Protective effects of long-term lithium administration in a slowly progressive SMA mouse model.

In the present study we evaluated the long-term effects of lithium administration to a knock-out double transgenic mouse model (Smn-/-; SMN1A2G+/-; SMN2+/+) of Spinal Muscle Atrophy type III (SMA-III). This model is characterized by very low levels of the survival motor neuron protein, slow disease progression and motor neuron loss, which enables to detect disease-modifying effects at delayed time intervals. Lithium administration attenuates the decrease in motor activity and provides full protection from motor neuron loss occurring in SMA-III mice, throughout the disease course. In addition, lithium prevents motor neuron enlargement and motor neuron heterotopy and suppresses the occurrence of radial-like glial fibrillary acidic protein immunostaining in the ventral white matter of SMA-III mice. In SMA-III mice long-term lithium administration determines a dramatic increase of survival motor neuron protein levels in the spinal cord. These data demonstrate that long-term lithium administration during a long-lasting motor neuron disorder attenuates behavioural deficit and neuropathology. Since low level of survival motor neuron protein is bound to disease severity in SMA, the robust increase in protein level produced by lithium provides solid evidence which calls for further investigations considering lithium in the long-term treatment of spinal muscle atrophy.

The role of locus coeruleus in the antiepileptic activity induced by vagus nerve stimulation.

Stimulation of the vagus nerve produces antiepileptic effects. This is used clinically to treat drug-refractory epilepsies. The mechanisms responsible for these effects depend on the activation of vagal afferents reaching the nucleus of the solitary tract. This review focuses on the neuroanatomy of the nucleus of the solitary tract and its relation with the nucleus locus coeruleus as a preferential anatomical substrate in producing antiepileptic effects. In fact, following the transient or permanent inactivation of locus coeruleus neurons, some antiepileptic effects of vagus nerve stimulation are lost. The activation of locus coeruleus per se is known to limit the spread of a seizure and the duration of a variety of seizure types. This is due to the fine chemical neuroanatomy of norepinephrine pathways that arise from the locus coeruleus, which produce widespread changes in cortical areas. These changes may be sustained by norepinephrine alone, or in combination with its co-transmitters. In addition, vagus nerve stimulation may prevent seizures by activating the serotonin-containing dorsal raphe neurons.

Expression of 3-nitrotyrosine, a marker for peroxynitrite, in nasal polyps of nonatopic patients.

BACKGROUND: Several works have reported that nitric oxide and free oxygen radicals are up-regulated in nasal polyposis. This study aimed to assess the distribution of peroxynitrite in nasal polyps from nonatopic patients. Occurrence of peroxynitrite also was analyzed in relation with eosinophil infiltration and epithelial alterations. MATERIAL/METHODS: Hematoxylin and eosin staining was used for histologic study. Peroxynitrite was assessed by 3-nitrotyrosine immunohistochemistry. Quantitative evaluation was done by measuring the total number of eosinophils, the number of 3-nitrotyrosine-positive eosinophils, and the extension of the various epithelial alterations. RESULTS: Hematoxylin and eosin staining showed that the nasal polyp epithelium is characterized by progressive disruption or squamous metaplasia. In both cases, infiltrating eosinophils were found in the epithelium and lamina propria. The regions featuring epithelial disruption exhibited 3-nitrotyrosine immunostaining in eosinophils and epithelial cells; hematoxylin-and-eosin - stained eosinophils and 3-nitrotyrosine - positive eosinophils showed conspicuous variations in number. Within the regions featuring squamous metaplasia, 3-nitrotyrosine-positive eosinophils were rarely found, and the epithelium exhibited 3-nitrotyrosine only in the superficial cells. In these regions, hematoxylin-eosin - stained eosinophils showed slight variations in number. CONCLUSIONS: Peroxynitrite plays a pivotal role in the pathophysiology of nasal polyps. In fact, strong expression of peroxynitrite is associated with epithelial disruption, while poor expression of peroxynitrite is associated with squamous metaplasia. Peroxynitrite could influence afflux of eosinophils in the nasal mucosa; moreover, the total number of eosinophils is not critical in generating alterations of nasal polyp mucosa.

MPTP-induced Parkinsonism is associated with damage to Leydig cells and testosterone loss.

