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PubMed2006

HCN1 ion channel immunoreactivity in spinal cord and medulla oblongata.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) non-selective cation channels in neurons carry currents proposed to perform diverse functions, including the hyperpolarization activated Ih current. The 4 HCN subunits have unique but overlapping patterns of expression in the CNS. Here, we examined the distribution of HCN1 channel subunits in the brainstem and spinal cord using immunohistochemistry. At all levels of the spinal cord dorsal horn, HCN1 immunoreactivity (HCN1-IR) was predominantly absent from laminae I and II, while a dense band of punctate labeling was visible in lamina III. Labeled neurons were identified in close vicinity to the central canal, in the lateral spinal nucleus, in the ventral horn and occasionally in lamina II and III. Those in the ventral horn were identified as alpha motor neurons using retrograde tracing and/or double or triple immunostaining with neuronal markers neurofilament 200 (NF200) and choline acetyltransferase. HCN1-IR neurons in the brainstem included neurons in sensory pathways such as the dorsal column nuclei, the area postrema, the spinal trigeminal nucleus as well as identified motor neurons in motor nuclei. In the nucleus ambiguus, a mixed visceral/motor nucleus, HCN1-IR was present only in NF200-IR cells, suggesting that it is expressed in motor but not autonomic preganglionic neurons. HCN1-IR motor neurons in the nucleus ambiguus also expressed the neurokinin 1 receptor and were labeled retrogradely from the larnyx. At the light microscopic level, the NTS and inferior olive contained punctate labeling, which ultrastructural examination revealed to be present in predominantly synaptic terminals or dendrites respectively. These data therefore described the first localization of the HCN1 subunit in the spinal cord and extend previous reports from the brainstem.

Animals↗
PubMed2006

The supragenual nucleus: a putative relay station for ascending vestibular signs to head direction cells.

Head direction (HD) cells located in several regions of the brain, including the postsubiculum, retrosplenial cortex, lateral dorsal thalamic nucleus, anterior dorsal thalamic nucleus, and lateral mammillary nucleus, provide a signal of the rat's momentary directional heading. Experimental evidence suggests that vestibular inputs are critical for the maintenance these cells' directional sensitivity. However, it is still unclear how vestibular information is conveyed to the HD cell-related circuitry. In a recent study, the supragenual nucleus (SG) was suggested as a putative relay of vestibular inputs to this circuitry. In the present study, using anterograde and retrograde tract-tracing methods, we first investigated whether the SG is in a position to convey vestibular inputs. Next, we examined the projections of the SG with the Phaseolus vulgaris leucoagglutinin method. Our results indicate that the SG receives direct inputs from the medial vestibular nucleus and projects to elements of the HD cell-related circuitry, providing a massive input to the contralateral dorsal tegmental nucleus and a moderately dense projection to the shell region of the lateral mammillary nucleus. Overall, the present findings serve to clarify how vestibular inputs reach the HD cell-related circuit and point out the SG as an important interface to this end.

Animals↗
PubMed2006

Topographic organization of the projections from the interstitial system of the spinal trigeminal tract to the parabrachial nucleus in the rat.

Neurons in the paratrigeminal nucleus are known to project to the parabrachial region, but both these areas are heterogeneous, and the subnuclei that account for these connections are not known. To characterize better these projections, we injected small amounts of fluorogold or latex beads labeled with rhodamine or fluorescein into the parabrachial area in the rat and evaluated the retrograde transport of tracer to the paratrigeminal nucleus and neighboring regions. The results show that the rostral part of the paratrigeminal nucleus projects to the medial subnucleus of the parabrachial nucleus. The intermediary part of the paratrigeminal nucleus projects to both the external lateral and to the external medial subnuclei of the parabrachial nucleus. The caudal part of the paratrigeminal nucleus projects to the ventral lateral subnucleus of the parabrachial nucleus. The dorsal paramarginal nucleus projects to the external lateral and the extreme lateral subnuclei of the parabrachial nucleus. Lamina I and II of the spinal trigeminal nucleus also project to the external lateral and the extreme lateral subnuclei of the parabrachial nucleus. In conclusion, the rostral, intermediate, and caudal parts of the paratrigeminal nucleus and the dorsal paramarginal nucleus each have clearly different projection patterns and presumably have different functions.

