Vagal afferent controls of feeding: a possible role for gastrointestinal BDNF

Introduction

Vagal gastrointestinal (GI) afferents do not appear to contribute to long-term controls of feeding, despite downstream connections that could support such a role. This view is largely attributable to a lack of evidence for long-term effects, especially the failure of vagal afferent lesions to produce hyperphagia or obesity.

Aims

Here, the possibility is evaluated that “side effects” of vagal lesion methods resulting largely from complexities of vagal organization would probably suppress long-term effects. Criteria based on knowledge of vagal organization were utilized to critique and compare vagal lesion methods and to interpret their effects on GI function, feeding and body weight.

Results and conclusions

This analysis suggested that it was premature to eliminate a long-term vagal GI afferent role based on the effects of these lesions and highlighted aspects of vagal organization that must be addressed to reduce the problematic side effects of vagal lesions. The potential of “genetic” lesions that alter vagal sensory development to address these aspects, examination of the feasibility of this approach, and the properties of brain-derived neurotrophic factor (BDNF) that made it an attractive candidate for application of this approach are described. BDNF knockout from GI smooth muscle unexpectedly demonstrated substantial overeating and weight gain associated with increased meal size and frequency. The decay of eating rate during a scheduled meal was also reduced. However, meal-induced c-Fos activation was increased in the dorsal motor nucleus of the vagus, suggesting that the effect on eating rate was due to augmentation of GI reflexes by vagal afferents or other neural systems.     

Evaluation of afferent pain pathways in adrenomyeloneuropathic patients

Objective

Patients with adrenomyeloneuropathy may have dysfunctions of visual, auditory, motor and somatosensory pathways. We thought on examining the nociceptive pathways by means of laser evoked potentials (LEPs), to obtain additional information on the pathophysiology of this condition.

The anion in salt taste: a possible role for paracellular pathways

It is well established from psychophysical and electrophysiological measurements that both Na and Cl contribute to the taste response to NaCl. The contribution of Na to the NaCl response can be studied using amiloride, a drug that inhibits Na transport in taste and other epithelial cells. The pathways involved in response to Cl are less well understood. We undertook a series of experiments in the rat to determine whether tonic chorda tympani responses to NaCl are inhibited by specific inhibitors of anion transport. Whole nerve responses to NaCl were unchanged by bathing the tongue in SITS, DIDS, bumetanide, furosemide, 9-anthracene carboxylic acid, or an antibody that blocks Cl conductance pathways in many epithelia. Thus, Cl co-transporters, exchangers, and channels (at least in the apical membrane of taste cells) are probably not involved in NaCl taste responses. When other anions (acetate, isethionate, methane sulfonate, gluconate, tartrate), which are generally impermeant in other Cl-selective pathways, were substituted for Cl, the dose-response curves for the chorda tympani response were shifted toward higher concentrations than the response to NaCl, but achieved the same maximum value at sufficiently high concentrations (1.0 M Na). For all the organic Na salts, the amiloride-insensitive portion of the response was substantially less than for NaCl. Experiments with Na acetate at different pHs showed that intracellular acidification is not responsible for the differences between NaCl and organic salts of Na. One possibility which remains is that apical stimulation with these other Na salts results in a taste cell membrane potential that is hyperpolarized with respect to the membrane potential in NaCl.(ABSTRACT TRUNCATED AT 250 WORDS)     

Novel pathway for LPS-induced afferent vagus nerve activation: possible role of nodose ganglion

The afferent vagus nerve has been suggested to be an important component for transmitting peripheral immune signals to the brain. However, there is inconsistent evidence showing that subdiaphragmatic vagotomy did not inhibit the brain mediated behavioral and neural effects induced by the peripheral application of lipopolysaccharide (LPS). LPS triggers innate immune cells through Toll-like receptor 4 (TLR4). In the present study, we found that TLR4 mRNA and protein was expressed in the rat nodose ganglion. Thus, it is suggested that LPS could activate afferent vagus nerve at the level of nodose ganglion, which exists centrally from the subdiaphragmatic level of vagus nerve. The results could provide evidence for the novel pathway of LPS-induced afferent vagus nerve activation.     