Genital dysfunction and testosterone deficiency occur frequently in Parkinson's disease and represent a typical non-motor symptom of the disorder. Despite that, to our knowledge no study investigated whether at experimental level this can be reproduced with classic Parkinsonism-inducing neurotoxins. In this study we evaluated the effects produced in the testis following administration of the Parkinsonism-inducing neurotoxin 1-methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine in mice. At 7 days following treatment, in the presence of a severe nigrostriatal dopamine depletion, we found a marked decrease in testosterone plasma levels in 1-methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine-treated mice. Such testosterone loss occurred concomitantly with loss of Leydig cells and the presence of altered morphology in the interstitium with severe mitochondrial degeneration in spared Leydig cells. The loss of Leydig cells was accompanied by a marked decrease in TH immunohistochemistry and TH protein in the interstitium. This was accompanied by a significant decrease in norepinephrine levels in the testis. These effects shed novel light to understand genital dysfunction and testosterone deficiency in Parkinsonism, while offering a new experimental model to reproduce genital dysfunction in Parkinson's disease.

Lifestyle and testicular dysfunction: a brief update.

The incidence of testicular cancer, cryptorchidism and defective spermatogenesis is increasing probably due to environmental and lifestyle-related factors. The aim of this review is to briefly describe and comment on the principal lifestyle factors. The recent findings that the electromagnetic waves following the use of the cell phone and the prolonged exposure to the noise stress cause relevant testicular dysfunction in man or animals reinforce the hypothesis of the importance of lifestyle-related factors.

Curcumin protects Leydig cells of mice from damage induced by chronic alcohol administration.

BACKGROUND: It is known that alcohol consumption inhibits testosterone production and causes testicular atrophy. Curcumin is a phytochemical characterized by anti-inflammatory and antioxidant properties. It was also observed that curcumin protects the liver, pancreas, and nervous system from the toxic effects of alcohol consumption. The goal of this study was to determine if curcumin protects the Leydig cells of mice from chronic alcohol administration. MATERIAL/METHODS: Fifteen mice were treated daily for four weeks with a 3.0 g/kg of a 25% solution of alcohol. Fifteen mice received curcumin (80 mg/kg) added to the same alcohol solution. Fifteen mice were treated with a solution of maltose dextrins isocaloric to ethanol. Fifteen untreated mice were used as controls. RESULTS: In the alcohol-fed mice, numerous Leydig cells showed cytoplasmic rarefaction and increased diameter of the mitochondria. Several mitochondria had diameters three or more times larger than that of mitochondria from control mice. Numerous necrotic Leydig cells were observed. Testosterone plasma levels significantly decreased in comparison with control mice. In alcohol plus curcumin-treated mice the number of necrotic Leydig cells was reduced compared with alcohol-fed mice; the diameters of the mitochondria were significantly decreased. Testosterone plasma levels were not significantly different from those of the controls. CONCLUSION: This study demonstrates that curcumin exerts efficacious protection against damages caused in the Leydig cells of mice by chronic alcohol ingestion and that the preservation of mitochondrial structure and size in Leydig cells is a specific effect of curcumin.

The "Parkinsonian heart": from novel vistas to advanced therapeutic approaches in Parkinson's disease.

The present manuscript reviews novel data on the progressive involvement of different regions of the central nervous system as well as peripheral nerves in Parkinson's disease. Most of these regions are involved in the regulation of the autonomic nervous system, and their damage is concomitant with the specific loss of sympathetic cardiac axon terminals. This causes a cardiovascular dysfunction, which occurs solely in Parkinsonian patients. In order to specify the peculiarity of this cardiovascular alteration we coined the term "Parkinsonian Heart". This is characterized by a severe loss of the physiological noradrenergic innervation and a slight impairment of central autonomic control and it is often characterized by drug-induced morpho-functional alterations. In fact, the current dopamine substitution therapy could make worse such an already abnormal heart. For instance, structure-activity studies on dopamine substitutive drugs report that dopamine agonists belonging to the class of ergot derivatives may produce, with a high frequency, valvular fibrosis in Parkinsonian patients. These effects recently became a major issue and led to consider all ergot dopamine agonists as dangerous for the treatment of Parkinson's disease. In the present review we re-describe the effects of dopamine agonist within the specific context of the Parkinsonian heart. In line with this, additional factors need to be considered: 1--The lack of noradrenergic innervation which might play a significant role in the fibrogenic mechanism. 2--The ergot structure per se, which is not sufficient, but it is rather the ability to act as agonist at 5HT(2B) or alpha-noradrenergic receptors to determine the fibrotic reaction. Therefore, we suggest that binding to these receptor subtypes, joined with the lack of endogenous noradrenergic innervation, might synergize to produce the cardiac fibrosis.