Animals↗
PubMed2004

Axonal connections from posterior paralaminar thalamic neurons to basomedial amygdaloid projection neurons to the lateral entorhinal cortex in rats.

Stimulation of amygdaloid nuclei and emotionally relevant stimuli are known to influence the induction and maintenance of long-term potentiation in the hippocampal formation and the formation of long-term declarative memories. Because the thalamic projection from the posterior paralaminar thalamic nuclei is an important sensory afferent projection to amygdaloid nuclei mediating the fast acquisition of fear-potentiated behavior, we were interested in verifying whether this projection establishes synaptic contacts on amygdala neurons that project to the hippocampal formation. Thalamic afferents were labeled with the anterograde tracer Phaseolus vulgaris leucoagglutinin and amygdalo-hippocampal neurons were identified by injection of the retrograde tracer Fluorogold into the lateral entorhinal cortex. A massive overlap of both projection systems was observed especially in the anterior basomedial nucleus of the amygdala. Light microscopic examination revealed that single anterogradely labeled boutons were in close apposition to retrogradely labeled neurons suggesting synaptic contacts. The occurrence of such synaptic contacts was confirmed with electron microscopy. However, despite the massive overlap of anterogradely labeled axons and retrogradely labeled neurons observed at the light microscopic level, electron microscopy revealed that only 10% of all labeled profiles make direct contacts on each other; anterogradely labeled boutons predominantly contacted unlabeled profiles but synapses with direct contact between labeled profiles were rare. Altogether the findings demonstrate that the thalamic connection with the basomedial nucleus of the amygdala may represent an anatomical substrate for modulating amygdala output to the hippocampal formation.

Amygdala↗
PubMed2006

Changes in vanilloid receptor 1 (TRPV1) expression following lingual nerve injury.

We have investigated a possible role for vanilloid receptor 1 (TRPV1), a transducer of noxious stimuli, in the development of neuropathic pain following injury to a peripheral branch of the trigeminal nerve. In nine adult ferrets the left lingual nerve was sectioned and recovery permitted for 3 days, 3 weeks or 3 months (3 ferrets per group). A retrograde tracer, fluorogold, was injected into the damaged nerve to identify associated cell bodies in the trigeminal ganglion. Three further ferrets, receiving only tracer injection, served as uninjured controls. Indirect immunofluorescence for TRPV1 and image analysis was used to quantify the percentage area of staining (PAS) of TRPV1 in the left and right lingual nerves. Additionally, the proportion of fluorogold positive and fluorogold negative cells expressing TRPV1 in the ganglion was determined. TRPV1 expression increased significantly at the injury site of damaged nerves 3 days after injury and this was matched by a reduction in the proportion of fluorogold positive cells expressing TRPV1 in the ganglion. At 3 weeks TRPV1 expression at the injury site was still high, while in the ganglion was significantly greater than in the controls. In the 3-month recovery group TRPV1 expression in both nerve fibres and ganglion cells, was not significantly different from controls and there were no changes in expression in the fluorogold negative cells in the ganglion at any time point studied. These data suggest that after injury there is an increase in the axonal transport of TRPV1 from the cell bodies to the damaged axons and this is followed by an increase in synthesis in the ganglion. These changes in expression may be involved in development of sensory disturbances or dysaesthesia after injury.

Animals↗
PubMed2004

Axonal reinjury reveals the survival and re-expression of regeneration-associated genes in chronically axotomized adult mouse motoneurons.

Recently, we reported that chronically axotomized rubrospinal neurons survive for up to 1 year in an atrophied state. This finding contrasted previous work suggesting the death of up to 50% of the neurons over time. In the adult mouse, the majority of facial motoneurons appear to be lost as a result of chronic nerve resection. Here, we sought to determine if chronically resected adult mouse facial motoneurons, like rubrospinal neurons, survive in an atrophied state. To test this hypothesis, we asked whether a second nerve injury, 10 weeks after an initial nerve resection, could stimulate a regenerative cell body response. After chronic resection (10 weeks), mouse facial motoneurons underwent atrophy resulting in a loss of countable neuronal cell bodies. In addition, the motoneurons failed to maintain their initial increase in expression of GAP-43 and alpha-tubulin mRNA. Reinjury of 10-week chronically resected facial motoneurons by the removal of the neuroma reversed the atrophy of the cell bodies and increased the percentage of identifiable cell bodies from 36% of contralateral to 79% in C57BL/6-C3H mice and from 28% of contralateral to 40% in Balb/c mice. Moreover, the reinjured motoneurons displayed an increase in GAP-43 and alpha-tubulin mRNA expression. The results of this study indicate that a second axon injury stimulates regenerative cell body responses in chronically resected mouse facial motoneurons and suggest previous studies using this model may have overestimated the number of dying motoneurons.

