Recovery of synapses in axotomized adult cat spinal motoneurons after reinnervation into muscle

 Peripheral axotomy of adult cat spinal motoneurons induces a marked loss of synaptic boutons from the cell bodies and dendritic trees. The aim of the present study was to analyze the recovery of synaptic contacts in axotomized motoneurons following reinnervation into muscle. Adult cat spinal motoneurons were first deprived of their muscular contacts for 12 weeks and, then, allowed to reinnervate their target muscle. Two years later, regenerated motoneurons were labeled with horseradish peroxidase to allow quantitative ultrastructural analyses of the synaptic covering of the cell bodies and dendrites. Presynaptic boutons were classified according to their size and the shape of their synaptic vesicles. Results show that a recovery of synaptic covering occurs in the axotomized neurons after muscle reinnervation, but it affects various bouton types to different degrees. The number of S-type boutons synapsing with the soma was 70% higher after reinnervation than at 12 weeks after axotomy, while the number of F-type boutons had increased by only 13%. Compared with the normal situation, the number of S-type boutons synapsing with the proximal dendrites increased from 82% at 12 weeks after axotomy to 180% in the reinnervated state. In conclusion, in adult cat spinal motoneurons, the reestablishment of muscular contact is followed by a normalization of some of the synaptological changes induced by a prolonged state of axotomy. In certain respects restitution is incomplete, but in others it results in overcompensation. Received: 10 December 1997 / Accepted: 30 July 1998     

Involvement of brain-derived neurotrophic factor and sonic hedgehog in the spinal cord plasticity after neurotoxic partial removal of lumbar motoneurons

Adult mammals could spontaneously achieve a partial sensory-motor recovery after spinal cord injury, by mechanisms including synaptic plasticity. We previously showed that this recovery is associated to the expression of synapsin-I, and that sonic hedgehog and Notch-1 could be also involved in plasticity. The role of brain-derived neurotrophic factor and glutamate receptors in regulating synaptic efficacy has been explored in the last decade but, although these mechanisms are now well-defined in the brain, the molecular mechanisms underlying the so called "spinal learning" are still less clear. Here, we measured the expression levels of choline acetyltransferase, synapsin-I, sonic hedgehog, Notch-1, glutamate receptor subunits (GluR1, GluR2, GluR4, NMDAR1) and brain-derived neurotrophic factor, in a motoneuron-depleted mouse spinal lesion model obtained by intramuscular injection of cholera toxin-B saporin. The lesion caused the down-regulation of the majority of analysed proteins. Moreover, we found that in lesioned but not in control spinal tissue, synapsin-I expression is associated to that of both brain-derived neurotrophic factor and sonic hedgehog, whereas GluR2 expression is linked to that of Shh. These results suggest that brain-derived neurotrophic factor and sonic hedgehog could collaborate in modulating synaptic plasticity after the removal of motoneurons, by a mechanism involving both pre- and post-synaptic processes. Interestingly, the involvement of sonic hedgehog showed here is novel, and offers new routes to address spinal cord plasticity and repair.     

Injured primary sensory neurons switch phenotype for brain-derived neurotrophic factor in the rat.

Peripheral nerve injury results in plastic changes in the dorsal root ganglia and spinal cord, and is often complicated with neuropathic pain. The mechanisms underlying these changes are not known. We have now investigated the expression of brain-derived neurotrophic factor in the dorsal root ganglia with histochemical and biochemical methods following sciatic nerve lesion in the rat. The percentage of neurons immunoreactive for brain-derived neurotrophic factor in the ipsilateral dorsal root ganglia was significantly increased as early as 24 h after the nerve lesion and the increase lasted for at least two weeks. The level of brain-derived neurotrophic factor messenger RNA was also significantly increased in the ipsibut not contralateral dorsal root ganglia. Both neurons and satellite cells in the lesioned dorsal root ganglia synthesized brain-derived neurotrophic factor messenger RNA after the nerve lesion. There was a dramatic shift in size distribution of positive neurons towards large sizes seven days after sciatic nerve lesion. Morphometric analysis and retrograde tracing studies showed that no injured neurons smaller than 600 microm2 were immunoreactive for brain-derived neurotrophic factor, whereas the majority of large injured neurons were immunoreactive in the ipsilateral dorsal root ganglia seven days postlesion. The brain-derived neurotrophic factor-immunoreactive nerve terminals in the ipsilateral spinal cord were reduced in the central region of lamina II, but increased in more medial regions or deeper into laminae III/IV. These studies indicate that sciatic nerve injury results in a differential regulation of brain-derived neurotrophic factor in different subpopulations of sensory neurons in the dorsal root ganglia. Small neurons switched off their normal synthesis of brain-derived neurotrophic factor, whereas larger ones switched to a brain-derived neurotrophic factor phenotype. The phenotypic switch may have functional implications in neuronal plasticity and generation of neuropathic pain after nerve injury.     

