Carotid Body: The Primary Peripheral Arterial Chemoreceptor.

The carotid body (CB) is a polymodal chemosensory organ that plays an essential role in initiating respiratory and cardiovascular adjustments to maintain blood gas homeostasis. Much of the available evidence suggests that chronic hypoxia induces marked morphological and neurochemical changes within the CB, but the detailed molecular mechanisms by which these affect the hypoxic chemosensitivity still remain to be elucidated. Dysregulation of the CB function and altered oxygen saturation are implicated in various physiological and pathophysiological conditions. Knowledge of the morphological and functional aspects of the CB would improve our current understanding of respiratory and cardiovascular homeostasis in health and disease.

History and Recent Progress in Carotid Body Studies.

This chapter describes the history of the carotid body (CB) and the subsequent research on its structure and function. The chronological development of ideas about its anatomical structure as a ganglion, the first descriptions of its glandular nature as a ball of highly vascular tissue (glomus), the discovery of its neural crest origin and relevant embryological views as a true paraganglion toward a more conclusive understanding of its sensory nature as a chemoreceptor for chemical changes in blood have been consistently demonstrated. The knowledge of the CB neurochemistry, physiology and pathophysiology has progressed immensely in the past century and a large and compelling body of evidence for the presence of a neurogenic niche in the CB has accumulated over the last two decades, thus underlying its function and possibility for the development of cell replacement therapies.

General Morphology of the Mammalian Carotid Body.

The carotid body (CB) is the main peripheral arterial chemoreceptor that registers the levels of pO2, pCO2 and pH in the blood and responds to their changes by regulating breathing. It is strategically located in the bifurcation of each common carotid artery. The organ consists of "glomera" composed of two cell types, glomus and sustentacular cells, interspersed by blood vessels and nerve bundles and separated by connective tissue. The neuron-like glomus or type I cells are considered as the chemosensory cells of the CB. They contain numerous cytoplasmic organelles and dense-cored vesicles that store and release neurotransmitters. They also form both conventional chemical and electrical synapses between each other and are contacted by peripheral nerve endings of petrosal ganglion neurons. The glomus cells are dually innervated by both sensory nerve fibers through the carotid sinus nerve and autonomic fibers of sympathetic origin via the ganglioglomerular nerve. The parasympathetic efferent innervation is relayed by vasomotor fibers of ganglion cells located around or inside the CB. The glial-like sustentacular or type II cells are regarded to be supporting cells although they sustain physiologic neurogenesis in the adult CB and are thus supposed to be progenitor cells as well. The CB is a highly vascularized organ and its intraorgan hemodynamics possibly plays a role in the process of chemoreception.

Structural Plasticity of the Carotid Body.

The mammalian carotid body (CB) exhibits considerable plasticity of its structure during development and aging and as a consequence of environmental, metabolic and inflammatory stimuli. The structural changes during maturation include an enlargement of the total and vascular volume of the CB. Conversely, aging results in a reduction in the number and volume of glomus cells with progressive cellular degeneration and an apparent increase in the surrounding connective tissue. Age-related structural alterations are similar to those during chronic hypoxia. Long-term hypoxic exposure and sodium nitrate treatment enlarge several-fold the size of the rat CB causing glomus cell hypertrophy and hyperplasia, and evoke changes in its vascular structure, inducing marked vasodilation and neovascularization. In humans, such structural CB adaptation responses to prolonged hypoxia occur during acclimatization to high altitudes. On the other hand, the hyperoxic CB is significantly smaller than those of age-matched normoxic controls. Morphological alterations in the CB in both hypertensive animals and humans are characterized by a slightly enlarged parenchyma without apparent vascular expansion and/or dilation. The CB structural plasticity depends on the existence of a population of multipotent neural crest-derived stem cells, which are activated during hypoxia to proliferate and differentiate into new both neuronal (glomus) and vascular cell types.

Mechanisms of Chemosensory Transduction in the Carotid Body.