Animals↗
PubMed2004

A neuroprotective role of glial cell line-derived neurotrophic factor following moderate spinal cord contusion injury.

The present study investigated neuroprotective effects of glial cell line-derived neurotrophic factor (GDNF), a distant member of the transforming growth factor-beta (TGF-beta) superfamily, following moderate contusive spinal cord injury (SCI) in adult rats. A T11 spinal cord contusion injury was made using an Infinite Horizon impactor (IH; impact force=150 kDyn) and recombinant human GDNF at two concentrations (rhGDNF; 1 or 5 microg/microl), or saline vehicle was delivered intrathecally for 28 days using an Alzet miniosmotic pump. We demonstrated that, at 7 weeks postinjury, GDNF infusion significantly reduced the total lesion volume by 34-42% (assessed stereologically) and increased the percentage of white matter sparing by 10-13% (measured at the injury epicenter), as compared to the vehicle infusion. Retrograde tracing revealed that GDNF infusion resulted in a significant increase in the number of FluoroGold (FG)-labeled neurons in propriospinal regions as well as in two supraspinal regions, that is, the medullary and pontine reticular formation, and the lateral vestibular nucleus. Immunofluorescent staining confirmed that the spared white matter contained neurofilament-positive axons. However, transcranial magnetic motor-evoked potential (tcMMEP) assessment revealed no significant difference in onset latency and amplitude between the GDNF- and vehicle-infused groups. These results suggest that GDNF has a strong neuroprotective effect on white matter sparing and the sparing of a subset of proprio- and supraspinal axons following injury. However, a return of tcMMEPs requires the sparing and/or myelination of axons in a defined region of the white matter which was either not spared or remyelinated at this level of injury severity.

Animals↗
PubMed2004

Rubrospinal neurons fail to respond to brain-derived neurotrophic factor applied to the spinal cord injury site 2 months after cervical axotomy.

Numerous experimental therapies to promote axonal regeneration have shown promise in animal models of acute spinal cord injury, but their effectiveness is often found to diminish with a delay in administration. We evaluated whether brain-derived neurotrophic factor (BDNF) application to the spinal cord injury site 2 months after cervical axotomy could promote a regenerative response in chronically axotomized rubrospinal neurons. BDNF was applied to the spinal cord in three different concentrations 2 months after cervical axotomy of the rubrospinal tract. The red nucleus was examined for reversal of neuronal atrophy, GAP43 and Talpha1 tubulin mRNA expression, and trkB receptor immunoreactivity. A peripheral nerve transplant paradigm was used to measure axonal regeneration into peripheral nerve transplants. Rubrospinal axons were anterogradely traced and trkB receptor immunohistochemistry performed on the injured spinal cord. We found that BDNF treatment did not reverse rubrospinal neuronal atrophy, nor promote GAP-43 and Talpha1 tubulin mRNA expression, nor promote axonal regeneration into peripheral nerve transplants. TrkB receptor immunohistochemistry demonstrated immunoreactivity on the neuronal cell bodies, but not on anterogradely labeled rubrospinal axons at the injury site. These findings suggest that the poor response of rubrospinal neurons to BDNF applied to the spinal cord injury site 2 months after cervical axotomy is not related to the dose of BDNF administered, but rather to the loss of trkB receptors on the injured axons over time. Such obstacles to axonal regeneration will be important to identify in the development of therapeutic strategies for chronically injured individuals.

Animals↗
PubMed2005

Electrical stimulation restores the specificity of sensory axon regeneration.