Neurons other than motor neurons in motor neuron disease.

Amyotrophic lateral sclerosis (ALS) is typically defined by a loss of motor neurons in the central nervous system. Accordingly, morphological analysis for decades considered motor neurons (in the cortex, brainstem and spinal cord) as the neuronal population selectively involved in ALS. Similarly, this was considered the pathological marker to score disease severity ex vivo both in patients and experimental models. However, the concept of non-autonomous motor neuron death was used recently to indicate the need for additional cell types to produce motor neuron death in ALS. This means that motor neuron loss occurs only when they are connected with other cell types. This concept originally emphasized the need for resident glia as well as non-resident inflammatory cells. Nowadays, the additional role of neurons other than motor neurons emerged in the scenario to induce non-autonomous motor neuron death. In fact, in ALS neurons diverse from motor neurons are involved. These cells play multiple roles in ALS: (i) they participate in the chain of events to produce motor neuron loss; (ii) they may even degenerate more than and before motor neurons. In the present manuscript evidence about multi-neuronal involvement in ALS patients and experimental models is discussed. Specific sub-classes of neurons in the whole spinal cord are reported either to degenerate or to trigger neuronal degeneration, thus portraying ALS as a whole spinal cord disorder rather than a disease affecting motor neurons solely. This is associated with a novel concept in motor neuron disease which recruits abnormal mechanisms of cell to cell communication.

The Neuroanatomy of the Reticular Nucleus Locus Coeruleus in Alzheimer's Disease.

Alzheimer's Disease (AD) features the accumulation of ß-amyloid and Tau aggregates, which deposit as extracellular plaques and intracellular neurofibrillary tangles (NFTs), respectively. Neuronal Tau aggregates may appear early in life, in the absence of clinical symptoms. This occurs in the brainstem reticular formation and mostly within Locus Coeruleus (LC), which is consistently affected during AD. LC is the main source of forebrain norepinephrine (NE) and it modulates a variety of functions including sleep-waking cycle, alertness, synaptic plasticity, and memory. The iso-dendritic nature of LC neurons allows their axons to spread NE throughout the whole forebrain. Likewise, a prion-like hypothesis suggests that Tau aggregates may travel along LC axons to reach out cortical neurons. Despite this timing is compatible with cross-sectional studies, there is no actual evidence for a causal relationship between these events. In the present mini-review, we dedicate special emphasis to those various mechanisms that may link degeneration of LC neurons to the onset of AD pathology. This includes the hypothesis that a damage to LC neurons contributes to the onset of dementia due to a loss of neuroprotective effects or, even the chance that, LC degenerates independently from cortical pathology. At the same time, since LC neurons are lost in a variety of neuropsychiatric disorders we considered which molecular mechanism may render these brainstem neurons so vulnerable.

Fine structure and biochemical mechanisms underlying nigrostriatal inclusions and cell death after proteasome inhibition.

Mutation of genes encoding for various components of a metabolic pathway named the ubiquitin-proteasome system (UP) leads to inherited forms of Parkinson's disease (PD), whereas various components of the UP are constantly present within neuronal inclusions, Lewy bodies, that characterize most genetic and sporadic forms of PD. It has been hypothesized that impairment of this metabolic pathway might be a common mechanism for the onset of PD, and a recent study demonstrated a dysfunction of the UP system within the substantia nigra of patients affected by sporadic PD. In search for the mechanisms underlying the selective toxicity for nigral neurons after inhibition of the UP system, we explored the selective effects after striatal microinfusions of lactacystin or epoxomycin and potential retrograde changes within the ipsilateral substantia nigra. We found that neurotoxicity was selective for striatal dopamine (DA) components and led to retrograde apoptosis within nigral DA cells, which developed neuronal inclusions staining for antigens of the UP system. We found the same ultrastructural features characterizing inclusions obtained in vivo and in vitro after UP inhibition. In vivo, lactacystin-epoxomycin-induced toxicity was suppressed by inhibiting DA synthesis. Similarly, in vitro inclusions and apoptosis were prevented by reducing endogenous DA. On the other hand, toxicity of proteasome inhibition was enhanced by drugs augmenting DA availability: l-3,4-dihydroxyphenylalanine, monoamine oxidase blockers, and DA beta-hydroxylase blockers. These findings demonstrate that impairment of the UP system produces cell death and neuronal inclusions selectively for DA-containing neurons that depend on the occurrence of endogenous DA.