Multiplicity of the afferent pathways mediating the exercise pressor reflex

The cardiovascular responses to isometric contraction of the triceps surae muscle of one leg were determined before and after transecting the ipsilateral L7 or L6 and S1 spinal roots. Sectioning only the L7 spinal root slightly attenuated the pressor, but not the heart rate response induced by skeletal muscle contraction, while cutting the L6 and S1 spinal roots (L7 intact) had no effect on the cardiovascular changes. This indicates that there is multiplicity in neural afferent pathways that mediate the exercise pressor reflex.     

Neural organization of afferent pathways from the stomatopod compound eye

Crustaceans and insects share many similarities of brain organization suggesting that their common ancestor possessed some components of those shared features. Stomatopods (mantis shrimps) are basal eumalacostracan crustaceans famous for their elaborate visual system, the most complex of which possesses 12 types of color photoreceptors and the ability to detect both linearly and circularly polarized light. Here, using a palette of histological methods we describe neurons and their neuropils most immediately associated with the stomatopod retina. We first provide a general overview of the major neuropil structures in the eyestalks lateral protocerebrum, with respect to the optical pathways originating from the six rows of specialized ommatidia in the stomatopod's eye, termed the midband. We then focus on the structure and neuronal types of the lamina, the first optic neuropil in the stomatopod visual system. Using Golgi impregnations to resolve single neurons we identify cells in different parts of the lamina corresponding to the three different regions of the stomatopod eye (midband and the upper and lower eye halves). While the optic cartridges relating to the spectral and polarization sensitive midband ommatidia show some specializations not found in the lamina serving the upper and lower eye halves, the general morphology of the midband lamina reflects cell types elsewhere in the lamina and cell types described for other species of Eumalacostraca.     

Immunohistochemical characterization of serotoninergic afferent pathways in the visual system of the rat

Using the immunohistochemical PAP-method occurrence, distribution and terminal aborization of serotoninergic axons were investigated in the visual system of the albino rat. The present study reveals that the innervation varies in quantitative and qualitative manner in the different parts of the visual system. A sparsly serotoninergic innervation was observed in the dorsal lateral geniculate body (d lgb) and in the nucleus lateralis posterior. An intensive serotoninergic innervation was found in the lateral part of the ventral lateral geniculate body (v lgb) and in the area praetectalis. Serotoninergic axons show a lamina specific orientation in the colliculus superior and in the visual cortex. Our findings indicate that serotoninergic axons have an intensive terminal aborization in subcortical visual nuclei, which are more or less connected with oculomotoric functions.     

On the horizon: possible neuroprotective role for glatiramer acetate

Inflammation and neurodegeneration characterize the pathogenesis of multiple sclerosis (MS). Slow axonal degeneration, rather than acute inflammation, is considered the cause of chronic disability in MS. The signs of acute axonal damage and loss have been shown to occur early in the lesion development of patients with chronic MS and often correlate with demyelination and inflammation. While immune activity in the central nervous system has traditionally been considered to be a detrimental event in MS, recent studies have found that autoimmune T cells may play an important role in protecting neurons from the ongoing spreading damage. Neuroprotection in MS is a new and evolving concept, and many questions remain with regard to potential targets for therapeutic intervention. Preliminary studies, both in animals and in humans, have suggested that glatiramer acetate (GA) may confer neuroprotective activity in addition to bystander suppression. Additional research is needed to determine if these promising neuroprotective effects correlated with the long-term effect of GA in MS.     

Central distribution of afferent pathways from the uterus of the cat.