Electrical stimulation at the time of nerve repair promotes motoneurons to reinnervate appropriate pathways leading to muscle and stimulates sensory neurons to regenerate. The present experiments examine the effects of electrical stimulation on the specificity of sensory axon regeneration. The unoperated rat femoral cutaneous branch is served by 2-3 times more DRG neurons than is the muscle branch. After transection and repair of the femoral trunk, equal numbers of DRG neurons project to both branches. However, 1 h of electrical stimulation restores the normal proportion of DRG neurons reinnervating skin and muscle. To ask if the redistribution of stimulated neurons results from enhanced specificity of target reinnervation, we developed a new technique of sequential double labeling. DRG neurons projecting to the femoral muscle branch were prelabeled with Fluoro Gold 2 weeks before the nerve was transected proximally and repaired with or without 1 h of 20-Hz electrical stimulation. Three weeks after repair, the muscle nerve was labeled a second time with Fluororuby. The percentage of regenerating neurons that both originally served muscle and returned to muscle after nerve repair increased from 40% without stimulation to 75% with stimulation. Electrical stimulation thus dramatically alters the distribution of regenerating sensory axons, replacing normally random behavior with selective reinnervation of tissue-specific targets. If the enhanced regeneration specificity resulting from electrical stimulation is found to improve function in a large animal model, this convenient and safe technique may be a useful adjunct to clinical nerve repair.

Animals↗
PubMed2005

The evidence for nitric oxide synthase immunopositivity in the monosynaptic Ia-motoneuron pathway of the dog.

In this study, nitric oxide synthase immunohistochemistry supported by nicotinamide adenine dinucleotide phosphate diaphorase histochemistry was used to demonstrate the nitric oxide synthase immunoreactivity in the monosynaptic Ia-motoneuron pathway exemplified by structural components of the afferent limb of the soleus H-reflex in the dog. A noticeable number of medium-sized intensely nitric oxide synthase immunoreactive somata (1000-2000 microm(2) square area) and large intraganglionic nitric oxide synthase immunoreactive fibers, presumed to be Ia axons, was found in the L7 and S1 dorsal root ganglia. The existence of nitric oxide synthase immunoreactive fibers (6-8 microm in diameter, not counting the myelin sheath) was confirmed in L7 and S1 dorsal roots and in the medial bundle of both dorsal roots before entering the dorsal root entry zone. By virtue of the funicular organization of nitric oxide synthase immunoreactive fibers in the dorsal funiculus, the largest nitric oxide synthase immunoreactive fibers represent stem Ia axons located in the deep portion of the dorsal funiculus close to the dorsomedial margin of the dorsal horn. Upon entering the gray matter of L7 and S1 segments and passing through the medial half of the dorsal horn, tapered nitric oxide synthase immunoreactive collaterals of the stem Ia fibers pass through the deep layers of the dorsal horn and intermediate zone, and terminate in the group of homonymous motoneurons in L7 and S1 segments innervating the gastrocnemius-soleus muscles. Terminal fibers issued in the ventral horn intensely nitric oxide synthase immunoreactive terminals with long axis ranging from 0.7 to >or=15.1 microm presumed to be Ia bNOS-IR boutons. This finding is unique in that it focuses directly on nitric oxide synthase immunopositivity in the signalling transmitted by proprioceptive Ia fibers. Nitric oxide synthase immunoreactive boutons were found in the neuropil of Clarke's column of L4 segment, varying greatly in size from 0.7 to >or=15.1 microm in length x 0.7 to 4.8 microm wide. Subsequent to identification of the afferent nitric oxide synthase immunoreactive limb of the monosynaptic Ia-motoneuron pathway on control sections, intramuscular injections of the retrograde tracer Fluorogold into the gastrocnemius-soleus muscles, combined with nitric oxide synthase immunohistochemistry of L7 and S1 dorsal root ganglia, confirmed the existence of a number of medium-sized nitric oxide synthase immunoreactive somata (1000-2000 microm(2) square area) in the dorsolateral part of both dorsal root ganglia, presumed to be proprioceptive Ia neurons. Concurrently, large nitric oxide synthase immunoreactive fibers were detected at the input and output side of both dorsal root ganglia. S1 and S2 dorsal rhizotomy caused a marked depletion of nitric oxide synthase immunoreactivity in the medial bundle of S1 and S2 dorsal roots and in the dorsal funiculus of S1, S2 and lower lumbar segments. In addition, anterograde degeneration of large nitric oxide synthase immunoreactive Ia fibers in the dorsal funiculus of L7-S2 segments produces direct evidence that the afferent limb of the soleus H-reflex is nitric oxide synthase immunoreactive and presents new immunohistochemical characteristics of the monosynaptic Ia-motoneuron pathway, unseparably coupled with the performance of the stretch reflex.

