Development of brain-derived neurotrophic factor and neurotrophin-3 immunoreactivity in the lower auditory brainstem of the postnatal gerbil.

The localization of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) in the gerbil auditory brainstem was studied during normal postnatal development. The principal objective of this paper was to compare the developmental distribution of BDNF and NT-3 proteins to the known developmental distribution of their cognate, high-affinity tyrosine kinase receptors. BDNF and NT-3 proteins were localized using standard immunohistochemistry. No specific immunoreactivity for BDNF or NT-3 was detected on the day of birth (P0) in any auditory structure, although fibers comprising the spinal tract of the Vth cranial nerve were well labelled with antibodies against BDNF. Diffuse immunoreactivity for both BDNF and NT-3 was first detected at P3 in the cochlear nucleus and in several second order auditory nuclei in the superior olivary complex. This diffuse immunoreactivity became clustered and restricted to neuronal cell bodies by P10. Immunoreactivity for both BDNF and NT-3 transiently disappeared in the lateral and medial superior olivary nuclei at P10. However, neurons in the medial nucleus of the trapezoid body remained immunopositive for both BDNF and NT-3. Fibers in the trapezoid body were labelled with BDNF immunoreactivity by P12. Between P12 and P15, the distribution of BDNF and NT-3 immunoreactivity in the cochlear nucleus and superior olivary complex became comparable to adult (P140) immunolabel. These results show that the normal developmental distribution of the neurotrophins BDNF and NT-3 in the lower auditory brainstem occurs during the first two postnatal weeks in parallel with the developmental expression of their cognate receptors, trkB and trkC.

Prevention and reversal of experimental posthemorrhagic vasospasm by the periadventitial administration of nitric oxide from a controlled-release polymer.

OBJECTIVE: Despite improvements in the care of patients with aneurysmal subarachnoid hemorrhage, delayed cerebral vasospasm remains a major cause of morbidity and death. There is now evidence that a decrease in the local availability of nitric oxide (NO) plays a role in delayed cerebral vasospasm. We evaluated a controlled-release polymer containing the NO donor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO) for the treatment of chronic posthemorrhagic vasospasm in the rat femoral artery model. METHODS: The release kinetics of ethylene/vinyl acetate copolymers loaded with 20% (w/w) DETA/NO were determined in vitro. Chronic vasospasm was induced in the left femoral artery of adult male Fischer 344 rats (n = 35) by exposure to autologous blood. At 1, 3, or 7 days after blood exposure, either a 5-mg polymer loaded with 20% (w/w) DETA/NO or an empty 5-mg polymer was placed in the periadventitial space next to the left femoral artery. At the same time, an empty 5-mg polymer was placed next to the right femoral artery. On the 8th day after blood exposure (at the peak of vasospasm in this model), rats were transcardially perfused with 4% paraformaldehyde, and the left and right femoral arteries were removed for histological processing and morphometric analyses. Vasospasm was expressed as the percent lumen patency of the treated left artery, compared with the control right artery. RESULTS: The in vitro release kinetics demonstrated that the 20% DETA/NO-loaded polymers released up to 15% of their total drug load during a 9-day period. DETA/NO treatments initiated at 1, 3, or 7 days after blood deposition all significantly inhibited vasospasm, compared with control values (94.6 +/- 7.2% versus 67.6 +/- 5.8%, 104.6 +/- 5.5% versus 64.9 +/- 1.7%, and 102.4 +/- 5.1% versus 73.6 +/- 1.4%, respectively; mean +/- standard error of the mean percent lumen patency; P < 0.001). No adverse effects of treatment were observed. CONCLUSION: The diazeniumdiolate NO donor DETA/NO can be effectively released from ethylene/vinyl acetate polymers. Administration of DETA/NO into the periadventitial space can prevent the development of chronic posthemorrhagic vasospasm in the rat femoral artery and can reverse established vasospasm. No adverse effects of DETA/NO were observed in this model.

Naturally occurring neuron death during postnatal development of the gerbil ventral cochlear nucleus begins at the onset of hearing.

Postnatal development of the gerbil ventral cochlear nucleus (VCN) was studied quantitatively under the light microscope in Nissl-stained serial sections at postnatal day 0 (P0), P5, P7, P10, P12, P15, and P140. VCN boundaries were unambiguous at all ages, and nucleus volume was calculated planimetrically for all groups. Measurements of neuron soma cross-sectional area and number were made in all groups except P0. Both VCN volume and soma area doubled between P5 and P10. Although somatic growth did not continue beyond P10, VCN volume increased a further 57% between P15 and P140. Neuron number did not change significantly between P5 and P10, averaging approximately 36,000 neurons. Between P10 and P12, neuron number decreased significantly by 22%, with no further change thereafter. Our data show that, following significant postnatal growth in the gerbil VCN, a brief period of naturally occurring neuron death begins at the onset of hearing.