Afferent pathways from the uterus of the cat were labeled by injections of horseradish peroxidase (HRP), wheat germ agglutinin-HRP, or fluorescent dyes into the uterine cervix and uterine horns. Afferent input to the uterus arises from small to medium size neurons (average size 31 x 28 microns) in dorsal root ganglia at many levels of the spinal cord (T12-S3). The segmental origin correlates with the location of the afferent terminal field in the uterus. Eighty-seven percent of the dorsal root ganglion cells (average, 822 on one side) innervating the cervix are located in sacral ganglia, whereas 97% of the cells innervating the uterine horn (average 479 on one side) are located in lumbar ganglia. Double dye labeling experiments indicate that a small percentage (average 15%) of lumbar neurons innervating the uterine cervix also innervate the uterine horn. The majority (70-80%) of afferent input to the uterine cervix passes through the pelvic nerve and the remainder through the pudendal nerve, whereas afferent input to the uterine horn must travel in sympathetic nerves. Ovariectomy (10-14 days) did not change significantly the number, sizes, or segmental distribution of uterine afferent neurons. In some cats (25%) injections of WGA-HRP into the uterine cervix labeled neurons (90-125 per animal) in lamina VII in the S2 spinal segment in the region of the sacral parasympathetic nucleus. Central projections of uterine horn afferent neurons were not labeled; however, afferent projections from the cervix were detected in the sacral spinal cord. The most prominent labeling was present in Lissauer's tract and in lamina I and outer lamina II on the lateral edge of the dorsal horn. From this region some labeled axons extended through lamina V into the dorsal gray commissure. Very few afferents were labeled on the medial side of the dorsal horn. These results are discussed in regard to the physiological function of uterine afferents and the possible transmitter role of vasoactive intestinal polypeptide, which is present in a large percentage (70%) of cervical afferent neurons.     

The renal afferent pathways in the rat: a pseudorabies virus study

Retrograde tract tracing studies have indicated that dorsal root ganglion cells from T₈ to L₂ innervate the rat's left kidney. Electrophysiology studies have indicated that putative second-order sympathetic afferents are found in the dorsal horn at spinal segments T₁₀ to L₁ in laminae V–VII. Here, the spread of pseudorabies virus through renal sensory pathways was examined following 2–5 days post-infection (PI) and the virus was located immunocytochemically using a rabbit polyclonal antibody. Two days PI, dorsal root ganglion neurons (first-order sympathetic afferents) were infected with PRV. An average of 1.2, 0.8, 2.1 and 4.4% of the infected dorsal root ganglion neurons were contralateral to the injected kidney at spinal segments T₁₀, T₁₁, T₁₂ and T₁₃, respectively. Four days PI, infected neurons were detected within laminae I and II of the dorsal horn of the caudal thoracic and upper lumbar spinal cord segments. The labeling patterns in the spinal cord are consistent with previous work indicating the location of renal sympathetic sensory pathways. The nodose ganglia were labeled starting 4 days PI, suggesting the involvement of parasympathetic sensory pathways. Five days PI, infected neurons were found in the nucleus tractus solitarius. In the present study, it was unclear whether the infected neurons in the nucleus tractus solitarius are part of sympathetic or parasympathetic afferent pathways or represent a convergence of sensory information. Renal denervation prevented the spread of the virus into the dorsal root ganglia and spinal cord. Sectioning the dorsal roots from T₁₀–L₃ blocked viral spread into the spinal cord dorsal horn, but did not prevent infection of neurons in dorsal root ganglion nor did it prevent infection of putative preganglionic neurons in the intermediolateral cell column. The present results indicated that renal afferent pathways can be identified after pseudorabies virus infection of the kidney. Our results suggest that renal afferents travel in sympathetic and parasympathetic nerves and that this information may converge at the NTS.     

Functional relationship between somatosensory cortex and specialized afferent pathways in the monkey

Previous work showed that the primate dorsal funiculus (DF) was necessary for tactile discrimination which entailed movement. The extra-DF spinal afferent fibers, by contrast, were sufficient for discrimination of tactile stimuli which did not require movement. This study investigated the association between various cortical regions and the specialized tactile roles of the separate afferent systems. Monkeys learned two sets of tasks, one of which was dependent on DF integrity, and the other was capable of mediation by the extra-DF pathways. The cortical distribution and processing of DF and extra-DF information has been defined here by whether or not these tasks were affected by lesions in the respective regions. Lesions in area 3b led to impairment of both tasks, but more severe and longer-lasting impairment of the DF tests. Lesions in areas 1, 5, or 7 were without effect on either type of function. Ablation of the forelimb region in area 2 selectively damaged only the DF discriminations. These results, in combination with the results of others which are considered here, suggest that (i) both the DF and the extra-DF tactile information converge into area 3b; (ii) the extra-DF information is then projected diffusely to widespread regions of the cortex which enables it to survive limited parietal ablations; and (iii) the DF information is transmitted compactly to a focal region in area 2.     