Afferent Pathways↗
PubMed2005

Progesterone restores retrograde labeling of cervical motoneurons in Wobbler mouse motoneuron disease.

The Wobbler mouse, a mutant characterized by motoneuron degeneration in the cervical spinal cord, has been used to test the efficacy of novel treatments for human motoneuron diseases (HMD). Previous reports have shown that slow axonal transport is impaired in Wobblers and other models of HMD. Since progesterone (PROG) corrects some morphological, molecular, and functional abnormalities of Wobbler mice, we studied if steroid exposure for 8 weeks restored retrograde axonal transport by measuring motoneuron labeling after injection of fluorogold into the limb muscles. The dye was injected into forelimb biceps bracchii and flexor or into the rearlimb gastrocnemius muscles; 6 days later, the number of fluorescent motoneurons and the total number of cresyl violet stained motoneurons were counted in the cervical (C5-T1) or lumbar (L3-L5) spinal cord regions. A pronounced reduction (- 42.2%) of the percent of fluorescent motoneurons in Wobbler mice cervical cord was noted, which was significantly corrected after PROG treatment. In contrast, labeling of lumbar motoneurons was not reduced in Wobbler mice and was not affected by PROG treatment. In no case PROG showed an effect in control mice. Concomitantly, PROG slightly but significantly increased biceps weight of Wobbler mice. Behaviorally, PROG-treated Wobblers performed better on a motor test (hanging time from a horizontal rope) compared to untreated counterparts. We postulate a dual role for PROG in the Wobbler mouse, in part by prevention of motoneuron degeneration and also by enhancement of axonal transport. The latter mechanism could improve the traffic of neurotrophic factors from the forelimb muscles into the ailing motoneurons, improving neuromuscular function in this murine model of HMD.

Animals↗
PubMed2005

Effect of spinal cord injury severity on alterations of the H-reflex.

The monosynaptic motoneuron response to stimulation of Ia afferents is known to be altered by spinal cord injury (SCI). Although the Hoffman (H)-reflex is a tool that is often used to measure this reflex in patients, there has not been a systematic study investigating the effect of SCI severity and time on the H-reflex. We used a clinically relevant model of spinal cord contusion (Mild and Moderate) as well as complete surgical transection to measure the H-reflex at 1, 4 and 8 weeks after injury. The H-reflex was recorded from rat hindpaw plantar muscles in order to measure the baseline reflex amplitude and its response to increased stimulus frequency, i.e. rate depression. We correlated the reflex amplitude at each frequency to spared white matter at the injury epicenter, hindlimb function and serotonin immunoreactivity associated with retrogradely labeled plantar muscle motoneurons. The three injury groups displayed different behavioral deficits and amount of spared white matter at all three times tested. H-reflex rate depression was abnormal in all three injury groups at all three time points. At 8 weeks, transected animals displayed more H-reflex rate depression than those with a mild contusion. Baseline H-reflex amplitude was increased in both contusion groups at 4 weeks and showed a positive linear correlation with serotonin immunoreactivity. This baseline amplitude was not increased after transection. Furthermore, in the contusion group, there was a U-shaped relationship between behavioral scores and H-reflex rate depression, suggesting that an intermediate sensitivity of the motoneuronal pool to afferent input is associated with better recovery of hindlimb function.

Analysis of Variance↗
PubMed2005

FAS deficiency reduces apoptosis, spares axons and improves function after spinal cord injury.

After spinal cord injury (SCI), apoptosis of neurons and oligodendrocytes is associated with axonal degeneration and loss of neurological function. Recent data have suggested a potential role for FAS death receptor-mediated apoptosis in the pathophysiology of SCI. In this study, we examined the effect of FAS deficiency on SCI in vitro and in vivo. FAS(Lpr/lpr) mutant mice and wildtype background-matched mice were subjected to a T5-6 clip compression SCI, and complementary studies were done in an organotypic slice culture model of SCI. Post-traumatic apoptosis in the spinal cord, which was seen in neurons and oligodendrocytes, was decreased in the FAS-deficient mice both in vivo and in vitro particularly in oligodendrocytes. FAS deficiency was also associated with improved locomotor recovery, axonal sparing and preservation of oligodendrocytes and myelin. However, FAS deficiency did not result in a significant increase in surviving neurons in the spinal cord at 6 weeks after injury, likely reflecting the importance of other cell death mechanisms for neurons. We conclude that inhibition of the FAS pathway may be a clinically attractive neuroprotective strategy directed towards oligodendroglial and axonal preservation in the treatment of SCI and neurotrauma.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2005

Caspase inhibition therapy abolishes brain trauma-induced increases in Abeta peptide: implications for clinical outcome.

