Mechanisms of sensorineural cell damage, death and survival in the cochlea.

The majority of acquired hearing loss, including presbycusis, is caused by irreversible damage to the sensorineural tissues of the cochlea. This article reviews the intracellular mechanisms that contribute to sensorineural damage in the cochlea, as well as the survival signaling pathways that can provide endogenous protection and tissue rescue. These data have primarily been generated in hearing loss not directly related to age. However, there is evidence that similar mechanisms operate in presbycusis. Moreover, accumulation of damage from other causes can contribute to age-related hearing loss (ARHL). Potential therapeutic interventions to balance opposing but interconnected cell damage and survival pathways, such as antioxidants, anti-apoptotics, and pro-inflammatory cytokine inhibitors, are also discussed

elPBN neurons regulate rVLM activity through elPBN-rVLM projections during activation of cardiac sympathetic afferent nerves.

The external lateral parabrachial nucleus (elPBN) within the pons and rostral ventrolateral medulla (rVLM) contributes to central processing of excitatory cardiovascular reflexes during stimulation of cardiac sympathetic afferent nerves (CSAN). However, the importance of elPBN cardiovascular neurons in regulation of rVLM activity during CSAN activation remains unclear. We hypothesized that CSAN stimulation excites the elPBN cardiovascular neurons and, in turn, increases rVLM activity through elPBN-rVLM projections. Compared with controls, in rats subjected to microinjection of retrograde tracer into the rVLM, the numbers of elPBN neurons double-labeled with c-Fos (an immediate early gene) and the tracer were increased after CSAN stimulation (P < 0.05). The majority of these elPBN neurons contain vesicular glutamate transporter 3. In cats, epicardial bradykinin and electrical stimulation of CSAN increased the activity of elPBN cardiovascular neurons, which was attenuated (n = 6, P < 0.05) after blockade of glutamate receptors with iontophoresis of kynurenic acid (Kyn, 25 mM). In separate cats, microinjection of Kyn (1.25 nmol/50 nl) into the elPBN reduced rVLM activity evoked by both bradykinin and electrical stimulation (n = 5, P < 0.05). Excitation of the elPBN with microinjection of dl-homocysteic acid (2 nmol/50 nl) significantly increased basal and CSAN-evoked rVLM activity. However, the enhanced rVLM activity induced by dl-homocysteic acid injected into the elPBN was reversed following iontophoresis of Kyn into the rVLM (n = 7, P < 0.05). These data suggest that cardiac sympathetic afferent stimulation activates cardiovascular neurons in the elPBN and rVLM sequentially through a monosynaptic (glutamatergic) excitatory elPBN-rVLM pathway

Connections of the corpus cerebelli in the green sunfish and the common goldfish

Examination of the connections of the corpus cerebelli in one perciform (Lepomis cyanellus) and one cypriniform teleost (Carassius auratus) reveal that ipsilateral afferent connections in both species arise from an anterior group of nuclei in the diencephalon and mesencephalon, and a posterior group of nuclei in the rhombencephalon. Some nuclei of the anterior group and all those of the posterior group have in addition a weaker, and the medial octavolateralis nucleus a stronger, contralateral component. The inferior olivary nucleus in both species projects solely contralaterally. Nucleus paracommissuralis, the ventral accessory optic nucleus and nucleus isthmi are minute in Carassius compared to Lepomis. The latter species has in addition a bilateral corpopetal projection (ipsilaterally stronger) from the lateral cuneate nucleus. Efferent fibers in both species reach the contralateral nucleus ruber, oculomotor nucleus, nucleus of the medial longitudinal fasciculus, torus semicircularis, ventromedial and ventrolateral thalamic nuclei, optic tectum and superior and inferior reticular formation. An additional weaker ipsilateral terminal field could be observed in all nuclei except in the ventrolateral and ventromedial thalamic nuclei, the dorsal periventricular pretectal nucleus and the optic tectum. Lepomis in addition has a bilateral terminal field in the ventral accessory optic nucleus (contralaterally stronger). In both species, stronger ipsilateral and weaker contralateral terminal fields were present in the torus Iongitudinalis and the valvula cerebelli. The two patterns of corpopetal connections in Lepomis and Carassius were used as models for perciforms and cypriniforms in the analysis of the existing information in the literature on teleosts. While most discrepancies in the literature on percomorphs and ostariophysines could be interpreted consistently, the available information on mormyrids revealed a very different pattern of corpopetal organization: presence of additional connections (from a division of the nucleus preglomerulosus) and absence of otherwise well-established corpopetal connections in teleosts. In a second step, a phyletic analysis of teleostean corpopetal organization revealed that while teleosts share with all other vertebrates a group of corpopetal connections from the rhombencephalon, they evolved many new, more anteriorly located afferent inputs to the corpus cerebelli. Furthermore, electroreceptive mormyrids in addition evolved newly at least one corpopetal connection and lost many others