The mammalian carotid body (CB) is a polymodal chemoreceptor, which is activated by blood-borne stimuli, most notably hypoxia, hypercapnia and acidosis, thus ensuring an appropriate cellular response to changes in physical and chemical parameters of the blood. The glomus cells are considered the CB chemosensory cells and the initial site of chemoreceptor transduction. However, the molecular mechanisms by which they detect changes in blood chemical levels and how these changes lead to transmitter release are not yet well understood. Chemotransduction mechanisms are by far best described for oxygen and acid/carbon dioxide sensing. A few testable hypotheses have been postulated including a direct interaction of oxygen with ion channels in the glomus cells (membrane hypothesis), an indirect interface by a reversible ligand like a heme (metabolic hypothesis), or even a functional interaction between putative oxygen sensors (chemosome hypothesis) or the interaction of lactate with a highly expressed in the CB atypical olfactory receptor, Olfr78, (endocrine model). It is also suggested that sensory transduction in the CB is uniquely dependent on the actions and interactions of gaseous transmitters. Apparently, oxygen sensing does not utilize a single mechanism, and later observations have given strong support to a unified membrane model of chemotransduction.

Neurochemical Plasticity of the Carotid Body.

A striking feature of the carotid body (CB) is its remarkable degree of plasticity in a variety of neurotransmitter/modulator systems in response to environmental stimuli, particularly following hypoxic exposure of animals and during ascent to high altitude. Current evidence suggests that acetylcholine and adenosine triphosphate are two major excitatory neurotransmitter candidates in the hypoxic CB, and they may also be involved as co-transmitters in hypoxic signaling. Conversely, dopamine, histamine and nitric oxide have recently been considered inhibitory transmitters/modulators of hypoxic chemosensitivity. It has also been revealed that interactions between excitatory and inhibitory messenger molecules occur during hypoxia. On the other hand, alterations in purinergic neurotransmitter mechanisms have been implicated in ventilatory acclimatization to hypoxia. Chronic hypoxia also induces profound changes in other neurochemical systems within the CB such as the catecholaminergic, peptidergic and nitrergic, which in turn may contribute to increased ventilatory and chemoreceptor responsiveness to hypoxia at high altitude. Taken together, current data suggest that complex interactions among transmitters markedly influence hypoxia-induced transmitter release from the CB. In addition, the expression of a wide variety of growth factors, proinflammatory cytokines and their receptors have been identified in CB parenchymal cells in response to hypoxia and their upregulated expression could mediate the local inflammation and functional alteration of the CB under hypoxic conditions.

Carotid Body Dysfunction and Mechanisms of Disease.

Emerging evidence shows that the carotid body (CB) dysfunction is implicated in various physiological and pathophysiological conditions. It has been revealed that the CB structure and neurochemical profile alter in certain human sympathetic-related and cardiometabolic diseases. Specifically, a tiny CB with a decrease of glomus cells and their dense-cored vesicles has been seen in subjects with sleep disordered breathing such as sudden infant death syndrome and obstructive sleep apnea patients and people with congenital central hypoventilation syndrome. Moreover, the CB degranulation is accompanied by significantly elevated levels of catecholamines and proinflammatory cytokines in such patients. The intermittent hypoxia stimulates the CB, eliciting augmented chemoreflex drive and enhanced cardiorespiratory and sympathetic responses. High CB excitability due to blood flow restrictions, oxidative stress, alterations in neurotransmitter gases and disruptions of local mediators is also observed in congestive heart failure conditions. On the other hand, the morpho-chemical changes in hypertension include an increase in the CB volume due to vasodilation, altered transmitter phenotype of chemoreceptor cells and elevated production of neurotrophic factors. Accordingly, in both humans and animal models CB denervation prevents the breathing instability and lowers blood pressure. Knowledge of the morphofunctional aspects of the CB, a better understanding of its role in disease and recent advances in human CB translational research would contribute to the development of new therapeutic strategies.

Stem Cell Niche in the Mammalian Carotid Body.

Accumulating evidence suggests that the mammalian carotid body (CB) constitutes a neurogenic center that contains a functionally active germinal niche. A variety of transcription factors is required for the generation of a precursor cell pool in the developing CB. Most of them are later silenced in their progeny, thus allowing for the maturation of the differentiated neurons. In the adult CB, neurotransmitters and vascular cytokines released by glomus cells upon exposure to chronic hypoxia act as paracrine signals that induce proliferation and differentiation of pluripotent stem cells, neuronal and vascular progenitors. Key proliferation markers such as Ki-67 and BrdU are widely used to evaluate the proliferative status of the CB parenchymal cells in the initial phase of this neurogenesis. During hypoxia sustentacular cells which are dormant cells in normoxic conditions can proliferate and differentiate into new glomus cells. However, more recent data have revealed that the majority of the newly formed glomus cells is derived from the glomus cell lineage itself. The mature glomus cells express numerous trophic and growth factors, and their corresponding receptors, which act on CB cell populations in autocrine or paracrine ways. Some of them initially serve as target-derived survival factors and then as signaling molecules in developing vascular targets. Morphofunctional insights into the cellular interactions in the CB stem cell microenvironment can be helpful in further understanding the therapeutic potential of the CB cell niche.