Progesterone up-regulates neuronal brain-derived neurotrophic factor expression in the injured spinal cord

Progesterone (PROG) provides neuroprotection to the injured central and peripheral nervous system. These effects may be due to regulation of myelin synthesis in glial cells and also to direct actions on neuronal function. Recent studies point to neurotrophins as possible mediators of hormone action. Here, we show that the expression of brain-derived neurotrophic factor (BDNF) at both the mRNA and protein levels was increased by PROG treatment in ventral horn motoneurons from rats with spinal cord injury (SCI). Semiquantitative in situ hybridization revealed that SCI reduced BDNF mRNA levels by 50% in spinal motoneurons (control: 53.5+/-7.5 grains/mm(2) vs. SCI: 27.5+/-1.2, P<0.05), while PROG administration to injured rats (4 mg/kg/day during 3 days, s.c.) elicited a three-fold increase in grain density (SCI+PROG: 77.8+/-8.3 grains/mm(2), P<0.001 vs. SCI). In addition, PROG enhanced BDNF immunoreactivity in motoneurons of the lesioned spinal cord. Analysis of the frequency distribution of immunoreactive densities (chi(2): 812.73, P<0.0001) showed that 70% of SCI+PROG motoneurons scored as dark stained whereas only 6% of neurons in the SCI group belonged to this density score category (P<0.001). PROG also prevented the lesion-induced chromatolytic degeneration of spinal cord motoneurons as determined by Nissl staining. In the normal intact spinal cord, PROG significantly increased BDNF inmunoreactivity in ventral horn neurons, without changes in mRNA levels. Our findings suggest that PROG enhancement of endogenous neuronal BDNF could provide a trophic environment within the lesioned spinal cord and might be part of the PROG activated-pathways to provide neuroprotection.     

Differential synaptic inputs to the cell body and proximal dendrites of preganglionic parasympathetic neurons in the rat conus medullaris

Preganglionic parasympathetic neurons (PPNs) reside in the intermediolateral (IML) nucleus of the rat lumbosacral spinal cord and contribute to the autonomic control of visceral pelvic organs. PPNs provide the final common pathway for efferent parasympathetic information originating in the spinal cord. We examined the detailed ultrastructure of the type and organization of synaptic inputs to the cell body and proximal dendrites of PPNs in the rat conus medullaris. The PPNs were retrogradely labeled by a systemic administration of the B subunit of cholera toxin conjugated to horseradish peroxidase. We demonstrate four distinct types of synaptic boutons in apposition with PPN somata and proximal dendrites: S-type boutons show clear, spheroid vesicles; F-type boutons show flattened vesicles; dense-cored vesicle-type (DCV-type) boutons show a mixture of clear and dense-cored vesicles; L-type boutons were rare, but large, exhibited clear spheroid vesicles, and were only encountered in apposition with the PPN dendrites in our sample. The membrane surface covered by apposed boutons was markedly higher for the proximal dendrites of PPNs, compared with their somata. The inhibitory synaptic influence was markedly higher over the PPN somata compared with their proximal dendrites, as suggested by the higher proportion of putative inhibitory F-type boutons in apposition with the soma and a higher frequency of S-type boutons per membrane length for the proximal dendrites. Our studies suggest that the synaptic input to PPNs originates from multiple distinct sources and is differentially distributed and integrated over the cell membrane surface.     