Ultrastructure of testicular macrophages in aging mice.

Testicular macrophages of aging mice were studied by TEM. Testicular macrophages retained with Leydig cells the close morphological relationships observed in the adult young animals, but digitations were not found. Lipofuscin granules like those of the Leydig cells from aging mice were observed in the cytoplasm. These organelles were generally absent in the testicular macrophages of young adult mice. Testicular macrophages did not display phagocytosis of the lipofuscin granules. In addition, the latter were not found in the intercellular spaces. These observations indicated that lipofuscin granules were formed, at least in a great part, within testicular macrophages as a consequence of metabolic changes occurring with age. Fine lamellar organization was seen in the lipofuscin granules of both Leydig cells and testicular macrophages. Frequently, lipofuscin granules originated from secondary lysosomes containing lipidic vacuoles only. Together with accumulation of the lipofuscin granules, changes of testicular macrophage fine morphology were observed. Endoplasmic reticulum and Golgi apparatus became poorly developed, and coated vesicles were rarely found. Fewer mitochondria were encountered, but their ultrastructure was not altered. These results suggest that in testicular macrophages lipofuscin accumulation is associated with a functional involution.

Immunohistochemical localization of 3-nitrotyrosine in the nasal respiratory mucosa of patients with vasomotor rhinitis.

CONCLUSION: This study demonstrates that, in the nasal respiratory mucosa of patients with vasomotor rhinitis, oxidative stress following peroxynitrite formation is confined to the respiratory epithelium. This suggests that the role of peroxynitrite in vasomotor rhinitis differs from its role in other diseases of the respiratory tract. The results of this study also support the concept that different pathogenetic mechanisms are probably involved in vasomotor rhinitis. OBJECTIVE: Previous studies indicated that nitric oxide (NO) is involved in the pathogenesis of vasomotor rhinitis, strong expression of NO synthase being detected in the smooth muscle cells of the cavernous sinuses and in the respiratory epithelium. However, most adverse effects of high levels of NO originate from the reaction of NO with superoxide anions to form peroxynitrite. Therefore, in this study we evaluated the involvement of peroxynitrite in the pathogenesis of vasomotor rhinitis. MATERIAL AND METHODS: Sites of peroxynitrite formation were identified by immunolabelling for 3-nitrotyrosine (3NT), its footprint in tissues. Samples of nasal mucosa were obtained from vasomotor rhinitis patients and from control subjects who had undergone corrective surgery of the nasal septum. All samples were obtained by reduction of the inferior turbinate. RESULTS: Examination of specimens from vasomotor rhinitis patients revealed that 3NT is absent in epithelium with a normal appearance, cells of the subepithelial connective tissue, the glands and the blood vessels, including the cavernous sinuses. In contrast, intense 3NT immunolabelling was found in the disrupted respiratory epithelium. 3NT was not present in any of the specimens from control subjects.

Ultrastructural studies of ALS mitochondria connect altered function and permeability with defects of mitophagy and mitochondriogenesis.

The key role of mitochondria in patients affected by amyotrophic lateral sclerosis (ALS) is well documented by electron microscopy studies of motor neurons within spinal cord and brainstem. Nonetheless, recent studies challenged the role of mitochondria placed within the cell body of motor neuron. In fact, it was demonstrated that, despite preservation of mitochondria placed within this compartment, there is no increase in the lifespan of transgenic mouse models of ALS. Thus, the present mini-review comments on morphological findings of mitochondrial alterations in ALS patients in connection with novel findings about mitochondrial dynamics within various compartments of motor neurons. The latter issue was recently investigated in relationship with altered calcium homeostasis and autophagy, which affect mitochondria in ALS. In fact, it was recently indicated that a pathological mitophagy, mitochondriogenesis and calcium homeostasis produce different ultrastructural effects within specific regions of motor neurons. This might explain why specific compartments of motor neurons possess different thresholds to mitochondrial damage. In particular, it appears that motor axons represent the most sensitive compartment which undergoes the earliest and most severe alterations in the course of ALS. It is now evident that altered calcium buffering is compartment-dependent, as well as mitophagy and mitochondriogenesis. On the other hand, mitochondrial homeostasis strongly relies on calcium handling, the removal of altered mitochondria through the autophagy flux (mitophagy) and the biogenesis of novel mitochondria (mitochondriogenesis). Thus, recent findings related to altered calcium storage and impaired autophagy flux in ALS may help to understand the occurrence of mitochondrial alterations as a hallmark in ALS patients. At the same time, the compartmentalization of such dysfunctions may be explained considering the compartments of calcium dynamics and autophagy flux within motor neurons.