The detrimental effects of traumatic brain injury (TBI) on brain tissue integrity involve progressive axonal damage, necrotic cell loss, and both acute and delayed apoptotic neuronal death due to activation of caspases. Post-injury accumulation of amyloid precursor protein (APP) and its toxic metabolite amyloid-beta peptide (Abeta) has been implicated in apoptosis as well as in increasing the risk for developing Alzheimer's disease (AD) after TBI. Activated caspases proteolyze APP and are associated with increased Abeta production after neuronal injury. Conversely, Abeta and related APP/Abeta fragments stimulate caspase activation, creating a potential vicious cycle of secondary injury after TBI. Blockade of caspase activation after brain injury suppresses apoptosis and improves neurological outcome, but it is not known whether such intervention also prevents increases in Abeta levels in vivo. The present study examined the effect of caspase inhibition on post-injury levels of soluble Abeta, APP, activated caspase-3, and caspase-cleaved APP in the hippocampus of nontransgenic mice expressing human Abeta, subjected to controlled cortical injury (CCI). CCI produced brain tissue damage with cell loss and elevated levels of activated caspase-3, Abeta(1-42) and Abeta(1-40), APP, and caspase-cleaved APP fragments in hippocampal neurons and axons. Post-CCI intervention with intracerebroventricular injection of 100 nM Boc-Asp(OMe)-CH(2)F (BAF, a pan-caspase inhibitor) significantly reduced caspase-3 activation and improved histological outcome, suppressed increases in Abeta and caspase-cleaved APP, but showed no significant effect on overall APP levels in the hippocampus after CCI. These data demonstrate that after TBI, caspase inhibition can suppress elevations in Abeta. The extent to which Abeta suppression contributes to improved outcome following inhibition of caspases after TBI is unclear, but such intervention may be a valuable therapeutic strategy for preventing the long-term evolution of Abeta-mediated pathology in TBI patients who are at risk for developing AD later in life.

Amyloid beta-Peptides↗
PubMed2006

Most neurons in the nucleus tractus solitarii do not send collateral projections to multiple autonomic targets in the rat brain.

The nucleus tractus solitarii (NTS) receives primary visceral afferents and sends projections to other autonomic nuclei at all levels of the neuroaxis. However, it is unknown if distinct populations of NTS neurons project to individual autonomic targets or if individual neurons in the NTS project to multiple autonomic targets. Understanding the basic circuitry of visceral reflex pathways is essential for the analyses of functional central autonomic networks. We examined projections from the NTS to autonomic targets within the hypothalamus (paraventricular nucleus, PVN), pons (parabrachial nucleus, PB), and medulla (caudal ventrolateral medulla, CVL) using retrograde tracing and immunohistochemistry. Dual retrograde tracer microinjections were made into pairs of targets (PVN + CVL; PVN + PB; PB + CVL), and the pattern of retrograde labeling was examined within NTS. The extent of collateralization, seen as dual retrogradely labeled neurons, was negligible for combined PVN and CVL injections and increased for injections combining PB with either PVN or CVL, but the majority of NTS neurons project to only one autonomic target. Immunohistochemistry for tyrosine hydroxylase (TH) was used to examine the pattern of TH-immunoreactivity (TH-ir) within retrogradely labeled NTS neurons. TH-ir was seen predominantly in projections to PVN, to a lesser degree in projections to PB, and was largely absent from projections to CVL. The percentage of dual retrogradely labeled neurons displaying TH-ir corresponded to the target displaying the most TH-ir, and TH-ir was not predictive of collateralization. Together, these results indicate that NTS neurons project to individual autonomic targets in the brain.