Changes in synaptology of adult cat spinal α-motoneurons after axotomy

The aim of this electron-microscopic study was to analyze the distribution of synaptic contacts on the cell bodies and dendrites of permanently axotomized adult cat spinal α-motoneurons. Following transection and ligation of the medial gastrocnemius nerve, the synaptic covering of the cell bodies and three different dendritic compartments of homonymous α-motoneurons was analyzed quantitatively at 3, 6, and 12 weeks postoperatively. The synaptic boutons were classified according to their size and the shape of their synaptic vesicles. On the soma, a transient increase in the number of boutons was noted at 3 weeks and 6 weeks postoperatively, while after 12 weeks the bouton number had decreased to half of its normal value. The transient increase was mainly due to an increase in the number of F-type boutons. At 12 weeks postoperatively, the synaptic covering was reduced by 83% on the soma and by 57% on the proximal dendrites. In the distal dendritic regions, the values for synaptic covering remained largely unchanged. In summary, axotomized motoneurons exhibit a reduction in synaptic covering which is maximal on the cell body and becomes less pronounced centrifugally along the dendrites. However, if also taking into account the loss of distal dendritic branches that occurs in axotomized motoneurons, the total loss of boutons is several times larger in the dendrites than on the soma. Received: 18 October 1996 / Accepted: 13 June 1997     

Ultrastructural observations on beaded alpha-motoneuron dendrites

Beaded dendrites of alpha-motoneurons intracellularly labelled with horseradish peroxidase (HRP) were studied ultrastructurally in eight adult cats. For comparison, adjacent unlabelled beaded dendrites of unknown origin were also included in the study. Electron microscopy revealed no signs of degeneration or poor fixation according to common criteria. With the exception of the HRP-reaction product no difference in structure was observed between labelled and unlabelled beaded dendrites. Both the beads and their interconnecting segments were postsynaptic to boutons of normal appearance containing spherical (S-type boutons) or flattened vesicles (F-type boutons). The values for synaptic covering and synaptic packing density of the beaded dendritic regions, which usually were located in the periphery of the dendritic trees, were clearly lower than values obtained previously for cell bodies and proximal dendrites of alpha-motoneurons.     

脊髓运动神经元胞体上的突触超微结构

本文报道了大白鼠脊髓运动神经元轴-体突触的超微结构特点。根据电镜观察的结果说明脊髓运动神经元胞体表面的突触前囊内有五种形态的突触小泡,它们包括S形小泡(圆形小泡)、E形小泡(椭圆形小泡)、F形小泡(扁平形小泡)、G形小泡(颗粒小泡)和Co形小泡(有被小泡)等。作者认为脊髓灰质前角内运动神经元的轴-体突触可以区分为四种类型、S型突触(含圆形小泡)、F形突触(含椭圆形小泡或扁平形小泡)、S-F型突触(以圆形小泡占优势)和F-S型突触(以扁平形小泡或椭圆形小泡占优势)。后二种类型的突触为运动神经元上的混合小泡型(Mv型)轴-体突触。有关突触连接部位的形态特征、突触小泡的形态、突触的分型、突触膜和突触裂的特点,以及突触与神经胶质间的关系等问题在论文中作了讨论。     

Ultrastructural observations on beaded α-motoneuron dendrites

Beaded dendrites of 1α-motoneurons intracellularly labelled with horseradish peroxidase (HRP) were studied ultrastructurally in eight adult cats. For comparison, adjacent unlabelled beaded dendrites of unknown origin were also included in the study. Electron microscopy revealed no signs of degeneration or poor fixation according to common criteria. With the exception of the HRP-reaction product no difference in structure was observed between labelled and unlabelled beaded dendrites. Both the beads and their interconnecting segments were postsynaptic to boutons of normal appearance containing spherical (S-type boutons) or flattened vesicles (F-type boutons). The values for synaptic covering and synaptic packing density of the beaded dendritic regions, which usually were located in the periphery of the dendritic trees, were clearly lower than values obtained previously for cell bodies and proximal dendrites of a-motoneurons.     

GABA- and glycine-immunoreactive terminals contacting motoneurons in lamprey spinal cord

Double postembedding GABA- and glycine-immunostaining was performed on the lamprey (Lampetra fluviatilis) spinal cord after previous HRP labeling of motoneurons. Immunopositive boutons contacting motoneurons were counted and distinguished as GABA (39%), glycine (30%) and both GABA+glycine-immunopositive (31%). Densely-packed, flattened synaptic vesicles were only observed in glycine-immunopositive boutons while GABA-immunoreactive and GABA+glycine-immunoreactive boutons contained rounded or oval synaptic vesicles. Dense-core vesicles of different diameters were associated with conventional synaptic vesicles in 74% of GABA-only-immunopositive boutons, 50% of double GABA+glycine-immunopositive boutons, but were only observed in 9% of glycine-only-immunopositive boutons. The presence of terminals immunoreactive to either GABA or glycine contacting the motoneurons suggests that there is a morphological substrate for both GABAergic and glycinergic postsynaptic inhibition of motoneurons in the lamprey spinal cord.     