Visual and Electrosensory Circuits of the Diencephalon in Mormyrids

Mormyrids are one of two groups of teleost fishes known to have evolved electroreception, and the concomitant neuroanatomical changes have confounded the interpretation of many of their brain areas in a comparative context, e.g., the diencephalon, where different sensory systems are processed and relayed. Recently, cerebellar and retinal connections of the diencephalon in mormyrids were reported. The present study reports on the telencephalic and tectal connections, specifically in Gnathonemus petersii, as these data are critical for an accurate interpretation of diencephalic nuclei in teleosts. Injections of horseradish peroxidase into the telencephalon retrogradely labeled neurons ipsilaterally in various thalamic, preglomerular, and tuberal nuclei, the nucleus of the locus coeruleus (also contralaterally), the superior raphe, and portions of the nucleus lateralis valvulae. Telencephalic injections anterogradely labeled the dorsal preglomerular and the dorsal tegmental nuclei bilaterally. Injections into the optic tectum retrogradely labeled neurons bilaterally in the central zone of area dorsalis telencephali and ipsilaterally in the torus longitudinalis, various thalamic, pretectal, and tegmental nuclei, some nuclei in the torus semicircularis, the nucleus of the locus coeruleus, the nucleus isthmi and the superior reticular formation, basal cells in the ipsilateral valvula cerebelli, and eurydendroid cells in the contralateral lobe C4 of the corpus cerebelli. Weaker contralateral projections were also observed to arise from the ventromedial thalamus and various pretectal and tegmental nuclei, and from the locus coeruleus and superior reticular formation. Tectal injections anterogradely labeled various pretectal nuclei bilaterally, as well as ipsilaterally the dorsal preglomerular and dorsal posterior thalamic nuclei, some nuclei in the torus semicircularis, the dorsal tegmental nucleus, nucleus isthmi, and, again bilaterally, the superior reticular formation. A comparison of retinal, cerebellar, tectal, and telencephalic connections in Gnathonemus with those in nonelectrosensory teleosts reveals several points: (1 the visual area of the diencephalon is highly reduced in Gnathonemus, (2) the interconnections between the preglomerular area and telencephalon in Gnathonemus are unusually well developed compared to those in other teleosts, and (3) two of the three corpopetal diencephalic nuclei are homologues of the central and dorsal periventricular pretectum in other teleosts. The third is a subdivision of the preglomerular area, rather than an accessory optic or pretectal nucleus, and is related to electroreception. The preglomerulo-cerebellar connections in Gnathonemus are therefore interpreted as uniquely derived characters for mormyrids

Purinergic mechanosensory transduction and visceral pain

In this review, evidence is presented to support the hypothesis that mechanosensory transduction occurs in tubes and sacs and can initiate visceral pain. Experimental evidence for this mechanism in urinary bladder, ureter, gut, lung, uterus, tooth-pulp and tongue is reviewed. Potential therapeutic strategies are considered for the treatment of visceral pain in such conditions as renal colic, interstitial cystitis and inflammatory bowel disease by agents that interfere with mechanosensory transduction in the organs considered, including P2X(3) and P2X(2/3) receptor antagonists that are orally bioavailable and stable in vivo and agents that inhibit or enhance ATP release and breakdown

State Estimation in the Cerebellum

An exciting hypothesis about the cerebellum is that its role is one of state estimation—a process that combines afferent copies of motor commands with afferent sensory signals to produce a representation of the current status of the peripheral motor system. Sensory inputs alone cannot provide a perfect state signal because of inevitable delays in their afferent pathways. We have recently reported the effects of transcranial magnetic stimulation (TMS) over the ipsilateral cerebellum as healthy subjects made rapid reaching movements towards visually defined targets (Miall et al. in PLoS Biology 5:2733–2744, 2007). Errors in the initial direction and in the final finger position of this reachto-target movement were consistent with the reaching movements being planned and initiated from an estimated hand position that was about 138 ms out of date. This interval is consistent with estimates of the delays in sensory motor pathways that would inform the central nervous system of the peripheral status. We now report new data using the same paradigm, testing the effects of varying the TMS stimulus train from one, two, or three pulses. We show that the errors in movement are relatively insensitive to the TMS pulse-train duration. The estimated time interval by which the hand position is mislocalized varied by only 12 ms as the TMS train duration increased by 100 ms. Thus, this interval is likely to reflect physiological processes within the cerebellum rather than the TMSstimulus duration. This new evidence supports our earlier claim that the cerebellum is responsible for predictively updating a central state estimate over an interval of about 120–140 ms. Dysfunction of the cerebellum, whether through disease or experimental procedures, leads to motor errors consistent with a loss of knowledge of the true state of the motor system

Soleus H-reflex Excitability Changes in Response to Sinusoidal Hip Stretches in the Injured Human Spinal Cord

Imposed static hip stretches substantially modulate the soleus H-reflex in people with an intact or injured spinal cord while stretch of the hip flexors affect the walking pattern in lower vertebrates and humans. The aim of this study was to assess the effects of dynamic hip stretches on the soleus H-reflex in supine spinal cord injured (SCI) subjects. Sinusoidal movements were imposed on the right hip joint at 0.2 Hz by a Biodex system. H-reflexes from the soleus muscle were recorded as the leg moved in flexion or extension. Stimuli were sent only once in every hip movement cycle that each lasted 5 s. Torque responses were recorded at the hip, knee, and ankle joints. A hip phase-dependent soleus H-reflex modulation was present in all subjects. The reflex was facilitated during hip extension and suppressed during hip flexion. There were no significant differences in pre- or post-stimulus soleus background activity between the two conditions. Oscillatory responses were present as the hip was maximally flexed. Sinusoidal hip stretches modulated the soleus H-reflex in a manner similar to that previously observed following static hip stretches. The amount of reflex facilitation depended on the angle of hip extension. Further research is needed on the afferent control of spinal reflex pathways in health and disease in order to better understand the neural control of movement in humans. This will aid in the development of rehabilitation strategies to restore motor function in these patients