Chronic alcohol administration causes expression of calprotectin and RAGE altering the distribution of zinc ions in mouse testis.

Several studies reported that chronic alcohol consumption alters the intestinal mucosa barrier, and subsequent entrance of endotoxins into the bloodstream. In many tissues endotoxin exposure causes the expression of calprotectin (CP) and the receptor for advanced glycation -end products (RAGE). In this study we investigated whether chronic alcohol administration causes expression of CP and RAGE in mouse testis. The distribution of free and loosely bound Zn(2+) (FLB-Zn(2+)) in the testicular tissues was also evaluated. Alcohol-induced testicular damage was documented by measuring testosterone blood levels and by light and electron microscope studies. Twenty mice were treated daily for three weeks with 3.0 g/kg of a 25% solution of alcohol. Ten mice were treated in the same period of time with a solution of maltose dextrins, isocaloric to alcohol. Twenty untreated mice were used as controls. Alcohol treated mice showed diffuse expression of CP and RAGE in the interstitial cells. RAGE was found also in the basal compartment of the seminiferous tubules. Depletion of FLB-Zn(2+) was observed in the adluminal compartment of the seminiferous tubules. Expression of CP and RAGE was not found in control mice and maltose dextrin treated mice. Our results indicated novel mechanisms by which alcohol acts in testis. Indeed, CP and RAGE may cause the generation of oxidants and inflammatory mediators, with negative impact on testicular functions. Depletion of FLB-Zn(2+) may contribute to the dysregulation of spermatogenesis.

Morphological alterations induced by loud noise in the myocardium: the role of benzodiazepine receptors.

Noise represents an environmental stress factor affecting several organs and apparati, including the cardiovascular system. In experimental animals undergoing noise exposure, subcellular myocardial changes have been reported, especially at mitochondrial level; in particular, after 6 hours of exposure only the atrium exhibited significant mitochondrial alterations, whereas after 12 hours as well as subchronic exposure both atrium and ventricle were damaged. The first part of the present article overviews the experimental evidence on effects of noise on the myocardium. In the second part, the review analyzes the role of benzodiazepine receptors and the potential efficacy of benzodiazepine ligands in preventing the mitochondrial damage induced by noise exposure. Drugs acting at both central and peripheral benzodiazepine receptors significantly prevent this damage. Differences in the amount and the duration of the protective effect might depend on variability in the potency and pharmacokinetics of the specific drug. The effects of the combined treatment with selective and non-selective peripheral benzodiazepine ligands on noise stimulation are discussed at biochemical level reviewing studies on the effects of noise exposure on mitochondrial fractions.

Ultrastructural and ultracytochemical study of the middle ear epithelium in the chicken, Gallus gallus domesticus.

The fine structure of the epithelium lining the tympanic cavity of the chicken was studied by TEM and SEM. In addition, the distribution of nonspecific esterase activity in the epithelium was investigated by TEM. Ultrastructural study revealed the presence of disk-like apical protrusions of the epithelial cells, previously not observed in other cell types. The protrusions contained some cytoplasmic organelles and were characterized by a ring-shaped thickening around their periphery. The ring was made up of a granulo-filamentous material. Our observations clearly indicate the existence of an apocrine secretory mechanism, consisting of a progressive detachment of disk-like protrusions from the apex of the epithelial cells. The ultracytochemical study demonstrated nonspecific esterase activity on the epithelial surface and in the secretory vesicles. We propose that nonspecific esterase is a marker for middle ear surfactant in birds.

Ultrastructural and ultracytochemical study of the human nasal respiratory epithelium in vasomotor rhinitis.