Brain-derived neurotrophic factor reduces necrotic zone and supports neuronal survival after spinal cord hemisection in adult rats

Spinal cord injury (SCI) often results in necrotic changes leading to cavity formation and glial scar tissue in the lesion zone. We have examined the effects of continuous topical administration of brain-derived neurotrophic factor (BDNF) on cavity formation and neuronal death after SCI. Following retrograde prelabeling of the tibial motoneurons in the L4–L6 spinal cord segments with the fluorescent dye Fast blue, a spinal hemisection was performed in the L5 segment. At 4 weeks postoperatively, only 66% of the labeled motoneurons remained in the untreated animals, while BDNF treatment resulted in a significant reduction in size of the lesion cavity and 92% motoneuron survival. A therapeutic potential of BDNF in the early treatment of SCI is suggested.     

Elimination of intramedullary axon collaterals of cat spinal α-motoneurons following peripheral nerve injury

Summary The motor nerve supplying the medial gastrocnemius (MG) muscle was transected in the popliteal fossa of adult cats. The proximal nerve stump was ligated to prevent reinnervation. Three, six or twelve weeks later, axotomized MG motoneurons were intracellularly labelled with horseradish peroxidase, and the morphology of their intramedullary axon collateral systems was investigated quantitatively. The results were compared with corresponding data obtained from normal MG motoneurons. The peripheral chronic axotomy induced a gradual decrease in the number of recurrent axon collaterals originating from the lesioned MG motoraxons within the spinal cord. At 12 weeks postoperatively, this decrease amounted to 40%. The elimination preferentially involved axon collaterals originating from juxta-somatic regions of the motoraxons. In the axon collateral trees persisting in the axotomized MG neurons the tree size, branching patterns and number of synaptic boutons were all normal. Thus, no signs of a gradual deterioration of individual axon collateral systems were observed at any postoperative stage studied. The results are discussed in relation to other retrograde degenerative and regenerative events induced by axotomy.     

Galectin-1 expression correlates with the regenerative potential of rubrospinal and spinal motoneurons

Axotomized spinal motoneurons are able to regenerate to their peripheral targets, whereas injured rubrospinal neurons that lie completely within the CNS fail to regenerate. The differing cell body reactions to axotomy of these two neuronal populations have been implicated in their disparate regenerative ability. Recently, the lectin galectin-1 has been shown to be involved in both spinal motoneurons and primary afferent regeneration. Using in situ hybridization, we compared the endogenous galectin-1 mRNA expression in spinal motoneurons and rubrospinal neurons after axotomy. We found that 7 and 14 days after axotomy, galectin-1 mRNA increased in spinal motoneurons but decreased in rubrospinal neurons. Infusion of the brain-derived neurotrophic factor into the vicinity of the injured rubrospinal nucleus, which we have previously shown to increase the regenerative capacity of rubrospinal neurons, significantly increased galectin-1 mRNA compared with uninjured control levels. Thus, the expression of galectin-1 in neurons correlates with the regenerative propensity.     

Alterations in expression of the neurotrophic factors glial cell line-derived neurotrophic factor, ciliary neurotrophic factor and brain-derived neurotrophic factor, in the target-deprived olfactory neuroepithelium

Neuronal growth factors play an important role in the development and maintenance of the nervous system. In the olfactory system, neurogenesis and synapse formation occur not only during development but throughout life and it would be expected that growth factors play a significant role in these ongoing processes. We have examined the expression of three neurotrophic factors, glial cell line-derived neurotrophic factor, ciliary neurotrophic factor and brain-derived neurotrophic factor in the normal rat olfactory system and following synaptic target ablation (olfactory bulbectomy). We found that brain-derived neurotrophic factor immunoreactivity was confined to the horizontal basal cells of the olfactory neuroepithelium and was unaltered by bulbectomy. Glial cell line-derived neurotrophic factor immunoreactivity was present in the mature olfactory neurons and also their synaptic target cells in the olfactory bulb. Following bulbectomy, glial cell line-derived neurotrophic factor immunoreactivity was abolished from the neuroepithelium. Ciliary neurotrophic factor was present throughout the olfactory neuronal lineage with strongest immunoreactivity in the horizontal basal cells and mature olfactory neurons as well as several cell types in the olfactory bulb. Postbulbectomy, there was loss of strong ciliary neurotrophic factor immunoreactivity in olfactory neurons, however, low levels persisted in the remaining neuronal population. Horizontal basal cell immunoreactivity persisted over three months. Our results would be consistent with glial cell line-derived neurotrophic factor expression in mature olfactory neurons being dependent upon functional synaptic contact with the olfactory bulb. Alternatively, this factor may be acting as target-derived growth factor for olfactory neurons, a role in keeping with its function in spinal motoneurons and in the nigrostriatal system. Brain-derived neurotrophic factor is implicated in the trophic support of immature neurons. Ciliary neurotrophic factor is clearly important in this unique neuronal system but elucidation of its role awaits further investigation.     