Neurochemical Anatomy of the Mammalian Carotid Body.

Carotid body (CB) glomus cells in most mammals, including humans, contain a broad diversity of classical neurotransmitters, neuropeptides and gaseous signaling molecules as well as their cognate receptors. Among them, acetylcholine, adenosine triphosphate and dopamine have been proposed to be the main excitatory transmitters in the mammalian CB, although subsequently dopamine has been considered an inhibitory neuromodulator in almost all mammalian species except the rabbit. In addition, co-existence of biogenic amines and neuropeptides has been reported in the glomus cells, thus suggesting that they store and release more than one transmitter in response to natural stimuli. Furthermore, certain metabolic and transmitter-degrading enzymes are involved in the chemotransduction and chemotransmission in various mammals. However, the presence of the corresponding biosynthetic enzyme for some transmitter candidates has not been confirmed, and neuroactive substances like serotonin, gamma-aminobutyric acid and adenosine, neuropeptides including opioids, substance P and endothelin, and gaseous molecules such as nitric oxide have been shown to modulate the chemosensory process through direct actions on glomus cells and/or by producing tonic effects on CB blood vessels. It is likely that the fine balance between excitatory and inhibitory transmitters and their complex interactions might play a more important than suggested role in CB plasticity.

Carotid Body and Cell Therapy.

During the past decade, the carotid body (CB) has been considered an innovative therapeutic target for the treatment of certain cardiorespiratory and metabolic diseases most of which are sympathetically mediated. It has recently been revealed that CB stem cells provide new target sites for the development of promising cell-based therapies. Specifically, generation of CB progenitors in vitro which can differentiate into functionally active glomus cells may be a useful procedure to produce the cell mass required for replacement cell therapy. Due to their dopaminergic nature, adult glomus cells can be used for an intrastriatal grafting in neurodegenerative brain disorders including Parkinson's disease. The beneficial effect of throphic factors such as glial cell-derived neurotrophic factor synergistically released by the transplanted cells then enables the transplant to survive. Likewise, intracerebral administration of CB cell aggregates or dispersed cells has been tested for the treatment of an experimental model of stroke. The systematic clinical applicability of CB autotransplants following glomectomy in humans is under investigation. In such autotransplantation studies, cell aggregates from unilaterally resected CB might be used as autografts. In addition, stem cells could offer an opportunity for tissue expansion and might settle the issue of small number of glomus cells available for transplantation.

The Carotid Body: A Tiny Structure with Many Roles.

Over the last century, the structure of the mammalian carotid body (CB) has repeatedly been studied, and our present understanding of its normal morphology is comprehensive. It has been demonstrated that the CB has an intricate internal structure and a remarkable ability to release a wide variety of neurotransmitters and neuromodulators in response to different chemical stimuli. The advances in modern cellular/molecular biological methods and newly developed single-cell electrophysiological techniques have provided an additional insight into the precise working mechanisms and roles of the CB in health and disease. Emerging experimental evidence has also shown that the CB exhibits an extraordinary structural and functional plasticity as a consequence of various environmental stimuli. Lately, the CB has attracted much clinical interest because its dysfunction relates to a number of cardiovascular and respiratory disorders. Expanding knowledge about the pathophysiological mechanisms that alter the CB cell function would certainly help to facilitate the translational research. Recent progress in cell fate experiments has further revealed that the CB is a neurogenic center with a functionally active germinal niche. This may lead to the development of promising new candidate therapies to combat these diseases and improve the quality of human life. Thus, the CB has entered the twenty-first century with its actual designation.

Sexual dimorphism in shape and size of the neurocranium.