Organization of afferent and efferent pathways in the pudendal nerve of the female cat

Application of horseradish peroxidase to the pudendal nerve in the female cat labelled lumbosacral afferent and efferent neurons and their processes. Afferent axons entered the spinal cord primarily at the S1 and S2 segments and traveled rostrocaudally in Lissauer's tract and the dorsal columns. A distinctive component of the dorsal column projection was located at the lamina I-dorsal column border as a densely labelled, compact bundle that distributed fibers to the dorsal horn at spinal levels near the segments of entry of the afferent axons. Afferent terminal labelling was located in the marginal zone, the intermediate gray matter, and the dorsal gray commissure in the lumbosacral and coccygeal spinal cord. A well-defined terminal field restricted to the S1 and rostral S2 segments was present in the medial third of the nucleus proprius and substantia gelatinosa. Labelled motoneurons in Onuf's nucleus (S1 and S2) exhibited longitudinal dendrites that extended rostrocaudally within the nucleus and three groups of transverse dendrites that emanated periodically from the nucleus and passed to the ventrolateral funiculus, the intermediate gray, and the dorsal gray commissure. Components of the pudendal nerve that innervate the anal and urethral sphincters were also labelled by injecting HRP into the respective sphincter muscles. Motoneurons innervating the anal and urethral sphincters were located in the dorsomedial and ventrolateral divisions, respectively, of Onuf's nucleus. Afferent projections from the two sphincters were similar; the most prominent terminations were present in the marginal zone, intermediate gray, and dorsal gray commissure. These results are discussed with respect to the physiological function of the pudendal nerve and its relationship with sacral autonomic pathways.     

IP3 receptor in the hair cells of frog semicircular canal and its possible functional role

The presence and functional role of inositol trisphosphate receptors (IP3R) was investigated by electrophysiology and immunohistochemistry in hair cells from the frog semicircular canal. Intracellular recordings were performed from single fibres of the posterior canal in the isolated, intact frog labyrinth, at rest and during rotation, in the presence of IP3 receptor inhibitors and drugs known to produce Ca2+ release from the internal stores or to increase IP3 production. Hair cell immunolabelling for IP3 receptor was performed by standard procedures. The drug 2-aminoethoxydiphenyl borate (2APB), an IP3 receptor inhibitor, produced a marked decrease of mEPSP and spike frequency at low concentration (0.1 mm), without affecting mEPSP size or time course. At high concentration (1 mm), 2APB is reported to block the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA pump) and increase [Ca2+]i; at the labyrinthine cytoneural junction, it greatly enhanced the resting and mechanically evoked sensory discharge frequency. The selective agonist of group I metabotropic glutamate receptors (RS)-3,5-dihydroxyphenylglycine (DHPG, 0.6 mm), produced a transient increase in resting mEPSP and spike frequency at the cytoneural junction, with no effects on mEPSP shape or amplitude. Pretreatment with cyclopiazonic acid (CPA, 0.1 mm), a SERCA pump inhibitor, prevented the facilitatory effect of both 2APB and DHPG, suggesting a link between Ca2+ release from intracellular stores and quantal emission. Consistently, diffuse immunoreactivity for IP3 receptors was observed in posterior canal hair cells. Our results indicate the presence and a possibly relevant functional role of IP3-sensitive stores in controlling [Ca2+]i and modulating the vestibular discharge.     

On the role of central program and afferent inflow in the control of scratching movements in the cat.

Rhythmical scratching movements of the hindlimb were evoked in decerebrate and decapitate cats by stimulation of C1-C2 segments of the spinal cord. Movements of the limb and electrical activity of its muscles were recorded. All muscles were divided into two groups according to their activity. Muscles of the first group supported the limb in a propriate position; they were active during most of the cycle and relaxed during small intervals when muscles of the second group contracted. A deafferented limb was also capable of rhythmical scratching movements with approximately the same cycle duration. However, after deafferentation, the mean position of the limb changed and the amplitude of oscillations increased. This is due mainly to decreased activity of the first group muscles. In curarized preparations, stimulation of C1-C2 segments evoked a rhythmical process within the lumbosacral spinal cord ('fictive' scratching) with a cycle duration nearly the same as in normal scratching. Electrical activity of the muscle nerves during 'fictive' scratching resembled that of corresponding muscles during normal movements. 'Fictive' scratching could be easily elicited provided that the limb was put in a position similar to that of normal scratching.