OBJECTIVES: Several pieces of evidence have suggested that nitric oxide (NO) fulfills important functions in the respiratory mucosa, under both normal and pathological conditions. This study was performed to investigate the role of NO in the nasal respiratory epithelium of patients affected by vasomotor rhinitis. The structure and ultrastructure of the epithelium were also examined. MATERIAL AND METHODS: The localization of NO synthase activity was determined by means of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase ultracytochemistry. Nasal mucosa was obtained from patients who had undergone surgical therapy for reduction of the inferior turbinate. RESULTS: Examination of hematoxylin-eosin-stained sections revealed that most of the nasal mucosa covering the surgical samples was characterized by severe epithelial damage. The ultrastructural study confirmed the light microscopic observations. Ciliary loss, absence of the intercellular junctions and distension of the intercellular spaces were found in the damaged epithelium. The basement membrane was frequently interrupted. Some epithelial cells were identified as basal cells. Other cells of the damaged epithelium were probably involuted ciliated and goblet cells. The ultracytochemical study showed that the basal cells were NADPH-diaphorase-negative in healthy subjects and strongly NADPH-diaphorase-positive in subjects with vasomotor rhinitis. CONCLUSIONS: It is suggested that NO has cytotoxic effects and causes inhibition of mitotic activity in the basal cells, leading to epithelial disruption and breakdown of the protective functions of the epithelium.

Giovanni Vitali: Discoverer of the paratympanic organ.

One-hundred years ago, the Italian anatomist Giovanni Vitali reported the discovery of the paratympanic organ, a sense organ in the middle ear of birds, in two issues of the Anatomischer Anzeiger (1911, 1912). In this minireview, we summarize Vitali's biography, and examine the scientific impact of his discovery of this sense organ. We also compile - for the first time - the entire bibliography of published papers on the paratympanic organ. Vitali described the ontogenetic development of this sense organ, examined its distribution among species, recognized its evolutionary relationship with the spiracular sense organ of fishes, and he developed the theory that it functions as a detector of changes in air pressure. He was the first to postulate that the paratympanic and spiracular sense organs were homologous organs that originate from homologous placodes - currently a hotly debated topic. His morphological work indicating the sensory nature of the PTO was validated by subsequent ultrastructural studies. Vitali's discovery of the paratympanic organ prompted his nomination for the Nobel Prize in 1934. Nevertheless, the paratympanic organ and the presumed barometric sense of hundreds of billions of living birds have failed to receive the recognition they deserve. Conclusive evidence of the function of the paratympanic organ remains a formidable challenge in vertebrate sensory physiology.

Motor neuron pathology and behavioral alterations at late stages in a SMA mouse model.

Spinal muscular atrophy (SMA) is a neurogenetic autosomal recessive disorder characterized by degeneration of lower motor neurons. The validation of appropriate animal models is key in fostering SMA research. Recent studies set up an animal model showing long survival and slow disease progression. This model is knocked out for mouse SMN (Smn(-/-)) gene and carries a human mutation of the SMN1 gene (SMN1A2G), along with human SMN2 gene. In the present study we used this knock out double transgenic mouse model (SMN2(+/+); Smn(-/-); SMN1A2G(+/-)) to characterize the spinal cord pathology along with motor deficit at prolonged survival times. In particular, motor neuron loss was established stereologically (44.77%) after motor deficit reached a steady state. At this stage, spared motor neurons showed significant cell body enlargement. Moreover, similar to what was described in patients affected by SMA we found neuronal heterotopy (almost 4% of total motor neurons) in the anterior white matter. The delayed disease progression was likely to maintain fair motor activity despite a dramatic loss of large motor neurons. This provides a wonderful tool to probe novel drugs finely tuning the survival of motor neurons. In fact, small therapeutic effects protracted over considerable time intervals (even more than a year) are expected to be magnified.

The chemical neuroanatomy of vagus nerve stimulation.

In this short overview a reappraisal of the anatomical connections of vagal afferents is reported. The manuscript moves from classic neuroanatomy to review details of vagus nerve anatomy which are now becoming more and more relevant for clinical outcomes (i.e. the therapeutic use of vagus nerve stimulation). In drawing such an updated odology of central vagal connections the anatomical basis subserving the neurochemical effects of vagal stimulation are addressed. In detail, apart from the thalamic projection of central vagal afferents, the monoaminergic systems appear to play a pivotal role. Stemming from the chemical neuroanatomy of monoamines such as serotonin and norepinephrine the widespread effects of vagal stimulation on cerebral cortical activity are better elucidated. This refers both to the antiepileptic effects and most recently to the beneficial effects of vagal stimulation in mood and cognitive disorders.