Sex identification is a primary step in forensic analysis of skeletal remains. The accuracy of sex estimation methods greatly depends on the sexual dimorphism manifested by the target anatomical region. The study aims to evaluate the sexual dimorphism in shape and size of the neurocranium and to compare the potential of shape and size of different cranial regions to classify correctly the male and female crania. The study was carried out on computed tomography images of 373 Bulgarian adults (161 males and 212 females). Three-dimensional coordinates of 32 landmarks were acquired. The landmarks were arranged in 4 configurations: neurocranium, frontal bone, parietotemporal region, and occipital bone. For each configuration, the presence of significant sex differences in shape and size was tested. Principal component analysis (PCA) was applied to explore the shape variation. The classification power of size and shape was tested using discriminant analysis and k-means clustering. The neurocranium shows significant sex differences in shape and size. The parietotemporal region is the most dimorphic neurocranial part in size and the frontal bone is the most differing one in shape. The size of the parietotemporal region and frontal bone classifies correctly more than 80% of the crania. The discrimination ability based on shape is rather low as the highest values of about 70% are obtained for the frontal and occipital bone. The PCA plots show large overlapping of the male and female crania. It can be inferred that the sex-specific size differences in the neurocranium are more important than the shape differences.

Neurochemical profile of the myenteric plexus in the rat colorectal region.

The enteric nervous system, a major subdivision of the autonomic nervous system, is known for its neurochemical heterogeneity and complexity. The myenteric plexus, one of its two principal components, primarily controls peristalsis and its dysfunction may lead to a number of gastrointestinal motility disorders. The myenteric neurons have been described to use a wide variety of neurotransmitters although no evidence has been reported for the existence of adrenergic neurons in the hindgut. This study aims at elucidating the chemical coding of neurons in the myenteric plexus of the rat colon and anorectal region with particular emphasis on cholinergic and the so-called nonadrenergic, noncholinergic (NANC) transmitter systems. The immunostaining for choline acetyltransferase revealed an intense staining of the myenteric ganglia with clear delineation of their neuronal cell bodies and without local distributional differences in the colonic region. The myenteric ATPergic structures were mostly limited to fiber bundles surrounding unstained myenteric neurons and penetrating the two muscle layers. We also observed an abundance of intensely stained varicose substance P-immunopositive fibers, ensheathing the immunonegative myenteric neuronal cell bodies in a basket-like manner. Applying NADPH-diaphorase histochemistry and nitric oxide synthase immunohistochemistry, we were able to demonstrate numerous nitrergic somata of myenteric neurons with Dogiel Type I morphology. Apart from the observed nitrergic distributional patterns, no distinct variations were found in the staining intensity or distribution of myenteric structures in the colon and anorectal area. Our results suggest that myenteric neurons in the distal intestinal portion utilize a broad spectrum of enteric transmitters, including classical and NANC transmitters.

Neurochemical plasticity of the carotid body in hypertension.

The carotid body (CB), a main peripheral arterial chemoreceptor, has lately been implicated in the pathophysiology of various cardiovascular disorders. Emerging experimental evidence supports a causal relationship between CB dysfunction and augmented sympathetic outflow which is the common hallmark of human sympathetic-related diseases, including essential hypertension. To gain insight into the neurotransmitter profile of chemosensory cells in the hypertensive CB, we examined the expression and cellular localization of some classical neurotransmitters, neuropeptides, and gaseous signaling molecules as well as neurotrophic factors and their receptors in the CB of spontaneously hypertensive rats, a common animal model of hypertension. Our immunohistochemical experiments revealed an elevated catecholamine and serotonin content in the hypertensive CB compared to normotensive controls. GABA immunostaining was seen in some peripherally located glomus cells in the CB of SHR and it was significantly lower than in control animals. The density of substance P and vasoactive intestinal peptide-immunoreactive fibers was diminished whereas that of neuropeptide Y-immunostained nerve fibers was increased and that of calcitonin gene-related peptide-containing fibers remained almost unchanged in the hypertensive CB. We have further demonstrated that in the hypertensive state the production of nitric oxide is impaired and that the components of the neurotrophin signaling system display an abnormal enhanced expression. Our results provide immunohistochemical evidence that the altered transmitter phenotype of CB chemoreceptor cells and the elevated production of neurotrophic factors modulate the chemosensory processing in hypertensive animals which contributes to autonomic dysfunction and elicits sympathetic hyperactivity, consequently leading to elevated blood pressure.

Histochemical and immunohistochemical localization of nitrergic structures in the carotid body of spontaneously hypertensive rats.