Animals↗
PubMed2006

A re-assessment of the consequences of delayed transplantation of olfactory lamina propria following complete spinal cord transection in rats.

This study is part of the NIH "Facilities of Research-Spinal Cord Injury" contract to support independent replication of published studies. We repeated a study reporting that delayed transplantation of olfactory lamina propria (OLP) into the site of a complete spinal cord transection led to significant improvement in hindlimb motor function and induced axon regeneration. Adult female rats received complete spinal cord transections at T10. Thirty days post-injury, pieces of OLP, which contains olfactory ensheathing cells (OECs), or respiratory lamina propria (RLP), which should not contain OECs, were placed into the transection site. Hindlimb motor function was tested using the BBB scale from day 1 post-injury through 10 weeks following transplantation. To assess axonal regeneration across the transection site, Fluorogold was injected into the distal segment, and the distribution of 5HT-containing axons was assessed using immunostaining. BBB analyses revealed no significant recovery after OLP transplantation and no significant differences between OLP vs. RLP transplant groups. Fluorogold injections into caudal segments did not lead to retrograde labeling in any animals. Immunostaining for 5HT revealed that a few 5HT-labeled axons extended into both RLP and OLP transplants and a few 5HT-labeled axons were present in sections caudal to the injury in 2 animals that received OLP transplants and 1 animal that received RLP transplants. Our results indicate that, although OLP transplants may stimulate regeneration under some circumstances, the effect is not so robust as to reliably overcome the hostile setting created by a complete transection paradigm.

Animals↗
PubMed2007

Anatomical integration of newly generated dentate granule neurons following traumatic brain injury in adult rats and its association to cognitive recovery.

The hippocampus is particularly vulnerable to traumatic brain injury (TBI), the consequences of which are manifested as learning and memory deficits. Following injury, substantive spontaneous cognitive recovery occurs, suggesting that innate repair mechanisms exist in the brain. However, the underlying mechanism contributing to this is largely unknown. The existence of neural stem cells in the adult hippocampal dentate gyrus (DG) and their proliferative response following injury led us to speculate that neurogenesis may contribute to cognitive recovery following TBI. To test this, we first examined the time course of cognitive recovery following lateral fluid percussion injury in rats. Cognitive deficits were tested at 11-15, 26-30 or 56-60 days post-injury using Morris Water Maze. At 11-15 and 26-30 days post-injury, animals displayed significant cognitive deficits, which were no longer apparent at 56-60 days post-TBI, suggesting an innate cognitive recovery at 56-60 days. We next examined the proliferative response, maturational fate and integration of newly generated cells in the DG following injury. Specifically, rats received BrdU at 2-5 days post-injury followed by Fluorogold (FG) injection into the CA3 region at 56 days post-TBI. We found the majority of BrdU+ cells which survived for 10 weeks became dentate granule neurons, as assessed by NeuN and calbindin labeling, approximately 30% being labeled with FG, demonstrating their integration into the hippocampus. Additionally, some BrdU+ cells were synaptophysin-positive, suggesting they received synaptic input. Collectively, our data demonstrate the extensive anatomical integration of new born dentate granule neurons at the time when innate cognitive recovery is observed.

Animals↗
PubMed2006

Neuronal organization of the rat inferior colliculus participating in four major auditory pathways.

The central nucleus of the inferior colliculus (CNIC) contains different types of neurons and is a source of ascending projection to the medial geniculate body (MGB), commissural projection to the contralateral IC, direct descending projection to the cochlea nucleus (CN) and indirect projection to the CN via the superior olivary complex (SOC). Using a retrograde tracing technique, we examined what kind of neurons and what percentage of neurons of each type recognized in the CNIC participated in the above-mentioned four projection pathways. We also examined whether the individual CNIC neurons send the collateral to the MGB, the contralateral IC, the CN and the SOC. In the present study, we demonstrated that the neurons participating in the four projections could be morphologically classified into two types of neurons with soma size variation. The percentages of neurons of each type differed among the four projection pathways. Using a double-labeling technique, we found very few double-labeled neurons, indicating the collateral projections to the ipsilateral MGB and the contralateral IC. There were no double-labeled neurons in the collateral projections between the other combinations of targets. Therefore, we conclude that the ascending projection, the commissural projection and the descending projection to these targets arise from separate populations of neurons.

Animals↗