Susceptibility of developing cochlear nucleus neurons to deafferentation-induced death abruptly ends just before the onset of hearing.

To investigate the ability of developing cochlear nucleus (CN) neurons to survive in the absence of afferent input, left cochlear removals were performed on gerbils at 2 day intervals from postnatal (P)3 to P11, and at P18 and P93. After a 3 month postsurgical survival period, Nissl-stained frontal sections through the brainstem were analyzed under the light microscope. CN volume, anteroventral cochlear nucleus (AVCN) neuron cross-sectional area, and total number of neurons in the CN were measured on both sides of the brain. Mean volume reduction of the deafferented CN relative to the intact CN ranged between 76% in the P3 group to 33% in the P11 group and did not differ significantly between P11 and P93. Cochlear removal at all ages reduced AVCN neuron cross-sectional area by approximately 40% in the deafferented CN relative to the intact CN, except for the P93 group where neuron atrophy was significantly less severe (23% mean reduction). Massive loss of CN neurons (>50% of the intact side) was observed following cochlear removal performed during the first postnatal week. However, between P7 and P9, neurons in all areas of the CN lose susceptibility to deafferentation-induced neuron death. No significant neuron loss was observed following cochlear removal after P7. This study shows that an abrupt transition in the ability of CN neurons to survive in the absence of afferent input is coincident with events leading to the onset of hearing.

Binaural interaction in human neonatal auditory brainstem.

Binaural interaction (BI) in brainstem auditory evoked response (BAER) were examined in normal term neonates. The BI components coincided consistently with the latency range of BAER wave IV through wave VII. Most BI components seen in the adults could be identified in the neonates, but the later components, i.e. those with longer latency, were underdeveloped in wave form. Wave DV was the most consistent and reproducible BI component. A marked difference between the neonatal and adult BI wave forms was that wave DVII was particularly small in the neonates. It appears that neuronal responses contributing to later BI components such as wave DVII are particularly immature at birth. Wave latencies and interpeak intervals were longer and amplitudes were smaller in the neonates than in the adults, which was associated with the differences between the neonates and adults in the BAER components. Changes in the BI components with stimulus intensity and rate in the neonates were fundamentally similar to but more significant compared with those in the adults. These findings suggest that neural connections in human auditory brainstem subserving the BI are established at birth but, particularly at higher levels of the brainstem, are immature.

Long-term effect of perinatal and postnatal asphyxia on developing human auditory brainstem responses: brainstem impairment.

Long-term effect of perinatal and postnatal asphyxia on the developing auditory brainstem was investigated in children, particularly those who exhibited residual neurodevelopmental deficits, by analyzing the central components of brainstem auditory evoked responses (BAER). The major abnormalities in the BAER were a reduction of wave V amplitude, followed by a decrease in V/I amplitude ratio, while abnormalities in interpeak intervals were relatively rare. These findings suggest that asphyxia could result in residual neural dysfunction of the brainstem but does not appear to exert any major long-term effect on neuronal transmission. BAER abnormalities occurred more frequently in the children with residual neurodevelopmental deficits than those without these deficits after perinatal asphyxia. The occurrence of BAER abnormalities was related to the duration as well as the degree of asphyxia. No significant difference was found in the abnormalities of the central BAER components between the children after perinatal asphyxia and those after postnatal asphyxia, suggesting that perinatal and postnatal asphyxia exerts a similar long-term effect on the developing central nervous system.

Development of human peripheral hearing revealed by brainstem auditory evoked potentials.

Development of human peripheral hearing from birth to 6 years was investigated by recording brainstem auditory evoked potentials (BAEPs). The threshold of BAEPs decreased rapidly during the first 3 months after birth (2.7 dB/week during the neonatal period, 2.6 dB/month at 1-3 months), after which further decrease occurred more slowly but continued through 1 year of age (0.26 dB/month at 3-12 months). A few days after birth, the threshold was 18 dB higher compared to the adults, and progressively decreased to 10, 5 and 2 dB at 1, 3 and 12 months, respectively. The latencies of waves I and V decreased as a function of age at a rate of 0.01 and 0.05 ms/week during the neonatal period, 0.02 and 0.10 ms/month at 1-3 months and 0.014 and 0.076 ms/month at 3-12 months, respectively. Adult latency value was attained by 2 and 4 years for waves I and V, respectively. These findings suggest that although the ear is reported to be almost adult-like at birth, the immaturity in neural functional properties limits auditory sensitivity during early childhood. It appears that human peripheral hearing threshold decreases rapidly through the third postnatal month and thereafter continues to improve slowly through early childhood. It is postulated that the first 3 months after birth are likely to be a critical period in postnatal development of human peripheral hearing.