The carotid body (CB) is a multipurpose metabolic sensor that acts to initiate cardiorespiratory reflex adjustments to maintain homeostasis of blood-borne chemicals. Emerging evidence suggests that nitric oxide increases the CB chemosensory activity and this enhanced peripheral chemoreflex sensitivity contributes to sympathoexcitation and consequent pathology. The aim of this study was to examine by means of NADPH-diaphorase histochemistry and nitric oxide synthase (NOS) immunohistochemistry the presence and distribution of nitrergic structures in the CB of spontaneously hypertensive rats (SHRs) and to compare their expression patterns to that of age-matched normotensive Wistar rats (NWRs). Histochemistry revealed that the chemosensory glomus cells were NADPH-d-negative but were encircled by fine positive varicosities, which were also dispersed in the stroma around the glomeruli. The NADPH-d-reactive fibers showed the same distributional pattern in the CB of SHRs, however their staining activity was weaker when compared with NWRs. Thin periglomerular, intraglomerular and perivascular varicose fibers, but not glomus or sustentacular cells in the hypertensive CB, constitutively expressed two isoforms of NOS, nNOS and eNOS. In addition, clusters of glomus cells and blood vessels in the CB of SHRs exhibited moderate immunoreactivity for the third known NOS isoenzyme, iNOS. The present study demonstrates that in the hypertensive CB nNOS and eNOS protein expression shows statistically significant down-regulation whereas iNOS expression is up-regulated in the glomic tissue compared to normotensive controls. Our results suggest that impaired NO synthesis could contribute to elevated blood pressure in rats via an increase in chemoexcitation and sympathetic nerve activity in the CB.

Data mining for sex estimation based on cranial measurements.

The aim of the present study is to develop effective and understandable classification models for sex estimation and to identify the most dimorphic linear measurements in adult crania by means of data mining techniques. Furthermore, machine learning models and models developed through logistic regression analysis are compared in terms of performance. Computed tomography scans of 393 adult individuals were used in the study. A landmark-based approach was applied to collect the metric data. The three-dimensional coordinates of 47 landmarks were acquired and used for calculation of linear measurements. Two datasets of cranial measurements were assembled, including 37standard measurements and 1081 interlandmark distances, respectively. Three data mining algorithms were applied: the rule induction algorithms JRIP and Ridor, and the decision tree algorithm J48. Two advanced attribute selection methods (Weka BestFirst and Weka GeneticSearch) were also used. The best accuracy result (91.9 %) was achieved by a set of rules learnt by the JRIP algorithm from the dataset constructed by application of the GeneticSearch selection algorithm to the dataset of standard cranial measurements. The set consisted of five rules including seven cranial measurements. Its accuracy was even better than the classification rates achieved by the logistic regression models. Concerning the second dataset of nonstandard measurements, the best accuracy (88.3 %) was obtained by using classification models learnt by two algorithms - JRIP with a dataset preprocessed by the BestFirst selection algorithm and Ridor with preprocessing by the GeneticSearch selection algorithm. Our experiments show that for the two datasets mentioned above the rule-based models contain smaller sets of rules with shorter lists of measurements and achieve better classification accuracy results in comparison with decision tree-based models.

Efferent projections of the anterior and posterodorsal regions of the medial nucleus of the amygdala in the mouse.

The efferent projections of the anterior and posterodorsal part of the medial nucleus (MePD) in the mouse were studied by means of anterograde axonal tracing using biotinylated dextran amine. The MePD axons ran mainly via the stria terminalis and to a lesser extent via the ventral amygdalofugal pathway. The projections to the forebrain were broadly distributed and varied from very strong to scant. The most significant connections were destined to the bed nucleus of the stria terminalis in which all parts of the medial division were innervated by MePD neurons. Moderate projections reached the limbic striatum (nucleus accumbens), olfactory tubercle and the lateral septal nucleus. The substantia innominata was also innervated by the MePD, and especially the projection to its ventral portion was substantial. The profuse innervation of the medial preoptic nucleus and medial preoptic area indicated significant involvement of the MePD in sexual behavior. Many hypothalamic nuclei were innervated but to a different extent. The very strong innervation of the ventral premammillary nucleus further indicated the involvement of the MePD in the neuronal circuitry for sexual behavior. Substantial projections also reached the anterior hypothalamus and tuber cinereum, while the connections to the lateral hypothalamus were widespread but showed moderate density. MePD strongly innervated the ventrolateral part of the ventromedial hypothalamic nucleus and moderately its remaining parts. The neurosecretory hypothalamic nuclei and the arcuate nucleus contained only a few MePD terminals. The thalamic innervation was very scant and reached the lateral habenular nucleus and the nuclei of the midline. The mesencephalic connections were moderate to sparse and projected to the mesolimbic dopaminergic groups in the ventral tegmental area, the pars lateralis and the dorsal tier of the substantia nigra pars compacta, the periaqueductal gray and the dorsal raphe nucleus. The present results principally resembled data known in other rodent species; however, the efferents of the MePD often differed in extent and/or topical distribution.