Electron microscopic observations on the synaptology of cat sciatic gamma-motoneurons after intracellular staining with horseradish peroxidase

Four cat sciatic motoneurons with axon conduction velocities below 30 m/s, and thus considered to be of the gamma-type, were intracellularly labelled with horseradish peroxidase (HRP) and subsequently studied in the electron microscope. The labelled neurons were apposed by synaptic terminals with spherical (S-type) and flattened vesicles (F-type) but not by large terminals with spherical vesicles (M- and C-types) seen on alpha-motoneurons. Quantitative analysis of a complete series of ultrathin sections through one of the neurons showed that the synaptic covering on the cell body (24.2%) was considerably larger than what has been reported for triceps surae gamma-motoneurons, but within the range of values for gamma-motoneurons in the thoracic region of the spinal cord.     

重组腺病毒载体AxCA-BDNF基因转染修复坐骨神经损伤

背景：如何促进周围神经损伤修复与再生一直是基础与临床研究的热点。基因治疗有可能成为今后解决该问题的主要手段之一。 目的：观察携带小鼠脑源性神经营养因子(brain-derived neurotrophic factor,BDNF) cDNA表达片段的重组腺病毒载体AxCA-BDNF转染大鼠损伤坐骨神经后BDNF的表达,以及脊髓前角运动神经元的存活和神经生长情况。 方法：切除成年Wistar大鼠股中部10 mm长的坐骨神经,AxCA-BDNF转染组、BDNF组和对照组分别用硅胶管内置AxCA-BDNF原液,BDNF溶液或空白病毒稀释液桥接坐骨神经两断端。术后3,7,14 d,1,2,4个月应用原位杂交和免疫组织化学方法检测损伤坐骨神经及相应脊髓节段BDNF mRNA和蛋白的表达,并观察损伤坐骨神经的组织学及超微结构改变,再生的神经元及有髓神经纤维数目和髓鞘厚度。 结果与结论：术后3,7,14 d及1个月时,AxCA-BDNF转染组损伤坐骨神经近、远端神经干及脊髓(L_3~6)中BDNF mRNA和蛋白水平明显高于BDNF组和对照组(P < 0.01)。光、电镜病理组织学检查和图像分析证实,BDNF基因转染后,脊髓前角运动神经元存活数量、新生神经纤维数目及其髓鞘厚度、神经联接的再形成均明显优于对照组(P < 0.01)。说明经腺病毒介导转染的BDNF基因可在大鼠坐骨神经内有效表达,并通过轴突逆行转运到了相应的脊髓神经元,不仅能促进损伤神经纤维再生,也能保护损伤的脊髓神经元。     

Spontaneous phagocytosis of boutons on spinal motoneurons during early postnatal development. An electron microscopical study in the cat

Summary The boutons making synaptic contact with different regions of spinal motoneurons have been studied during the early postnatal period. The observations suggest that a spontaneous glial phagocytosis of boutons of different types occurs mainly during the second postnatal week. This finding is discussed in relation to the previously demonstrated disappearance of boutons from the initial axon segment of spinal motoneurons during the same period of development and also in relation to other degenerative and eliminatory phenomena associated with the normal development of the nervous system.     

