that relay protopathic and nociceptive stimuli, namely the spinal dorsal horn and the spinal trigeminal and solitary nuclei, both in humans [ 70 , 71 , 72 , 73 , 74 , 75 ] and in laboratory animals [ 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ]. Recently, we have formally defined additional distinctive subdivisions of the human dorsal column nuclei, evident from prenatal to old life [ 92 ]. Extending early observations on the presence of gray matter areas that are strongly immunoreactive to SP in the territory of the human cuneate nucleus and adjacent fascicle [ 70 , 71 ], we have shown that the cuneate nucleus fields rich in SP also host neural structures immunoreactive to the neuropeptides CGRP, methionine- and leucine-enkephalin, peptide histidine-isoleucine, somatostatin and galanin, the trophin glial cell line-derived neurotrophic factor, and the neuroplasticity proteins polysialylated neural cell adhesion molecule and growth-associated protein-43 [ 92 ] and references therein.…”

“…Recently, we have formally defined additional distinctive subdivisions of the human dorsal column nuclei, evident from prenatal to old life [ 92 ]. Extending early observations on the presence of gray matter areas that are strongly immunoreactive to SP in the territory of the human cuneate nucleus and adjacent fascicle [ 70 , 71 ], we have shown that the cuneate nucleus fields rich in SP also host neural structures immunoreactive to the neuropeptides CGRP, methionine- and leucine-enkephalin, peptide histidine-isoleucine, somatostatin and galanin, the trophin glial cell line-derived neurotrophic factor, and the neuroplasticity proteins polysialylated neural cell adhesion molecule and growth-associated protein-43 [ 92 ] and references therein. Moreover, the topographical distribution of the structures immunoreactive to all those markers in relation to each other clearly showed that the neurochemistry of those cuneate nucleus gray matter fields, at variance with the remaining nuclear territory, was strikingly similar to that of the spinal cord dorsal horn and the spinal nucleus of the trigeminal nerve [ 70 , 71 , 92 , 93 , 94 , 95 , 96 , 97 ].…”

NADPH diaphorase neuronal dystrophy in gracile nucleus, cuneatus nucleus and spinal trigeminal nucleus in aged rat

“…In general, spinal trigeminal nuclei innervate the viscerotopic representation of the upper alimentary tract in the sensory ganglia of the IXth and Xth cranial nerves and in the subnuclei of the solitary and spinal trigeminal tracts [76]. It still needs to study the correlation between dorsal column nuclei with Spinal trigeminal nucleus [77][78][79]. Afferent inputs of sensory sciatic nerve can be detected in the dorsal lateral medulla in the rat, in which, neuronal tracing reveals a partial overlapping region [80].…”