Histaminergic and dopaminergic traits in the human carotid body.

Carotid body (CB) chemoreceptors are the main sensors detecting systemic hypoxia. Studies in animals revealed that dopamine and histamine may serve as transmitters between the chemoreceptor cells and the afferent nerve. To gain insight whether histamine and dopamine could play a role in the human CB and thus be important for the understanding of breathing disorders, we have investigated the chemosensory traits in human CBs from nine subjects of different ages obtained at autopsy. Immunohistochemistry revealed expression of histidine decarboxylase, vesicular monoamine transporter 2, histamine receptors 1 and 3 in virtually all chemosensory cells within the glomeruli of different ages. By contrast, catecholaminergic traits (tyrosine hydroxylase and vesicular monoamine transporter 1) were only detected in a subset of CB chemosensory cells at each age group while dopamine D2 receptors were expressed in the great majority of them. Our data suggest that histamine along with catecholamines may serve as transmitters between chemoreceptor cells and the afferent nerve in humans as well.

Sex estimation by Mastoid Triangle using 3D models.

Mastoid Triangle (MT) is a triangle constructed between the landmarks porion, mastoidale and asterion. The aim of the study is to evaluate the sex differences in the MT size in Bulgarian adults and to develop discriminant functions for sex estimation based on the MT sides and area. The study was carried out on 148 head CT scans. A sample of 53 males and 53 females was used for development of discriminant functions, and a test sample of 21 males and 21 females was applied for their validation. Using the software InVesalius©, 3D models of the skulls were segmented and exported in STL format. The 3D coordinates of the landmarks porion, asterion and mastoidale were collected using the software MeshLab©. The MT sides, area and angles were calculated. The sex differences were assessed by the independent t-test. Bilateral differences were evaluated using the paired t-test. Univariate and multivariate discriminant function analyses were applied. The results showed that the MT sides and area differed significantly between both sexes. Sex differences were also established for the angle at mastoidale. Bilateral differences were found in males for the distance porion-mastoidale, which was significantly greater on the right side. The MT dimensions showed sufficient discriminating power for sex estimation among Bulgarians (up to 89%), and the total MT area proved to be the best single sex discriminating trait. The test sample corroborated the usefulness of the MT in sex estimation demonstrating similar or higher overall accuracy rates.

Neurobiology of orofacial proprioception.

Primary sensory fibers innervating the head region derive from neurons of both the trigeminal ganglion (TG) and mesencephalic trigeminal nucleus (MTN). The trigeminal primary proprioceptors have their cell bodies in the MTN. Unlike the TG cells, MTN neuronal somata are centrally located within the brainstem and receive synaptic inputs that potentially modify their output. They are a crucial component of the neural circuitry responsible for the generation and control of oromotor activities. Gaining an insight into the chemical neuroanatomy of the MTN is, therefore, of fundamental importance for the understanding of neurobiology of the head proprioceptive system. This paper summarizes the recent advances in our knowledge of pre- and postsynaptic mechanisms related to orofacial proprioceptive signaling in mammals. It first briefly describes the neuroanatomy of the MTN, which is involved in the processing of proprioceptive information from the face and oral cavity, and then focuses on its neurochemistry. In order to solve the puzzle of the chemical coding of the mammalian MTN, we review the expression of classical neurotransmitters and their receptors in mesencephalic trigeminal neurons. Furthermore, we discuss the relationship of neuropeptides and their corresponding receptors in relaying of masticatory proprioception and also refer to the interactions with other atypical neuromessengers and neurotrophic factors. In extension of previous inferences, we provide conclusive evidence that the levels of transmitters vary according to the environmental conditions thus implying the neuroplasticity of mesencephalic trigeminal neurons. Finally, we have also tried to give an integrated functional account of the MTN neurochemical profiles.