Synaptic organization of the Purkinje cells in the cerebellum of the cat

Summary An attempt at distinction between excitatory and inhibitory synapses is made in the cat cerebellum. The former are assumed to contain spheroid vesicles (S-type) of average diameter of 500 Å, while the latter flattened vesicles (F-type) of smaller size than the former. The elongation index (the ratio of the length of major versus minor axis of the vesicles) of S-type synaptic vesicles was about 1.2, while that of the F-type was more than 1.7. Parallel fibers of granule cells make S-type synaptic contacts (en-passant type or crossing-over synapse) mostly on the spines of the smaller branchlets of Purkinje cells. Climbing fibers make also S-type synapses on the smaller spines with short necks of the larger dendrites of Purkinje cells, but not frequently on the direct surface of them. It must be emphasized that almost no F-type synapse has been recognized which makes synaptic contacts directly on the spine of any type. It makes synaptic contacts usually on the direct surface of dendrites of Purkinje cells. Basket cell axons embrace directly the somas of the Purkinje cells. Their synaptic contacts were always of F-type and of en-passant character.The hypothesis is proposed that excitatory (E-type) synapses can be identified with synapses of S-type, whereas inhibitory (I-type) synapses would correspond to the F-type terminals.     

Reactive changes in dorsal roots and dorsal root ganglia after C7 dorsal rhizotomy and ventral root avulsion/replantation in rabbits

Current surgical treatment of spinal root injuries aims at reconnecting ventral roots to the spinal cord while severed dorsal roots are generally left untreated. Reactive changes in dorsal root ganglia (DRGs) and in injured dorsal roots after such complex lesions have not been analysed in detail. We studied dorsal root remnants and lesioned DRGs 6 months after C7 dorsal rhizotomy, ventral root avulsion and immediate ventral root replantation in adult rabbits. Replanted ventral roots were fixed to the spinal cord with fibrin glue only or with glue containing ciliary neurotrophic factor and/or brain-derived neurotrophic factor. Varying degrees of degeneration were observed in the deafferented dorsal spinal cord in all experimental groups. In cases with well-preserved morphology, small myelinated axons extended into central tissue protrusions at the dorsal root entry zone, suggesting sprouting of spinal neuron processes into the central dorsal root remnant. In lesioned DRGs, the density of neurons and myelinated axons was not significantly altered, but a slight decrease in the relative frequency of large neurons and an increase of small myelinated axons was noted (significant for axons). Unexpectedly, differences in the degree of these changes were found between control and neurotrophic factor-treated animals. Central axons of DRG neurons formed dorsal root stumps of considerable length which were attached to fibrous tissue surrounding the replanted ventral root. In cases where gaps were apparent in dorsal root sheaths, a subgroup of dorsal root axons entered this fibrous tissue. Continuity of sensory axons with the spinal cord was never observed. Some axons coursed ventrally in the direction of the spinal nerve. Although the animal model does not fully represent the situation in human plexus injuries, the present findings provide a basis for devising further experimental approaches in the treatment of combined motor/sensory root lesions.     

Gender and environmental effects on regional brain-derived neurotrophic factor expression after experimental traumatic brain injury

Alterations in brain-derived neurotrophic factor expression have been reported in multiple brain regions acutely after traumatic brain injury, however neither injury nor post-injury environmental enrichment has been shown to affect hippocampal brain-derived neurotrophic factor gene expression in male rats chronically post-injury. Studies have demonstrated hormone-related neuroprotection for female rats after traumatic brain injury, and estrogen and exercise both influence brain-derived neurotrophic factor levels. Despite recent studies suggesting that exposure post-traumatic brain injury to environmental enrichment improves cognitive recovery in male rats, we have shown that environmental enrichment mediated improvements with spatial learning are gender specific and only positively affect males. Therefore the purpose of this study was to evaluate the effect of gender and environmental enrichment on chronic post-injury cortical and hippocampal brain-derived neurotrophic factor protein expression. Sprague-Dawley male and cycling female rats were placed into environmental enrichment or standard housing after controlled cortical impact or sham surgery. Four weeks post-surgery, hippocampal and frontal cortex brain-derived neurotrophic factor expression were examined using Western blot. Results revealed significant increases in brain-derived neurotrophic factor expression in the frontal cortex ipsilateral to injury for males (P=0.03). Environmental enrichment did not augment this effect. Neither environmental enrichment nor injury significantly affected cortical brain-derived neurotrophic factor expression for females. In the hippocampus ipsilateral to injury brain-derived neurotrophic factor expression for both males and females was half (49% and 51% respectively) of that observed in shams housed in the standard environment. For injured males, there was a trend in this region for environmental enrichment to restore brain-derived neurotrophic factor levels to sham values. However, there were robust increases in hippocampal brain-derived neurotrophic factor expression ipsilateral to the injury for injured females in environmental enrichment compared with both sham and injured females placed in standard housing (P相似文献